Old page wikitext, before the edit (old_wikitext) | '{{Short description|Cancer that originates in mammary glands}}
{{pp-pc1}}
{{Use dmy dates|date=June 2021}}
{{Infobox medical condition (new)
| name = Breast cancer
| image = Breast Cancer.png
| caption = An illustration of breast cancer
| field = [[Oncology]]
| symptoms = A lump in a breast, a change in breast shape, dimpling of the skin, fluid from the [[nipple]], a newly inverted nipple, a red scaly patch of skin on the breast<ref name=NCI2014Pt/>
| complications =
| onset =
| duration =
| causes =
| risks = Being female, [[obesity]], lack of exercise, alcohol, [[hormone replacement therapy]] during [[menopause]], [[ionizing radiation]], early age at [[menarche|first menstruation]], having children late in life or not at all, older age, prior breast cancer, family history of breast cancer, [[Klinefelter syndrome]]<ref name=NCI2014Pt /><ref name=WCR2014 /><ref name = NICHD>{{cite web |url = http://www.nichd.nih.gov/health/topics/klinefelter_syndrome.cfm |title = Klinefelter Syndrome |date = 24 May 2007 |publisher = [[Eunice Kennedy Shriver National Institute of Child Health and Human Development]] |archive-url = https://web.archive.org/web/20121127030744/http://www.nichd.nih.gov/health/topics/klinefelter_syndrome.cfm |archive-date = 27 November 2012 |url-status = dead}}</ref>
| diagnosis = [[Tissue biopsy]]<ref name=NCI2014Pt /> [[Mammography]]
| differential =
| prevention =
| treatment = Surgery, [[radiation therapy]], [[chemotherapy]], [[Hormonal therapy (oncology)|hormonal therapy]], [[targeted therapy]]<ref name=NCI2014Pt />
| medication =
| prognosis = [[Five-year survival rate]] ≈85% (US, UK)<ref name=SEER2014 /><ref name=UK2013Prog />
| frequency = 2.2 million affected as of 2020<!-- prevalence --><ref name=Sung2021>{{cite journal | vauthors = Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F | title = Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries | journal = Ca | volume = 71 | issue = 3 | pages = 209–249 | date = May 2021 | pmid = 33538338 | doi = 10.3322/caac.21660 | s2cid = 231804598 }}</ref>
| deaths = 685,000 (2020)<ref name=Sung2021/>
| alt = As seen on the image above the breast is already affected with cancer
}}
<!-- Definitions and symptoms -->
'''Breast cancer''' is [[cancer]] that develops from [[breast]] tissue.<ref>{{cite web |title = Breast Cancer |url = http://www.cancer.gov/cancertopics/types/breast |website = NCI |access-date = 29 June 2014 |url-status = live |archive-url = https://web.archive.org/web/20140625232947/http://www.cancer.gov/cancertopics/types/breast |archive-date = 25 June 2014 |df = dmy-all |date = January 1980 }}</ref> Signs of breast cancer may include a [[Breast lump|lump]] in the breast, a change in breast shape, [[dimpling]] of the skin, fluid coming from the [[nipple]], a newly inverted nipple, or a red or scaly patch of skin.<ref name=NCI2014Pt>{{cite web |title = Breast Cancer Treatment (PDQ®) |url = http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page1/AllPages |website = NCI |date = 23 May 2014 |access-date = 29 June 2014 |url-status = live |archive-url = https://web.archive.org/web/20140705110404/http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page1/AllPages |archive-date = 5 July 2014 |df = dmy-all }}</ref> In those with [[Metastatic breast cancer|distant spread of the disease]], there may be [[bone pain]], swollen [[lymph node]]s, [[shortness of breath]], or [[jaundice|yellow skin]].<ref>{{cite book | vauthors = Saunders C, Jassal S |title = Breast cancer |date = 2009 |publisher = Oxford University Press |location = Oxford |isbn = 978-0-19-955869-8 |page = Chapter 13 |edition = 1. |url = https://books.google.com/books?id=as46WowY_usC&pg=PT123 |url-status = live |archive-url = https://web.archive.org/web/20151025013217/https://books.google.com/books?id=as46WowY_usC&pg=PT123 |archive-date = 25 October 2015 |df = dmy-all }}</ref>
<!-- Causes and diagnosis' -->
Risk factors for developing breast cancer include [[obesity]], a [[Lethargy|lack of physical exercise]], [[alcoholism]], [[hormone replacement therapy]] during [[menopause]], [[ionizing radiation]], an early age at [[menarche|first menstruation]], having children late in life or not at all, older age, having a prior history of breast cancer, and a family history of breast cancer.<ref name=NCI2014Pt /><ref name="WCR2014">{{cite book |title = World Cancer Report 2014 |date = 2014 |publisher = World Health Organization |isbn = 978-92-832-0429-9 |pages = Chapter 5.2 }}</ref> About 5–10% of cases are the result of a genetic predisposition inherited from a person's parents,<ref name=NCI2014Pt /> including [[BRCA1]] and [[BRCA2]] among others.<ref name=NCI2014Pt /> Breast cancer most commonly develops in cells from the lining of [[lactiferous duct|milk ducts]] and the [[lobules]] that supply these ducts with milk.<ref name=NCI2014Pt /> Cancers developing from the ducts are known as [[Mammary ductal carcinoma|ductal carcinomas]], while those developing from lobules are known as [[lobular carcinoma]]s.<ref name=NCI2014Pt /> There are more than 18 other sub-types of breast cancer.<ref name=WCR2014 /> Some, such as [[ductal carcinoma in situ]], develop from [[pre-invasive lesions]].<ref name=WCR2014 /> The diagnosis of breast cancer is confirmed by taking a [[breast biopsy|biopsy]] of the concerning tissue.<ref name=NCI2014Pt /> Once the diagnosis is made, further tests are done to determine if the cancer has spread beyond the breast and which treatments are most likely to be effective.<ref name=NCI2014Pt />
<!-- Screening and treatments -->
The balance of benefits versus harms of [[breast cancer screening]] is controversial. A 2013 [[Cochrane review]] found that it was unclear if [[mammography|mammographic]] screening does more harm than good, in that a large proportion of women who test positive turn out not to have the disease.<ref name="Got2013">{{cite journal | vauthors = Gøtzsche PC, Jørgensen KJ | title = Screening for breast cancer with mammography | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 6 | pages = CD001877 | date = June 2013 | pmid = 23737396 | pmc = 6464778 | doi = 10.1002/14651858.CD001877.pub5 }}</ref> A 2009 review for the [[US Preventive Services Task Force]] found evidence of benefit in those 40 to 70 years of age,<ref>{{cite journal|vauthors= Nelson HD, Tyne K, Naik A, Bougatsos C, Chan B, Nygren P, Humphrey L|title= Screening for Breast Cancer: Systematic Evidence Review Update for the US Preventive Services Task Force [Internet]|date= November 2009| pmid = 20722173 |journal= U.S. Preventive Services Task Force Evidence Syntheses|location= Rockville, MD|publisher= Agency for Healthcare Research and Quality|id=Report No.: 10-05142-EF-1}}</ref> and the organization recommends screening every two years in women 50 to 74 years of age.<ref name="USPSTFScreen2016">{{cite journal | vauthors = Siu AL | title = Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement | journal = Annals of Internal Medicine | volume = 164 | issue = 4 | pages = 279–96 | date = February 2016 | pmid = 26757170 | doi = 10.7326/M15-2886 | doi-access = free }}</ref> The medications [[tamoxifen]] or [[raloxifene]] may be used in an effort to prevent breast cancer in those who are at high risk of developing it.<ref name=WCR2014 /> [[Preventive mastectomy|Surgical removal of both breasts]] is another preventive measure in some high risk women.<ref name=WCR2014 /> In those who have been diagnosed with cancer, a number of treatments may be used, including surgery, [[radiation therapy]], [[chemotherapy]], [[Hormonal therapy (oncology)|hormonal therapy]], and [[targeted therapy]].<ref name=NCI2014Pt /> Types of surgery vary from [[breast-conserving surgery]] to [[mastectomy]].<ref name="ACSfive">{{Cite web |date = September 2013 |title = Five Things Physicians and Patients Should Question |publisher = [[American College of Surgeons]] |work = [[Choosing Wisely]]: an initiative of the [[ABIM Foundation]] |url = http://www.choosingwisely.org/doctor-patient-lists/american-college-of-surgeons/ |access-date = 2 January 2013 |url-status = live |archive-url = https://web.archive.org/web/20131027085747/http://www.choosingwisely.org/doctor-patient-lists/american-college-of-surgeons/ |archive-date = 27 October 2013 |df = dmy-all }}</ref><ref name=NCI2014TxProf>{{cite web |title = Breast Cancer Treatment (PDQ®) |url = http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page1/AllPages |website = NCI |access-date = 29 June 2014 |date = 26 June 2014 |url-status = live |archive-url = https://web.archive.org/web/20140705110521/http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page1/AllPages |archive-date = 5 July 2014 |df = dmy-all }}</ref> [[Breast reconstruction]] may take place at the time of surgery or at a later date.<ref name=NCI2014TxProf /> In those in whom the cancer has spread to other parts of the body, treatments are mostly aimed at improving quality of life and comfort.<ref name=NCI2014TxProf />
<!-- Prognosis and epidemiology-->
Outcomes for breast cancer vary depending on the cancer type, the [[cancer staging|extent of disease]], and the person's age.<ref name=NCI2014TxProf /> The [[five-year survival rate]]s in England and the United States are between 80 and 90%.<ref name=WCR2008>{{cite web |publisher = [[International Agency for Research on Cancer]] |year = 2008 |title = World Cancer Report |url = http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/wcr_2008.pdf |access-date = 26 February 2011 |url-status = dead |archive-url = https://web.archive.org/web/20110720232417/http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/wcr_2008.pdf |archive-date = 20 July 2011 |df = dmy-all }}</ref><ref name=SEER2014>{{cite web |title = SEER Stat Fact Sheets: Breast Cancer |url = http://seer.cancer.gov/statfacts/html/breast.html |website = NCI |access-date = 18 June 2014 |url-status = live |archive-url = https://web.archive.org/web/20140703030149/http://seer.cancer.gov/statfacts/html/breast.html |archive-date = 3 July 2014 |df = dmy-all }}</ref><ref name=UK2013Prog>{{cite web |title = Cancer Survival in England: Patients Diagnosed 2007–2011 and Followed up to 2012 |url = http://www.ons.gov.uk/ons/dcp171778_333318.pdf |website = Office for National Statistics |access-date = 29 June 2014 |date = 29 October 2013 |url-status = live |archive-url = https://web.archive.org/web/20141129124915/http://www.ons.gov.uk/ons/dcp171778_333318.pdf |archive-date = 29 November 2014 |df = dmy-all }}</ref> In developing countries, five-year survival rates are lower.<ref name=WCR2014 /> Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases.<ref name="WCR2014Epi">{{cite book |title = World Cancer Report 2014 |date = 2014 |publisher = World Health Organization |isbn = 978-92-832-0429-9 |pages = Chapter 1.1 }}</ref> In 2018, it resulted in 2 million new cases and 627,000 deaths.<ref name=Bra2018>{{cite journal | vauthors = Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A | title = Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries | journal = CA: A Cancer Journal for Clinicians | volume = 68 | issue = 6 | pages = 394–424 | date = November 2018 | pmid = 30207593 | doi = 10.3322/caac.21492 | s2cid = 52188256 | doi-access = free}}</ref> It is more common in developed countries<ref name=WCR2014 /> and is more than 100 times more common in women than [[Male breast cancer|in men]].<ref name=WCR2008 /><ref>{{cite web |title = Male Breast Cancer Treatment |publisher = [[National Cancer Institute]] |year = 2014 |url = http://www.cancer.gov/cancertopics/pdq/treatment/malebreast/HealthProfessional |access-date = 29 June 2014 |url-status = live |archive-url = https://web.archive.org/web/20140704182515/http://www.cancer.gov/cancertopics/pdq/treatment/malebreast/HealthProfessional |archive-date = 4 July 2014 |df = dmy-all }}</ref>
{{TOC limit|3}}
== Signs and symptoms ==
[[File:Breast cancer.jpg|thumb|Breast cancer showing an inverted nipple, lump, and skin dimpling]]
[[File:En Breast cancer illustrations.png|thumb|Early signs of possible breast cancer]]
Breast cancer most commonly presents as a [[breast lump|lump]] that feels different from the rest of the breast tissue. More than 80% of cases are discovered when a person detects such a lump with the fingertips.<ref name="merck">{{cite web |author = Merck Manual of Diagnosis and Therapy |date = February 2003 |title = Breast Disorders: Breast Cancer |url = http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/breast_cancer.html |access-date = 5 February 2008 |url-status = live |archive-url = https://web.archive.org/web/20111002141649/http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/breast_cancer.html |archive-date = 2 October 2011 |df = dmy-all |author-link = Merck Manual of Diagnosis and Therapy }}</ref> The earliest breast cancers, however, are detected by a [[mammogram]].<ref name="acs cancer facts 2007" /><ref>{{cite journal | vauthors = Boyd NF, Guo H, Martin LJ, Sun L, Stone J, Fishell E, Jong RA, Hislop G, Chiarelli A, Minkin S, Yaffe MJ | display-authors = 6 | title = Mammographic density and the risk and detection of breast cancer | journal = The New England Journal of Medicine | volume = 356 | issue = 3 | pages = 227–36 | date = January 2007 | pmid = 17229950 | doi = 10.1056/NEJMoa062790 | s2cid = 13831558 }}</ref> Lumps found in lymph nodes located in the armpits<ref name="merck" /> may also indicate breast cancer.
Indications of breast cancer other than a lump may include thickening different from the other breast tissue, one breast becoming larger or lower, a nipple changing position or shape or becoming inverted, skin puckering or dimpling, a rash on or around a nipple, discharge from nipple/s, constant pain in part of the breast or armpit and swelling beneath the armpit or around the collarbone.<ref>{{cite journal | vauthors = Watson M |title = Assessment of suspected cancer |journal = InnoAiT |volume = 1 |issue = 2 |pages = 94–107 |year = 2008 |doi = 10.1093/innovait/inn001 |s2cid = 71908359 }}</ref> Pain ("[[mastodynia]]") is an unreliable tool in determining the presence or absence of breast cancer, but may be indicative of other [[breast health]] issues.<ref name="merck" /><ref name="acs cancer facts 2007">{{cite web |author = American Cancer Society |year = 2007 |title = Cancer Facts & Figures 2007 |url = http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf |access-date = 26 April 2007 |archive-url = https://web.archive.org/web/20070410025934/http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf |archive-date = 10 April 2007 }}</ref><ref name="eMed">{{Cite web|website=eMedicine|date=23 August 2006|title=Breast Cancer Evaluation|url=http://www.emedicine.com/med/TOPIC3287.HTM|access-date=5 February 2008|url-status=dead|archive-url=https://web.archive.org/web/20080212070431/http://www.emedicine.com/med/TOPIC3287.HTM|archive-date=12 February 2008}}</ref>
Another symptom complex of breast cancer is [[Paget's disease of the breast]]. This syndrome presents as skin changes resembling eczema; such as redness, discoloration or mild flaking of the nipple skin. As Paget's disease of the breast advances, symptoms may include tingling, itching, increased sensitivity, burning, and pain. There may also be discharge from the nipple. Approximately half the women diagnosed with Paget's disease of the breast also have a lump in the breast.<ref>{{cite journal | vauthors = Ashikari R, Park K, Huvos AG, Urban JA | title = Paget's disease of the breast | journal = Cancer | volume = 26 | issue = 3 | pages = 680–5 | date = September 1970 | pmid = 4318756 | doi = 10.1002/1097-0142(197009)26:3<680::aid-cncr2820260329>3.0.co;2-p | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kollmorgen DR, Varanasi JS, Edge SB, Carson WE | title = Paget's disease of the breast: a 33-year experience | journal = Journal of the American College of Surgeons | volume = 187 | issue = 2 | pages = 171–7 | date = August 1998 | pmid = 9704964 | doi = 10.1016/S1072-7515(98)00143-4 }}</ref>
[[Inflammatory Breast Cancer|Inflammatory breast cancer]] is a rare (only seen in less than 5% of breast cancer diagnosis) yet aggressive form of breast cancer characterized by the swollen, red areas formed on the top of the breast. The visual effects of inflammatory breast cancer is a result of a blockage of lymph vessels by cancer cells. This type of breast cancer is seen in more commonly diagnosed in younger ages, obese women and African American women. As inflammatory breast cancer does not present as a lump there can sometimes be a delay in diagnosis.<ref>{{cite journal | vauthors = Kleer CG, van Golen KL, Merajver SD | title = Molecular biology of breast cancer metastasis. Inflammatory breast cancer: clinical syndrome and molecular determinants | journal = Breast Cancer Research | volume = 2 | issue = 6 | pages = 423–9 | date = 1 December 2000 | pmid = 11250736 | pmc = 138665 | doi = 10.1186/bcr89 }}</ref>
[[Mammary secretory carcinoma]] (MSC) is a rare form of the [[secretory carcinoma]]s that occurs exclusively in the breast.<ref name="pmid34282256">{{cite journal | vauthors = Gong P, Xia C, Yang Y, Lei W, Yang W, Yu J, Ji Y, Ren L, Ye F | title = Clinicopathologic profiling and oncologic outcomes of secretory carcinoma of the breast | journal = Scientific Reports | volume = 11 | issue = 1 | pages = 14738 | date = July 2021 | pmid = 34282256 | pmc = 8289843 | doi = 10.1038/s41598-021-94351-w | bibcode = 2021NatSR..1114738G | url = }}</ref> It usually develops in adults but in a significant percentage of cases also affects children:<ref name="pmid35156343">{{cite journal | vauthors = Carretero-Barrio I, Santón A, Caniego Casas T, López Miranda E, Reguero-Callejas ME, Pérez-Mies B, Benito A, Palacios J | title = Cytological and molecular characterization of secretory breast carcinoma | journal = Diagnostic Cytopathology | volume = 50| issue = 7| pages = E174–E180| date = February 2022 | pmid = 35156343 | doi = 10.1002/dc.24945 | pmc = 9303577 | s2cid = 246813006 | url = }}</ref> MSC accounts for 80% of all childhood breast cancers.<ref name="pmid34243852">{{cite journal | vauthors = Knaus ME, Grabowksi JE | title = Pediatric Breast Masses: An Overview of the Subtypes, Workup, Imaging, and Management | journal = Advances in Pediatrics | volume = 68 | issue = | pages = 195–209 | date = August 2021 | pmid = 34243852 | doi = 10.1016/j.yapd.2021.05.006 | s2cid = 235786044 | url = }}</ref> MSC lesions are typically slow growing, painless, small [[Invasive carcinoma of no special type|ductal breast tumors]] that have invaded the tissue around their [[Lactiferous duct|ducts]] of origin, often spread to [[sentinel lymph nodes]] and/or [[axillary lymph nodes]], but rarely metastasized to distant tissues.<ref name="pmid35106856">{{cite journal | vauthors = Loo SK, Yates ME, Yang S, Oesterreich S, Lee AV, Wang XS | title = Fusion-associated carcinomas of the breast: Diagnostic, prognostic, and therapeutic significance | journal = Genes, Chromosomes & Cancer | volume = 61 | issue = 5 | pages = 261–273 | date = May 2022 | pmid = 35106856 | pmc = 8930468 | doi = 10.1002/gcc.23029 | url = }}</ref> These tumors typically have distinctive microscopic features and tumor cells that carry a balanced [[genetic translocation]] in which part of the ''[[NTRK3]]'' gene is fused to part of the ''[[ETV6]]'' gene<ref name="pmid34277491">{{cite journal | vauthors = Banerjee N, Banerjee D, Choudhary N | title = Secretory carcinoma of the breast, commonly exhibits the features of low grade, triple negative breast carcinoma- A Case report with updated review of literature | journal = Autopsy & Case Reports | volume = 11 | issue = | pages = e2020227 | date = 2021 | pmid = 34277491 | pmc = 8101654 | doi = 10.4322/acr.2020.227 | url = }}</ref> to form a [[fusion gene]], ''[[ETV6-NTRK3 gene fusion|ETV6-NTRK3]]''. This fusion gene encodes a [[chimeric protein]] termed ETV6-NTRK3. The NTRK3 part of ETV6-NTRK3 protein has up-regulated [[tyrosine kinase]] activity that stimulates two [[cell signaling|signaling]] pathways, the [[PI3K/AKT/mTOR pathway|PI3K/AKT/mTOR]] and [[MAPK/ERK pathway]]s, which promote cell proliferation and survival and thereby may contribute to the development of MSC.<ref name="pmid35156343"/> Conservative surgery, modified radical mastectomy, and radical mastectomy have been the most frequent procedures used to treat adults, while simple mastectomy, local excision with [[sentinel lymph node]] biopsy, and complete axillary dissection have been recommended to treat children with MSC.<ref name="pmid31119054">{{cite journal | vauthors = Li L, Wu N, Li F, Li L, Wei L, Liu J | title = Clinicopathologic and molecular characteristics of 44 patients with pure secretory breast carcinoma | journal = Cancer Biology & Medicine | volume = 16 | issue = 1 | pages = 139–146 | date = February 2019 | pmid = 31119054 | pmc = 6528460 | doi = 10.20892/j.issn.2095-3941.2018.0035 | url = }}</ref> In all cases, long-term, e.g. >20 years, follow-up examinations are recommended.<ref name="pmid34282256"/><ref name="pmid34277491"/> The relatively rare cases of MSC that have metastasized to distant tissues have shown little or no responses to chemotherapy and radiotherapy. Three patients with metastatic disease had good partial responses to [[Entrectinib]], a drug that inhibits the tyrosine kinase activity of the ETV6-NTRK3 fusion protein.<ref name="pmid34176200">{{cite journal | vauthors = Mortensen L, Ordulu Z, Dagogo-Jack I, Bossuyt V, Winters L, Taghian A, Smith BL, Ellisen LW, Kiedrowski LA, Lennerz JK, Bardia A, Spring LM | title = Locally Recurrent Secretory Carcinoma of the Breast with NTRK3 Gene Fusion | journal = The Oncologist | volume = 26 | issue = 10 | pages = 818–824 | date = October 2021 | pmid = 34176200 | pmc = 8488779 | doi = 10.1002/onco.13880 | url = }}</ref> Because of its slow growth and low rate of metastasis to distant tissues, individuals with MSC have had 20 year survival rates of 93.16%.<ref name="pmid34282256"/>
In rare cases, what initially appears as a [[fibroadenoma]] (hard, movable non-cancerous lump) could in fact be a [[phyllodes tumor]]. Phyllodes tumors are formed within the [[Stroma (tissue)|stroma]] (connective tissue) of the breast and contain glandular as well as stromal tissue. Phyllodes tumors are not staged in the usual sense; they are classified on the basis of their appearance under the microscope as benign, borderline or malignant.<ref name="phyllodes-tumor">{{cite web |author = answers.com |title = Oncology Encyclopedia: Cystosarcoma Phyllodes |website = [[Answers.com]] |url = http://www.answers.com/topic/phyllodes-tumor |access-date = 10 August 2010 |url-status = live |archive-url = https://web.archive.org/web/20100908032727/http://www.answers.com/topic/phyllodes-tumor |archive-date = 8 September 2010 |df = dmy-all }}</ref>
Malignant tumors can result in metastatic tumors – secondary tumors (originating from the primary tumor) that spread beyond the site of origination. The symptoms caused by metastatic breast cancer will depend on the location of metastasis. Common sites of metastasis include bone, liver, lung, and brain.<ref name="pmid17158753">{{cite journal | vauthors = Lacroix M | title = Significance, detection and markers of disseminated breast cancer cells | journal = Endocrine-Related Cancer | volume = 13 | issue = 4 | pages = 1033–67 | date = December 2006 | pmid = 17158753 | doi = 10.1677/ERC-06-0001 | doi-access = free }}</ref> When cancer has reached such an invasive state, it is categorized as a stage 4 cancer, cancers of this state are often fatal.<ref>{{cite web |title=Stage 4 :: The National Breast Cancer Foundation |url=https://www.nationalbreastcancer.org/breast-cancer-stage-4 |website=www.nationalbreastcancer.org }}</ref> Common symptoms of stage 4 cancer include unexplained weight loss, bone and joint pain, jaundice and neurological symptoms. These symptoms are called [[non-specific symptoms]] because they could be manifestations of many other illnesses.<ref name="nci metastatic">{{cite web |author = National Cancer Institute |date = 1 September 2004 |title = Metastatic Cancer: Questions and Answers |url = http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic |access-date = 6 February 2008 |url-status = live |archive-url = https://web.archive.org/web/20080827093333/http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic |archive-date = 27 August 2008 |df = dmy-all |author-link = National Cancer Institute }}</ref> Rarely breast cancer can spread to exceedingly uncommon sites such as peripancreatic lymph nodes causing biliary obstruction leading to diagnostic difficulties.<ref>{{cite journal | vauthors = Perera N, Fernando N, Perera R | title = Metastatic breast cancer spread to peripancreatic lymph nodes causing biliary obstruction | journal = The Breast Journal | volume = 26 | issue = 3 | pages = 511–13 | date = March 2020 | doi = 10.1111/tbj.13531 | pmid = 31538691 | doi-access = free }}</ref>
[[File:Brust Computertomographie mit Kontrastmittel Tumor.jpg|alt=Tumor in the breast visualized by Breast-CT|thumb|403x403px|Tumor in the breast visualized by Breast-Computertomography (Breast-CT)]]
Most symptoms of breast disorders, including most lumps, do not turn out to represent underlying breast cancer. Less than 20% of lumps, for example, are cancerous,<ref>{{cite book|title=Interpreting Signs and Symptoms|url={{google books |plainurl=y |id=PcARTQwHLpIC|page=99}}|year=2007|publisher=Lippincott Williams & Wilkins|isbn=978-1-58255-668-0|pages=99–}}</ref> and [[benign breast disease]]s such as [[mastitis]] and [[fibroadenoma]] of the breast are more common causes of breast disorder symptoms.<ref name="merck breasts">{{cite web |author = Merck Manual of Diagnosis and Therapy |date = February 2003 |title = Breast Disorders: Overview of Breast Disorders |url = http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/overview_of_breast_disorders.html |access-date = 5 February 2008 |url-status = live |archive-url = https://web.archive.org/web/20111003004918/http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/overview_of_breast_disorders.html |archive-date = 3 October 2011 |df = dmy-all |author-link = Merck Manual of Diagnosis and Therapy }}</ref>
== Risk factors ==
{{Main|Risk factors of breast cancer}}
Risk factors can be divided into two categories:
* ''modifiable'' risk factors (things that people can change themselves, such as consumption of alcoholic beverages), and
* ''fixed'' risk factors (things that cannot be changed, such as age and physiological sex).<ref name="Hay2013">{{cite journal|vauthors=Hayes J, Richardson A, Frampton C|date=November 2013|title=Population attributable risks for modifiable lifestyle factors and breast cancer in New Zealand women|journal=Internal Medicine Journal|volume=43|issue=11|pages=1198–204|doi=10.1111/imj.12256|pmid=23910051|s2cid=23237732}}</ref>
The primary risk factors for breast cancer are being female and older age.<ref>{{Cite book |vauthors = Reeder JG, Vogel VG |chapter = Breast cancer prevention |volume = 141 |pages = 149–64 |year = 2008 |pmid = 18274088 |doi = 10.1007/978-0-387-73161-2_10 |series = Cancer Treatment and Research |isbn = 978-0-387-73160-5 |title = Advances in Breast Cancer Management, Second Edition }}</ref> Other potential risk factors include genetics,<ref name="Am I at risk">{{cite web |title = Am I at risk? |url = http://www.breastcancercare.org.uk/breast-cancer-information/breast-awareness/am-i-risk/risk |publisher = Breast Cancer Care |access-date = 22 October 2013 |url-status = live |archive-url = https://web.archive.org/web/20131025074635/http://www.breastcancercare.org.uk/breast-cancer-information/breast-awareness/am-i-risk/risk |archive-date = 25 October 2013 |df = dmy-all |date = 23 February 2018 }}</ref> lack of childbearing or lack of breastfeeding,<ref>{{cite journal | author = Collaborative Group on Hormonal Factors in Breast Cancer | title = Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease | journal = Lancet | volume = 360 | issue = 9328 | pages = 187–95 | date = July 2002 | pmid = 12133652 | doi = 10.1016/S0140-6736(02)09454-0 | s2cid = 25250519 }}</ref> higher levels of certain hormones,<ref>{{cite journal | vauthors = Yager JD, Davidson NE | title = Estrogen carcinogenesis in breast cancer | journal = The New England Journal of Medicine | volume = 354 | issue = 3 | pages = 270–82 | date = January 2006 | pmid = 16421368 | doi = 10.1056/NEJMra050776 }}</ref><ref>{{cite web |url = http://www.center4research.org/hormone-therapy-menopause/ |title = Hormone Therapy and Menopause |publisher = National Research Center for Women & Families |vauthors = Mazzucco A, Santoro E, DeSoto, M, Hong Lee J |date = February 2009 }}</ref> certain dietary patterns, and obesity. One study indicates that exposure to light pollution is a risk factor for the development of breast cancer.<ref>{{cite book | vauthors = Haim A, Portnov BP |title=Light Pollution as new risk factor for human Breast and Prostate Cancers |date=2013 |publisher=Springer |location=Dordrecht |isbn=978-94-007-6220-6}}</ref>
If all adults maintained the healthiest possible lifestyles, including not drinking [[alcoholic beverages]], maintaining a healthy [[body composition]], never [[smoking]], eating [[Healthy diet|healthful food]], and other actions, then almost a quarter of breast cancer cases worldwide could be prevented.<ref name=":2">{{cite journal | vauthors = Zhang YB, Pan XF, Chen J, Cao A, Zhang YG, Xia L, Wang J, Li H, Liu G, Pan A | display-authors = 6 | title = Combined lifestyle factors, incident cancer, and cancer mortality: a systematic review and meta-analysis of prospective cohort studies | journal = British Journal of Cancer | volume = 122 | issue = 7 | pages = 1085–1093 | date = March 2020 | pmid = 32037402 | pmc = 7109112 | doi = 10.1038/s41416-020-0741-x }}</ref> The remaining three-quarters of breast cancer cases cannot be prevented through lifestyle changes.<ref name=":2" />
=== Lifestyle ===
{{See also|List of breast carcinogenic substances}}
[[File:NIH standard drink comparison.jpg|alt=Diagram of different sizes, showing how big a single serving of alcohol is for different types of alcoholic beverages|thumb|All types of [[alcoholic beverages]], including beer, wine, or liquor, cause breast cancer.]]
{{Image frame
| caption=Drinking alcohol, even at low levels, increases the risk of breast cancer<br/>{{legend|red| Additional risk from drinking<ref name="Choi"/><ref name="Bagnardi">{{cite journal | vauthors = Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V, Scotti L, Jenab M, Turati F, Pasquali E, Pelucchi C, Galeone C, Bellocco R, Negri E, Corrao G, Boffetta P, La Vecchia C | display-authors = 6 | title = Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis | journal = British Journal of Cancer | volume = 112 | issue = 3 | pages = 580–593 | date = February 2015 | pmid = 25422909 | pmc = 4453639 | doi = 10.1038/bjc.2014.579 }}</ref>}}
{{legend|pink| Original breast cancer risk ({{=}}100%)}}
| content = {{Graph:Chart|width=300|height=150
|xAxisTitle=Maximum drinks per day
|yAxisTitle=Risk
|legend=Legend
| y1Title=Risk due to drinking
| y2Title=Baseline
|type=stackedrect
| x=0,1,2,3,4+
| y1=0,9,13,23,60
| y2=100,100,100,100,100
|colors=red, pink}}
}}
[[Alcohol and breast cancer|Drinking alcoholic beverages increases the risk of breast cancer]], even among very light drinkers (women drinking less than half of one alcoholic drink per day).<ref name="Choi">{{cite journal | vauthors = Choi YJ, Myung SK, Lee JH | title = Light Alcohol Drinking and Risk of Cancer: A Meta-Analysis of Cohort Studies | journal = Cancer Research and Treatment | volume = 50 | issue = 2 | pages = 474–487 | date = April 2018 | pmid = 28546524 | pmc = 5912140 | doi = 10.4143/crt.2017.094 }}</ref> The risk is highest among heavy drinkers.<ref name="Shield">{{cite journal | vauthors = Shield KD, Soerjomataram I, Rehm J | title = Alcohol Use and Breast Cancer: A Critical Review | journal = Alcoholism, Clinical and Experimental Research | volume = 40 | issue = 6 | pages = 1166–1181 | date = June 2016 | pmid = 27130687 | doi = 10.1111/acer.13071 | quote = All levels of evidence showed a risk relationship between alcohol consumption and the risk of breast cancer, even at low levels of consumption. }}</ref> Globally, about one in 10 cases of breast cancer is caused by women drinking alcoholic beverages.<ref name="Shield" /> Drinking alcoholic beverages is among the most common modifiable risk factors.<ref>{{cite journal | vauthors = McDonald JA, Goyal A, Terry MB | title = Alcohol Intake and Breast Cancer Risk: Weighing the Overall Evidence | journal = Current Breast Cancer Reports | volume = 5 | issue = 3 | pages = 208–221 | date = September 2013 | pmid = 24265860 | pmc = 3832299 | doi = 10.1007/s12609-013-0114-z }}</ref>
The correlation between [[obesity]] and breast cancer is anything but linear. Studies show that those who rapidly gain weight in adulthood are at higher risk than those who have been overweight since childhood. Likewise excess fat in the midsection seems to induce a higher risk than excess weight carried in the lower body. This implies that the food one eats is of greater importance than one's [[Body mass index|BMI]].<ref>{{cite web|title=Lifestyle-related Breast Cancer Risk Factors|url=https://www.cancer.org/cancer/breast-cancer/risk-and-prevention/lifestyle-related-breast-cancer-risk-factors.html|website=www.cancer.org}}</ref> Dietary factors that may increase risk include a high-fat diet<ref>{{cite journal | vauthors = Blackburn GL, Wang KA | title = Dietary fat reduction and breast cancer outcome: results from the Women's Intervention Nutrition Study (WINS) | journal = The American Journal of Clinical Nutrition | volume = 86 | issue = 3 | pages = s878-81 | date = September 2007 | pmid = 18265482 | doi = 10.1093/ajcn/86.3.878S | doi-access = free }}</ref> and obesity-related [[Hypercholesterolemia|high cholesterol]] levels.<ref>BBC report [http://news.bbc.co.uk/1/hi/health/5171838.stm Weight link to breast cancer risk] {{webarchive|url=https://web.archive.org/web/20070313141518/http://news.bbc.co.uk/1/hi/health/5171838.stm |date=13 March 2007 }}</ref><ref>{{cite journal | vauthors = Kaiser J | title = Cancer. Cholesterol forges link between obesity and breast cancer | journal = Science | volume = 342 | issue = 6162 | pages = 1028 | date = November 2013 | pmid = 24288308 | doi = 10.1126/science.342.6162.1028 }}</ref> Dietary iodine deficiency may also play a role.<ref>{{cite journal | vauthors = Aceves C, Anguiano B, Delgado G | title = Is iodine a gatekeeper of the integrity of the mammary gland? | journal = Journal of Mammary Gland Biology and Neoplasia | volume = 10 | issue = 2 | pages = 189–96 | date = April 2005 | pmid = 16025225 | doi = 10.1007/s10911-005-5401-5 | s2cid = 16838840 }}</ref> Evidence for fiber is unclear. A 2015 review found that studies trying to link fiber intake with breast cancer produced mixed results.<ref>{{cite journal | vauthors = Mourouti N, Kontogianni MD, Papavagelis C, Panagiotakos DB | title = Diet and breast cancer: a systematic review | journal = International Journal of Food Sciences and Nutrition | volume = 66 | issue = 1 | pages = 1–42 | date = February 2015 | pmid = 25198160 | doi = 10.3109/09637486.2014.950207 | s2cid = 207498132 }}</ref> In 2016, a tentative association between low fiber intake during adolescence and breast cancer was observed.<ref>{{cite news | vauthors = Aubrey A |date = 1 February 2016 |title = A Diet High In Fiber May Help Protect Against Breast Cancer |url = https://www.npr.org/sections/thesalt/2016/02/01/464854395/a-diet-high-in-fiber-may-help-protect-against-breast-cancer |newspaper = [[NPR]] |access-date = 1 February 2016 |url-status = live |archive-url = https://web.archive.org/web/20160201114307/http://www.npr.org/sections/thesalt/2016/02/01/464854395/a-diet-high-in-fiber-may-help-protect-against-breast-cancer |archive-date = 1 February 2016 |df = dmy-all }}</ref>
[[Tobacco smoking|Smoking tobacco]] appears to increase the risk of breast cancer, with the greater the amount smoked and the earlier in life that smoking began, the higher the risk.<ref name="Smoking2011">{{cite journal | vauthors = Johnson KC, Miller AB, Collishaw NE, Palmer JR, Hammond SK, Salmon AG, Cantor KP, Miller MD, Boyd NF, Millar J, Turcotte F | display-authors = 6 | title = Active smoking and secondhand smoke increase breast cancer risk: the report of the Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk (2009) | journal = Tobacco Control | volume = 20 | issue = 1 | pages = e2 | date = January 2011 | pmid = 21148114 | doi = 10.1136/tc.2010.035931 | s2cid = 448229 }}</ref> In those who are long-term smokers, the relative risk is increased 35% to 50%.<ref name="Smoking2011" />
A lack of physical activity has been linked to about 10% of cases.<ref>{{cite journal | vauthors = Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT | title = Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy | journal = Lancet | volume = 380 | issue = 9838 | pages = 219–29 | date = July 2012 | pmid = 22818936 | pmc = 3645500 | doi = 10.1016/S0140-6736(12)61031-9 }}</ref> [[Sitting]] regularly for prolonged periods is associated with higher mortality from breast cancer. The risk is not negated by regular exercise, though it is lowered.<ref name="Biswas">{{cite journal | vauthors = Biswas A, Oh PI, Faulkner GE, Bajaj RR, Silver MA, Mitchell MS, Alter DA | title = Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis | journal = Annals of Internal Medicine | volume = 162 | issue = 2 | pages = 123–32 | date = January 2015 | pmid = 25599350 | doi = 10.7326/M14-1651 | s2cid = 7256176 }}</ref>
[[Hormone replacement therapy|Hormone therapy]] to treat [[menopause]] is also associated with an increased risk of breast cancer.<ref>{{cite journal | vauthors = | title = Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence | journal = Lancet | volume = 394 | issue = 10204 | pages = 1159–1168 | date = September 2019 | pmid = 31474332 | pmc = 6891893 | doi = 10.1016/S0140-6736(19)31709-X }}</ref> The use of [[hormonal birth control]] does not cause breast cancer for most women;<ref>{{cite journal | vauthors = Kanadys W, Barańska A, Malm M, Błaszczuk A, Polz-Dacewicz M, Janiszewska M, Jędrych M | title = Use of Oral Contraceptives as a Potential Risk Factor for Breast Cancer: A Systematic Review and Meta-Analysis of Case-Control Studies Up to 2010 | journal = International Journal of Environmental Research and Public Health | volume = 18 | issue = 9 | pages = 4638 | date = April 2021 | pmid = 33925599 | pmc = 8123798 | doi = 10.3390/ijerph18094638 | doi-access = free }}</ref> if it has an effect, it is small (on the order of 0.01% per user–year; comparable to the rate of [[maternal mortality in the United States]]<ref name=":0" />), temporary, and offset by the users' significantly reduced risk of ovarian and endometrial cancers.<ref name=":0">{{cite journal | vauthors = Chelmow D, Pearlman MD, Young A, Bozzuto L, Dayaratna S, Jeudy M, Kremer ME, Scott DM, O'Hara JS | display-authors = 6 | title = Executive Summary of the Early-Onset Breast Cancer Evidence Review Conference | journal = Obstetrics and Gynecology | volume = 135 | issue = 6 | pages = 1457–1478 | date = June 2020 | pmid = 32459439 | pmc = 7253192 | doi = 10.1097/AOG.0000000000003889 }}</ref> Among those with a family history of breast cancer, use of modern oral contraceptives does not appear to affect the risk of breast cancer.<ref>{{cite journal | vauthors = Gaffield ME, Culwell KR, Ravi A | title = Oral contraceptives and family history of breast cancer | journal = Contraception | volume = 80 | issue = 4 | pages = 372–380 | date = October 2009 | pmid = 19751860 | doi = 10.1016/j.contraception.2009.04.010 }}</ref> It is less certain whether hormonal contraceptives could increase the already high rates of breast cancer in women with mutations in the breast cancer susceptibility genes [[BRCA mutation|''BRCA1'' or ''BRCA2'']].<ref>{{cite journal | vauthors = Huber D, Seitz S, Kast K, Emons G, Ortmann O | title = Use of oral contraceptives in BRCA mutation carriers and risk for ovarian and breast cancer: a systematic review | journal = Archives of Gynecology and Obstetrics | volume = 301 | issue = 4 | pages = 875–884 | date = April 2020 | pmid = 32140806 | pmc = 8494665 | doi = 10.1007/s00404-020-05458-w }}</ref>
[[Breast feeding]] reduces the risk of several types of cancers, including breast cancer.<ref name=":3">{{cite journal | vauthors = Chowdhury R, Sinha B, Sankar MJ, Taneja S, Bhandari N, Rollins N, Bahl R, Martines J | display-authors = 6 | title = Breastfeeding and maternal health outcomes: a systematic review and meta-analysis | journal = Acta Paediatrica | volume = 104 | issue = 467 | pages = 96–113 | date = December 2015 | pmid = 26172878 | pmc = 4670483 | doi = 10.1111/apa.13102 }}</ref><ref>{{cite web|url=https://www.who.int/health-topics/breastfeeding#tab=tab_1|title=Breastfeeding|work= [[World Health Organization]]}}</ref><ref>{{cite web| url=https://www.cdc.gov/breastfeeding/faq/index.htm#benefits|title=Breastfeeding:Frequently Asked Questions (FAQs)|work= U.S. Center for disease control and prevention(CDC)|date=10 August 2021}}</ref><ref>{{cite journal | title = Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease | journal = Lancet | volume = 360 | issue = 9328 | pages = 187–195 | date = July 2002 | pmid = 12133652 | doi = 10.1016/S0140-6736(02)09454-0 | s2cid = 25250519 | author1 = Collaborative Group on Hormonal Factors in Breast Cancer }}</ref> In the 1980s, the [[abortion–breast cancer hypothesis]] posited that [[induced abortion]] increased the risk of developing breast cancer.<ref name="RUSSO_505">{{cite journal | vauthors = Russo J, Russo IH | title = Susceptibility of the mammary gland to carcinogenesis. II. Pregnancy interruption as a risk factor in tumor incidence | journal = The American Journal of Pathology | volume = 100 | issue = 2 | pages = 497–512 | date = August 1980 | pmid = 6773421 | pmc = 1903536 | quote = In contrast, abortion is associated with increased risk of carcinomas of the breast. The explanation for these epidemiologic findings is not known, but the parallelism between the DMBA-induced rat mammary carcinoma model and the human situation is striking. ... Abortion would interrupt this process, leaving in the gland undifferentiated structures like those observed in the rat mammary gland, which could render the gland again susceptible to carcinogenesis. }}</ref> This hypothesis was the subject of extensive scientific inquiry, which concluded that neither [[miscarriage]]s nor abortions are associated with a heightened risk for breast cancer.<ref>{{cite journal | vauthors = Beral V, Bull D, Doll R, Peto R, Reeves G | title = Breast cancer and abortion: collaborative reanalysis of data from 53 epidemiological studies, including 83?000 women with breast cancer from 16 countries | journal = Lancet | volume = 363 | issue = 9414 | pages = 1007–16 | date = March 2004 | pmid = 15051280 | doi = 10.1016/S0140-6736(04)15835-2 | s2cid = 20751083 }}</ref>
Other risk factors include [[radiation]]<ref name="acs bc facts 2005-6" /> and [[Circadian rhythm|circadian]] disruptions related to [[shift-work]]<ref>{{cite journal | vauthors = Wang XS, Armstrong ME, Cairns BJ, Key TJ, Travis RC | title = Shift work and chronic disease: the epidemiological evidence | journal = Occupational Medicine | volume = 61 | issue = 2 | pages = 78–89 | date = March 2011 | pmid = 21355031 | pmc = 3045028 | doi = 10.1093/occmed/kqr001 }}</ref> and routine late-night eating.<ref>{{cite journal | vauthors = Marinac CR, Nelson SH, Breen CI, Hartman SJ, Natarajan L, Pierce JP, Flatt SW, Sears DD, Patterson RE | display-authors = 6 | title = Prolonged Nightly Fasting and Breast Cancer Prognosis | journal = JAMA Oncology | volume = 2 | issue = 8 | pages = 1049–55 | date = August 2016 | pmid = 27032109 | pmc = 4982776 | doi = 10.1001/jamaoncol.2016.0164 }}</ref> A number of chemicals have also been linked, including [[polychlorinated biphenyls]], [[polycyclic aromatic hydrocarbons]], and [[organic solvents]]<ref>{{cite journal | vauthors = Brody JG, Rudel RA, Michels KB, Moysich KB, Bernstein L, Attfield KR, Gray S | title = Environmental pollutants, diet, physical activity, body size, and breast cancer: where do we stand in research to identify opportunities for prevention? | journal = Cancer | volume = 109 | issue = 12 Suppl | pages = 2627–34 | date = June 2007 | pmid = 17503444 | doi = 10.1002/cncr.22656 | s2cid = 34880415 }}</ref> Although the radiation from [[mammography]] is a low dose, it is estimated that yearly screening from 40 to 80 years of age will cause approximately 225 cases of fatal breast cancer per million women screened.<ref>{{cite journal | vauthors = Hendrick RE | title = Radiation doses and cancer risks from breast imaging studies | journal = Radiology | volume = 257 | issue = 1 | pages = 246–53 | date = October 2010 | pmid = 20736332 | doi = 10.1148/radiol.10100570 | doi-access = free }}</ref>
=== Genetics ===
Genetics is believed to be the primary cause of 5–10% of all cases.<ref name="Gage2012">{{cite journal | vauthors = Gage M, Wattendorf D, Henry LR | title = Translational advances regarding hereditary breast cancer syndromes | journal = Journal of Surgical Oncology | volume = 105 | issue = 5 | pages = 444–51 | date = April 2012 | pmid = 22441895 | doi = 10.1002/jso.21856 | s2cid = 3406636 }}</ref> Women whose mother was diagnosed before 50 have an increased risk of 1.7 and those whose mother was diagnosed at age 50 or after has an increased risk of 1.4.<ref>{{cite journal | vauthors = Colditz GA, Kaphingst KA, Hankinson SE, Rosner B | title = Family history and risk of breast cancer: nurses' health study | journal = Breast Cancer Research and Treatment | volume = 133 | issue = 3 | pages = 1097–104 | date = June 2012 | pmid = 22350789 | pmc = 3387322 | doi = 10.1007/s10549-012-1985-9 }}</ref> In those with zero, one or two affected relatives, the risk of breast cancer before the age of 80 is 7.8%, 13.3%, and 21.1% with a subsequent mortality from the disease of 2.3%, 4.2%, and 7.6% respectively.<ref>{{cite journal | title = Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease | journal = Lancet | volume = 358 | issue = 9291 | pages = 1389–99 | date = October 2001 | pmid = 11705483 | doi = 10.1016/S0140-6736(01)06524-2 | author1 = Collaborative Group on Hormonal Factors in Breast Cancer | s2cid = 24278814 }}</ref> In those with a first degree relative with the disease the risk of breast cancer between the age of 40 and 50 is double that of the general population.<ref>{{cite journal | vauthors = Nelson HD, Zakher B, Cantor A, Fu R, Griffin J, O'Meara ES, Buist DS, Kerlikowske K, van Ravesteyn NT, Trentham-Dietz A, Mandelblatt JS, Miglioretti DL | display-authors = 6 | title = Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis | journal = Annals of Internal Medicine | volume = 156 | issue = 9 | pages = 635–48 | date = May 2012 | pmid = 22547473 | pmc = 3561467 | doi = 10.7326/0003-4819-156-9-201205010-00006 }}</ref>
In less than 5% of cases, genetics plays a more significant role by causing a [[hereditary breast–ovarian cancer syndrome]].<ref name="Genetics2010">{{cite book | vauthors = Pasche B |title = Cancer Genetics (Cancer Treatment and Research) |publisher = Springer |location = Berlin |year = 2010 |pages = 19–20 |isbn = 978-1-4419-6032-0 }}</ref> This includes those who carry the [[BRCA mutation|''BRCA1'' and ''BRCA2'' gene mutation]].<ref name=Genetics2010 /> These mutations account for up to 90% of the total genetic influence with a risk of breast cancer of 60–80% in those affected.<ref name=Gage2012 /> Other significant mutations include ''p53'' ([[Li–Fraumeni syndrome]]), ''PTEN'' ([[Cowden syndrome]]), and ''STK11'' ([[Peutz–Jeghers syndrome]]), ''CHEK2'', ''ATM'', ''BRIP1'', and ''PALB2''.<ref name=Gage2012 /> In 2012, researchers said that there are four genetically distinct types of the breast cancer and that in each type, hallmark genetic changes lead to many cancers.<ref name=nyt23912>{{cite news | vauthors = Kolata G |title = Genetic Study Finds 4 Distinct Variations of Breast Cancer |url = https://www.nytimes.com/2012/09/24/health/study-finds-variations-of-breast-cancer.html |newspaper = The New York Times |date = 23 September 2012 |access-date = 23 September 2012 |url-status = live |archive-url = https://web.archive.org/web/20120924091105/http://www.nytimes.com/2012/09/24/health/study-finds-variations-of-breast-cancer.html |archive-date = 24 September 2012 |df = dmy-all }}</ref>
Other genetic predispositions include the density of the breast tissue and hormonal levels. Women with [[dense breast tissue]] are more likely to get tumors and are less likely to be diagnosed with breast cancer – because the dense tissue makes tumors less visible on mammograms. Furthermore, women with naturally high estrogen and progesterone levels are also at higher risk for tumor development.<ref>{{cite web |title=CDC – What Are the Risk Factors for Breast Cancer? |url=https://www.cdc.gov/cancer/breast/basic_info/risk_factors.htm |website=www.cdc.gov |date=14 December 2018}}</ref><ref>{{cite journal | vauthors = Tian JM, Ran B, Zhang CL, Yan DM, Li XH | title = Estrogen and progesterone promote breast cancer cell proliferation by inducing cyclin G1 expression | journal = Brazilian Journal of Medical and Biological Research | volume = 51 | issue = 3 | pages = 1–7 | date = January 2018 | pmid = 29513878 | pmc = 5912097 | doi = 10.1590/1414-431X20175612 | url = https://www.popline.org/node/328955 | access-date = 29 April 2019 | archive-date = 14 May 2017 | archive-url = https://web.archive.org/web/20170514183905/http://www.popline.org/node/328955 | url-status = dead }}</ref>
=== Medical conditions ===
Breast changes like [[atypical ductal hyperplasia]]<ref name="urlUnderstanding Breast Changes – National Cancer Institute">{{cite web |url = http://www.cancer.gov/cancertopics/understanding-breast-changes/page6#F8 |title = Understanding Breast Changes – National Cancer Institute |url-status = dead |archive-url = https://web.archive.org/web/20100527185336/http://www.cancer.gov/cancertopics/understanding-breast-changes/page6 |archive-date = 27 May 2010 }}</ref> and [[lobular carcinoma in situ|lobular carcinoma ''in situ'']],<ref>{{cite web |url = http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/page6 |title = Breast Cancer Treatment |publisher = National Cancer Institute |url-status = live |archive-url = https://web.archive.org/web/20150425224841/http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page6 |archive-date = 25 April 2015 |df = dmy-all |date = January 1980 }}</ref><ref name="pmid18562954">{{cite journal | vauthors = Afonso N, Bouwman D | title = Lobular carcinoma in situ | journal = European Journal of Cancer Prevention | volume = 17 | issue = 4 | pages = 312–6 | date = August 2008 | pmid = 18562954 | doi = 10.1097/CEJ.0b013e3282f75e5d | s2cid = 388045 }}</ref> found in benign breast conditions such as [[fibrocystic breast changes]], are correlated with an increased breast cancer risk.
[[Diabetes mellitus]] might also increase the risk of breast cancer.<ref name="pmid23709491">{{cite journal | vauthors = Anothaisintawee T, Wiratkapun C, Lerdsitthichai P, Kasamesup V, Wongwaisayawan S, Srinakarin J, Hirunpat S, Woodtichartpreecha P, Boonlikit S, Teerawattananon Y, Thakkinstian A | display-authors = 6 | title = Risk factors of breast cancer: a systematic review and meta-analysis | journal = Asia-Pacific Journal of Public Health | volume = 25 | issue = 5 | pages = 368–87 | date = September 2013 | pmid = 23709491 | doi = 10.1177/1010539513488795 | s2cid = 206616972 }}</ref> Autoimmune diseases such as [[lupus erythematosus]] seem also to increase the risk for the acquisition of breast cancer.<ref name="pmid21237645">{{cite journal | vauthors = Böhm I | title = Breast cancer in lupus | journal = Breast | volume = 20 | issue = 3 | pages = 288–90 | date = June 2011 | pmid = 21237645 | doi = 10.1016/j.breast.2010.12.005 | doi-access = free }}</ref>
The major causes of sporadic breast cancer are associated with hormone levels. Breast cancer is promoted by estrogen. This hormone activates the development of breast throughout puberty, menstrual cycles and pregnancy. The imbalance between estrogen and progesterone during the menstrual phases causes cell proliferation. Moreover, oxidative metabolites of estrogen can increase DNA damage and mutations. Repeated cycling and the impairment of repair process can transform a normal cell into pre-malignant and eventually malignant cell through mutation. During the premalignant stage, high proliferation of stromal cells can be activated by estrogen to support the development of breast cancer. During the ligand binding activation, the ER can regulate gene expression by interacting with estrogen response elements within the promotor of specific genes. The expression and activation of ER due to lack of estrogen can be stimulated by extracellular signals.<ref>{{cite journal | vauthors = Williams C, Lin CY | title = Oestrogen receptors in breast cancer: basic mechanisms and clinical implications | journal = Ecancermedicalscience | volume = 7 | pages = 370 | date = November 2013 | pmid = 24222786 | pmc = 3816846 | doi = 10.3332/ecancer.2013.370 }}</ref> Interestingly, the ER directly binding with the several proteins, including growth factor receptors, can promote the expression of genes related to cell growth and survival.<ref>{{cite journal | vauthors = Levin ER, Pietras RJ | title = Estrogen receptors outside the nucleus in breast cancer | journal = Breast Cancer Research and Treatment | volume = 108 | issue = 3 | pages = 351–361 | date = April 2008 | pmid = 17592774 | doi = 10.1007/s10549-007-9618-4 | s2cid = 11394158 }}</ref>
Raised [[prolactin]] levels in the blood are associated with increased risk of breast cancer.<ref>{{cite journal | vauthors = Wang M, Wu X, Chai F, Zhang Y, Jiang J | title = Plasma prolactin and breast cancer risk: a meta- analysis | journal = Scientific Reports | volume = 6 | pages = 25998 | date = May 2016 | pmid = 27184120 | pmc = 4869065 | doi = 10.1038/srep25998 | bibcode = 2016NatSR...625998W }}</ref> A meta-analysis of observational research with over two million individuals has suggested a moderate association of antipsychotic use with breast cancer, possibly mediated by prolactin-inducing properties of specific agents.<ref>{{cite journal | vauthors = Leung JC, Ng DW, Chu RY, Chan EW, Huang L, Lum DH, Chan EW, Smith DJ, Wong IC, Lai FT | display-authors = 6 | title = Association of antipsychotic use with breast cancer: a systematic review and meta-analysis of observational studies with over 2 million individuals | journal = Epidemiology and Psychiatric Sciences | volume = 31 | pages = e61 | date = September 2022 | pmid = 36059215 | pmc = 9483823 | doi = 10.1017/S2045796022000476 }}</ref>
== Pathophysiology ==
{{See also|Carcinogenesis}}
[[File:Lobules and ducts of the breast.jpg|thumb|[[Lactiferous duct|Ducts]] and lobules, the main locations of breast cancers]]
[[File:Signal transduction pathways.svg|thumb|Overview of signal transduction pathways involved in [[apoptosis|programmed cell death]]. Mutations leading to loss of this ability can lead to cancer formation.]]
Breast cancer, like other [[cancers]], occurs because of an interaction between an environmental (external) factor and a genetically susceptible host. Normal cells divide as many times as needed and stop. They attach to other cells and stay in place in tissues. Cells become cancerous when they lose their ability to stop dividing, to attach to other cells, to stay where they belong, and to die at the proper time.
Normal cells will self-destruct ([[apoptosis|programmed cell death]]) when they are no longer needed. Until then, cells are protected from programmed death by several protein clusters and pathways. One of the protective pathways is the [[PI3K]]/[[AKT]] pathway; another is the [[Ras (protein)|RAS]]/[[Mitogen-activated protein kinase kinase|MEK]]/[[Extracellular signal-regulated kinases|ERK]] pathway. Sometimes the genes along these protective pathways are mutated in a way that turns them permanently "on", rendering the cell incapable of self-destructing when it is no longer needed. This is one of the steps that causes cancer in combination with other mutations. Normally, the [[PTEN (gene)|PTEN]] protein turns off the PI3K/AKT pathway when the cell is ready for programmed cell death. In some breast cancers, the gene for the PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the "on" position, and the cancer cell does not self-destruct.<ref>{{cite conference | vauthors = Lee A, Arteaga C |title = 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium |book-title = Sunday Morning Year-End Review |date = 14 December 2009 |url = http://www.sabcs.org/Newsletter/Docs/SABCS_2009_Issue5.pdf |url-status = dead |archive-url = https://web.archive.org/web/20130813021816/http://www.sabcs.org/Newsletter/Docs/SABCS_2009_Issue5.pdf |archive-date = 13 August 2013 }}</ref>
Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.<ref name="pmid16675129">{{cite journal | vauthors = Cavalieri E, Chakravarti D, Guttenplan J, Hart E, Ingle J, Jankowiak R, Muti P, Rogan E, Russo J, Santen R, Sutter T | display-authors = 6 | title = Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer| volume = 1766 | issue = 1 | pages = 63–78 | date = August 2006 | pmid = 16675129 | doi = 10.1016/j.bbcan.2006.03.001 }}</ref> Additionally, G-protein coupled [[estrogen receptor]]s have been associated with various cancers of the female reproductive system including breast cancer.<ref>{{cite journal | vauthors = Filardo EJ | title = A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 176 | pages = 38–48 | date = February 2018 | pmid = 28595943 | doi = 10.1016/j.jsbmb.2017.05.005 | s2cid = 19644829 }}</ref>
Abnormal [[growth factor]] signaling in the interaction between [[stromal cell]]s and [[epithelial cell]]s can facilitate malignant cell growth.<ref name="pmid12817994">{{cite journal | vauthors = Haslam SZ, Woodward TL | title = Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland | journal = Breast Cancer Research | volume = 5 | issue = 4 | pages = 208–15 | date = June 2003 | pmid = 12817994 | pmc = 165024 | doi = 10.1186/bcr615 }}</ref><ref>{{cite journal | vauthors = Wiseman BS, Werb Z | title = Stromal effects on mammary gland development and breast cancer | journal = Science | volume = 296 | issue = 5570 | pages = 1046–9 | date = May 2002 | pmid = 12004111 | pmc = 2788989 | doi = 10.1126/science.1067431 | bibcode = 2002Sci...296.1046W }}</ref> In breast adipose tissue, overexpression of leptin leads to increased cell proliferation and cancer.<ref name="pmid20889333">{{cite journal | vauthors = Jardé T, Perrier S, Vasson MP, Caldefie-Chézet F | title = Molecular mechanisms of leptin and adiponectin in breast cancer | journal = European Journal of Cancer | volume = 47 | issue = 1 | pages = 33–43 | date = January 2011 | pmid = 20889333 | doi = 10.1016/j.ejca.2010.09.005 }}</ref>
In the United States, 10 to 20 percent of women with breast cancer or [[ovarian cancer]] have a first- or second-degree relative with one of these diseases. Men with breast cancer have an even higher likelihood. The familial tendency to develop these cancers is called [[hereditary breast–ovarian cancer syndrome]]. The best known of these, the [[BRCA mutation|''BRCA'' mutations]], confer a lifetime risk of breast cancer of between 60 and 85 percent and a lifetime risk of ovarian cancer of between 15 and 40 percent. Some mutations associated with cancer, such as ''[[p53]]'', ''[[BRCA1]]'' and ''[[BRCA2]]'', occur in mechanisms to correct errors in [[DNA]]. These mutations are either inherited or acquired after birth. Presumably, they allow further mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant organs.<ref name="acs bc facts 2005-6">{{cite web |author = American Cancer Society |year = 2005 |title = Breast Cancer Facts & Figures 2005–2006 |url = http://www.cancer.org/downloads/STT/CAFF2005BrFacspdf2005.pdf |access-date = 26 April 2007 |archive-url = https://web.archive.org/web/20070613192148/http://www.cancer.org/downloads/STT/CAFF2005BrFacspdf2005.pdf |archive-date = 13 June 2007 }}</ref><ref>{{cite journal | vauthors = Dunning AM, Healey CS, Pharoah PD, Teare MD, Ponder BA, Easton DF | title = A systematic review of genetic polymorphisms and breast cancer risk | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 8 | issue = 10 | pages = 843–54 | date = October 1999 | pmid = 10548311 | url = http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10548311 }}</ref> However, there is strong evidence of residual risk variation that goes well beyond hereditary ''BRCA'' gene mutations between carrier families. This is caused by unobserved risk factors.<ref>{{cite journal | vauthors = Begg CB, Haile RW, Borg A, Malone KE, Concannon P, Thomas DC, Langholz B, Bernstein L, Olsen JH, Lynch CF, Anton-Culver H, Capanu M, Liang X, Hummer AJ, Sima C, Bernstein JL | display-authors = 6 | title = Variation of breast cancer risk among BRCA1/2 carriers | journal = JAMA | volume = 299 | issue = 2 | pages = 194–201 | date = January 2008 | pmid = 18182601 | pmc = 2714486 | doi = 10.1001/jama.2007.55-a }}</ref> This implicates environmental and other causes as triggers for breast cancers. The inherited mutation in ''BRCA1'' or ''BRCA2'' genes can interfere with repair of DNA cross links and DNA double strand breaks (known functions of the encoded protein).<ref>{{cite journal | vauthors = Patel KJ, Yu VP, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ, Colledge WH, Friedman LS, Ponder BA, Venkitaraman AR | display-authors = 6 | title = Involvement of Brca2 in DNA repair | journal = Molecular Cell | volume = 1 | issue = 3 | pages = 347–57 | date = February 1998 | pmid = 9660919 | doi = 10.1016/S1097-2765(00)80035-0 | doi-access = free }}</ref> These carcinogens cause DNA damage such as DNA cross links and double strand breaks that often require repairs by pathways containing BRCA1 and BRCA2.<ref>{{cite journal | vauthors = Marietta C, Thompson LH, Lamerdin JE, Brooks PJ | title = Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: implications for alcohol-related carcinogenesis | journal = Mutation Research | volume = 664 | issue = 1–2 | pages = 77–83 | date = May 2009 | pmid = 19428384 | pmc = 2807731 | doi = 10.1016/j.mrfmmm.2009.03.011 }}</ref><ref>{{cite journal | vauthors = Theruvathu JA, Jaruga P, Nath RG, Dizdaroglu M, Brooks PJ | title = Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde | journal = Nucleic Acids Research | volume = 33 | issue = 11 | pages = 3513–20 | year = 2005 | pmid = 15972793 | pmc = 1156964 | doi = 10.1093/nar/gki661 }}</ref> However, mutations in ''BRCA'' genes account for only 2 to 3 percent of all breast cancers.<ref>{{cite journal | vauthors = Wooster R, Weber BL | s2cid = 26602401 | title = Breast and ovarian cancer | journal = The New England Journal of Medicine | volume = 348 | issue = 23 | pages = 2339–47 | date = June 2003 | pmid = 12788999 | doi = 10.1056/NEJMra012284 }}</ref> Levin ''et al.'' say that cancer may not be inevitable for all carriers of ''BRCA1'' and ''BRCA2'' mutations.<ref name="Levin2012">{{cite journal | vauthors = Levin B, Lech D, Friedenson B | title = Evidence that BRCA1- or BRCA2-associated cancers are not inevitable | journal = Molecular Medicine | volume = 18 | issue = 9 | pages = 1327–37 | date = December 2012 | pmid = 22972572 | pmc = 3521784 | doi = 10.2119/molmed.2012.00280 }}</ref> About half of hereditary breast–ovarian cancer syndromes involve unknown genes. Furthermore, certain latent viruses, may decrease the expression of the ''BRCA1'' gene and increase the risk of breast tumors.<ref>{{cite journal | vauthors = Polansky H, Schwab H | title = How latent viruses cause breast cancer: An explanation based on the microcompetition model | journal = Bosnian Journal of Basic Medical Sciences | volume = 19 | issue = 3 | pages = 221–226 | date = August 2019 | pmid = 30579323 | pmc = 6716096 | doi = 10.17305/bjbms.2018.3950 }}</ref>
[[GATA-3]] directly controls the expression of estrogen receptor (ER) and other genes associated with epithelial differentiation, and the loss of GATA-3 leads to loss of differentiation and poor prognosis due to cancer cell invasion and metastasis.<ref>{{cite journal | vauthors = Kouros-Mehr H, Kim JW, Bechis SK, Werb Z | title = GATA-3 and the regulation of the mammary luminal cell fate | journal = Current Opinion in Cell Biology | volume = 20 | issue = 2 | pages = 164–70 | date = April 2008 | pmid = 18358709 | pmc = 2397451 | doi = 10.1016/j.ceb.2008.02.003 }}</ref>
== Diagnosis ==
Most types of breast cancer are easy to diagnose by microscopic analysis of a sample – or [[breast biopsy|biopsy]] [[abortion–breast cancer hypothesis|–]] of the affected area of the breast. Also, there are types of breast cancer that require specialized lab exams.
The two most commonly used screening methods, physical examination of the breasts by a healthcare provider and mammography, can offer an approximate likelihood that a lump is cancer, and may also detect some other lesions, such as a simple [[cyst]].<ref>{{cite journal | vauthors = Saslow D, Hannan J, Osuch J, Alciati MH, Baines C, Barton M, Bobo JK, Coleman C, Dolan M, Gaumer G, Kopans D, Kutner S, Lane DS, Lawson H, Meissner H, Moorman C, Pennypacker H, Pierce P, Sciandra E, Smith R, Coates R | display-authors = 6 | title = Clinical breast examination: practical recommendations for optimizing performance and reporting | journal = CA: A Cancer Journal for Clinicians | volume = 54 | issue = 6 | pages = 327–44 | year = 2004 | pmid = 15537576 | doi = 10.3322/canjclin.54.6.327 | doi-access = free }}</ref> When these examinations are inconclusive, a healthcare provider can remove a sample of the fluid in the lump for microscopic analysis (a procedure known as [[fine needle aspiration]], or fine needle aspiration and cytology, FNAC) to help establish the diagnosis. A needle aspiration can be performed in a healthcare provider's office or clinic. A local anesthetic may be used to numb the breast tissue to prevent pain during the procedure, but may not be necessary if the lump isn't beneath the skin. A finding of clear fluid makes the lump highly unlikely to be cancerous, but bloody fluid may be sent off for inspection under a microscope for cancerous cells. Together, physical examination of the breasts, mammography, and FNAC can be used to diagnose breast cancer with a good degree of accuracy.
Other options for biopsy include a [[core biopsy]] or [[vacuum-assisted breast biopsy]],<ref name="pmid20130983">{{cite journal | vauthors = Yu YH, Liang C, Yuan XZ | title = Diagnostic value of vacuum-assisted breast biopsy for breast carcinoma: a meta-analysis and systematic review | journal = Breast Cancer Research and Treatment | volume = 120 | issue = 2 | pages = 469–79 | date = April 2010 | pmid = 20130983 | doi = 10.1007/s10549-010-0750-1 | s2cid = 22685290 }}</ref> which are procedures in which a section of the breast lump is removed; or an [[excisional biopsy]], in which the entire lump is removed. Very often the results of physical examination by a healthcare provider, mammography, and additional tests that may be performed in special circumstances (such as imaging by [[medical ultrasonography|ultrasound]] or [[magnetic resonance imaging|MRI]]) are sufficient to warrant excisional biopsy as the definitive diagnostic and primary treatment method.<ref>{{cite journal | vauthors = Ferguson MJ | title = Multifocal invasive mucinous carcinoma of the breast | journal = Journal of Medical Radiation Sciences | volume = 67 | issue = 2 | pages = 155–158 | date = June 2020 | pmid = 31975569 | pmc = 7276192 | doi = 10.1002/jmrs.379 }}</ref>{{Primary source inline|date=July 2020}}
<gallery class="center">
File:Breast MRI T1W FSE ARC T2W FSE ARC T2W FSE IDEAL 09-arrow.jpg|MRI showing breast cancer
File:Breast cancer.JPG|Excised human [[breast]] [[tissue (biology)|tissue]], showing an irregular, dense, white [[wikt:stellate|stellate]] area of cancer 2 cm in diameter, within yellow fatty tissue
File:Invasive Ductal Carcinoma 40x.jpg|High-grade invasive ductal carcinoma, with minimal tubule formation, marked [[pleomorphism (cytology)|pleomorphism]], and prominent [[Breast cancer classification#Mitotic count|mitoses]], 40x field
File:Breast carcinoma in a lymph node.jpg|Micrograph showing a lymph node invaded by ductal breast carcinoma, with an extension of the tumor beyond the lymph node
File:Neuropilin-2 (Nrp2) expression in normal breast and breast carcinoma tissue.jpg|Neuropilin-2 expression in normal breast and breast carcinoma tissue
File:Mamma-CA.jpg|F-18 FDG PET/CT: A breast cancer metastasis to the right scapula
File:Needle Breast Biopsy.png|Needle breast biopsy
File:Manual compression elastography of invazive ductal carcinoma 00132.gif|Elastography shows stiff cancer tissue on ultrasound imaging.
File:Breast cancer ultrasound.jpg|Ultrasound image shows irregularly shaped mass of breast cancer.
File:Infiltrating breast carcinoma.jpg|Infiltrating (invasive) breast carcinoma
File:Mammo breast cancer wArrows.jpg|[[Mammograms]] showing a normal breast (left) and a breast with cancer (right)
</gallery>
=== Classification ===
{{Main|Breast cancer classification}}
Breast cancers are classified by several grading systems. Each of these influences the [[prognosis]] and can affect treatment response. Description of a breast cancer optimally includes all of these factors.
[[File:Pie chart of incidence and prognosis of histopathologic breast cancer types.png|thumb|upright=1.25|Histopathologic types of breast cancer, with relative incidences and prognoses]]
* '''Histopathology'''. Breast cancer is usually classified primarily by its [[Breast cancer classification#Histopathology|histological]] appearance. Most breast cancers are derived from the epithelium lining the ducts or lobules, and these cancers are classified as [[mammary ductal carcinoma|ductal]] or lobular carcinoma. ''Carcinoma in situ'' is growth of low-grade cancerous or precancerous cells within a particular tissue compartment such as the mammary duct without invasion of the surrounding tissue. In contrast, ''invasive carcinoma'' does not confine itself to the initial tissue compartment.<ref>{{cite book | vauthors = Kosir MA |date=July 2019|title=Merck Manual, Professional Edition|chapter-url=http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html|archive-url= https://web.archive.org/web/20111110075702/http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html|archive-date=10 November 2011|url-status=live|chapter=Ch. 253, Breast Cancer}}</ref>
* '''Grade'''. [[Breast cancer classification#Grade|Grading]] compares the appearance of the breast cancer cells to the appearance of normal breast tissue. Normal cells in an organ like the breast become differentiated, meaning that they take on specific shapes and forms that reflect their function as part of that organ. Cancerous cells lose that differentiation. In cancer, the cells that would normally line up in an orderly way to make up the milk ducts become disorganized. Cell division becomes uncontrolled. Cell nuclei become less uniform. Pathologists describe cells as well differentiated (low grade), moderately differentiated (intermediate grade), and poorly differentiated (high grade) as the cells progressively lose the features seen in normal breast cells. Poorly differentiated cancers (the ones whose tissue is least like normal breast tissue) have a worse prognosis.
* '''Stage'''. [[Breast cancer classification#Stage|Breast cancer staging]] using the [[Breast cancer classification#TNM system|TNM system]] is based on the size of the <u>t</u>umor ('''T'''), whether or not the tumor has spread to the [[lymph node|lymph]] <u>n</u>odes ('''N''') in the armpits, and whether the tumor has <u>m</u>etastasized ('''M''') (i.e. spread to a more distant part of the body). Larger size, nodal spread, and metastasis have a larger stage number and a worse prognosis. <br />The main stages are:
** Stage 0 is a pre-cancerous or marker condition, either [[ductal carcinoma in situ]] (DCIS) or [[lobular carcinoma in situ]] (LCIS).
** Stages 1–3 are within the breast or regional lymph nodes.
** Stage 4 is [[Metastatic breast cancer|'metastatic' cancer]] that has a less favorable prognosis since it has spread beyond the breast and regional lymph nodes.
<gallery>
File:Diagram showing stage T1 breast cancer CRUK 244.svg|Stage T1 breast cancer
File:Diagram showing stage T2 breast cancer CRUK 252.svg|Stage T2 breast cancer
File:Diagram showing stage T3 breast cancer CRUK 259.svg|Stage T3 breast cancer
File:Stage 4 of Breast Cancer.jpg|Metastatic or stage 4 breast cancer
</gallery>
:Where available, [[imaging studies]] may be employed as part of the staging process in select cases to look for signs of metastatic cancer. However, in cases of breast cancer with low risk for metastasis, the risks associated with [[Positron emission tomography|PET scans]], [[X-ray computed tomography|CT scans]], or [[Bone scintigraphy|bone scans]] outweigh the possible benefits, as these procedures expose the person to a substantial amount of potentially dangerous ionizing radiation.<ref name="ASCOfive">{{Citation |author1 = American Society of Clinical Oncology |author1-link = American Society of Clinical Oncology |title = Five Things Physicians and Patients Should Question |publisher = [[American Society of Clinical Oncology]] |work = Choosing Wisely: an initiative of the [[ABIM Foundation]] |url = http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf |access-date = 14 August 2012 |url-status = dead |archive-url = https://web.archive.org/web/20120731073425/http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf |archive-date = 31 July 2012 |df = dmy-all }}</ref><ref name="CarlsonBreast">{{cite journal | vauthors = Carlson RW, Allred DC, Anderson BO, Burstein HJ, Carter WB, Edge SB, Erban JK, Farrar WB, Goldstein LJ, Gradishar WJ, Hayes DF, Hudis CA, Jahanzeb M, Kiel K, Ljung BM, Marcom PK, Mayer IA, McCormick B, Nabell LM, Pierce LJ, Reed EC, Smith ML, Somlo G, Theriault RL, Topham NS, Ward JH, Winer EP, Wolff AC | display-authors = 6 | title = Breast cancer. Clinical practice guidelines in oncology | journal = Journal of the National Comprehensive Cancer Network | volume = 7 | issue = 2 | pages = 122–92 | date = February 2009 | pmid = 19200416 | doi = 10.6004/jnccn.2009.0012 | author29 = NCCN Breast Cancer Clinical Practice Guidelines Panel | doi-access = free }}</ref>
* '''Receptor status'''. Breast cancer cells have [[Breast cancer classification#Receptor status|receptors]] on their surface and in their [[cytoplasm]] and [[Cell nucleus|nucleus]]. Chemical messengers such as [[hormone]]s bind to [[receptor (biochemistry)|receptors]], and this causes changes in the cell. Breast cancer cells may or may not have three important receptors: [[estrogen receptor]] (ER), [[progesterone receptor]] (PR), and [[HER2/neu|HER2]]. <br />ER+ cancer cells (that is, cancer cells that have estrogen receptors) depend on estrogen for their growth, so they can be treated with drugs to block estrogen effects (e.g. [[tamoxifen]]), and generally have a better prognosis. Untreated, HER2+ breast cancers are generally more aggressive than HER2- breast cancers,<ref>{{cite book | vauthors = Kumar V, Abbas A |title = Robbins and Cotran Pathologic Basis of Disease |year = 2010 |publisher = Saunders, an imprint of Elsevier inc. |location = Philadelphia |isbn = 978-1-4160-3121-5 |page = 1090 }}</ref><ref name="sotirou">{{cite journal | vauthors = Sotiriou C, Pusztai L | title = Gene-expression signatures in breast cancer | journal = The New England Journal of Medicine | volume = 360 | issue = 8 | pages = 790–800 | date = February 2009 | pmid = 19228622 | doi = 10.1056/NEJMra0801289 }}</ref> but HER2+ cancer cells respond to drugs such as the [[monoclonal antibody]] [[trastuzumab]] (in combination with conventional chemotherapy), and this has improved the prognosis significantly.<ref>{{cite journal | vauthors = Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N | display-authors = 6 | title = Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer | journal = The New England Journal of Medicine | volume = 353 | issue = 16 | pages = 1673–84 | date = October 2005 | pmid = 16236738 | doi = 10.1056/NEJMoa052122 | s2cid = 9534884 }}</ref> Cells that do not have any of these three receptor types (estrogen receptors, progesterone receptors, or HER2) are called [[triple-negative breast cancer|triple-negative]], although they frequently do express receptors for other hormones, such as [[androgen receptor]] and [[prolactin receptor]].
* '''DNA assays'''. [[Breast cancer classification#DNA classification|DNA testing]] of various types including [[DNA microarray]]s have compared normal cells to breast cancer cells. The specific changes in a particular breast cancer can be used to classify the cancer in several ways, and may assist in choosing the most effective treatment for that DNA type.
<gallery>
File:Diagram showing stage 1A breast cancer CRUK 199.svg|Stage 1A breast cancer
File:Diagram showing stage 1B breast cancer CRUK 202.svg|Stage 1B breast cancer
File:Diagram 1 of 2 showing stage 2A breast cancer CRUK 003.svg|Stage 2A breast cancer
File:Diagram 2 of 2 showing stage 2A breast cancer CRUK 009.svg|Stage 2A breast cancer
File:Diagram 1 of 3 showing stage 2B breast cancer CRUK 006.svg|Stage 2B breast cancer
File:Diagram 2 of 3 showing stage 2B breast cancer CRUK 012.svg|Stage 2B breast cancer
File:Diagram 3 of 3 showing stage 2B breast cancer CRUK 015.svg|Stage 2B breast cancer
File:Diagram 1 of 3 showing stage 3A breast cancer CRUK 007.svg|Stage 3A breast cancer
File:Diagram 2 of 3 showing stage 3A breast cancer CRUK 013.svg|Stage 3A breast cancer
File:Diagram 3 of 3 showing stage 3A breast cancer CRUK 016.svg|Stage 3A breast cancer
File:Diagram 1 of 2 showing stage 3B breast cancer CRUK 004.svg|Stage 3B breast cancer
File:Diagram 2 of 2 showing stage 3B breast cancer CRUK 010.svg|Stage 3B breast cancer
File:Diagram showing stage 4 breast cancer CRUK 228.svg|Stage 4 breast cancer
</gallery>
== Screening ==
{{Main|Breast cancer screening}}
[[File:BreastScreen Aotearoa.JPG|thumb|A mobile breast cancer screening unit in New Zealand]]
Breast cancer screening refers to testing otherwise-healthy women for breast cancer in an attempt to achieve an earlier diagnosis under the assumption that early detection will improve outcomes. A number of screening tests have been employed including clinical and self [[breast exams]], [[mammography]], genetic screening, ultrasound, and magnetic resonance imaging.
A clinical or self breast exam involves feeling the breast for [[breast lump|lumps]] or other abnormalities. Clinical breast exams are performed by health care providers, while self-breast exams are performed by the person themselves.<ref>{{cite web |title = Screening |url = https://www.cdc.gov/cancer/breast/basic_info/screening.htm |work = Centers for Disease Control and Prevention |access-date = 17 November 2015 |url-status = live |archive-url = https://web.archive.org/web/20151118012201/http://www.cdc.gov/cancer/breast/basic_info/screening.htm |archive-date = 18 November 2015 |df = dmy-all |date = 11 September 2018 }}</ref> Evidence does not support the effectiveness of either type of breast exam, as by the time a lump is large enough to be found it is likely to have been growing for several years and thus soon be large enough to be found without an exam.<ref name=USPSTFScreen2009>{{cite web |title = Screening for Breast Cancer |url = http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm |work = US Preventive Services Task Force |date = December 2009 |access-date = 24 December 2012 |url-status = dead |archive-url = https://web.archive.org/web/20130102015424/http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm |archive-date = 2 January 2013 |df = dmy-all }}</ref><ref>{{cite journal | vauthors = Kösters JP, Gøtzsche PC | title = Regular self-examination or clinical examination for early detection of breast cancer | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD003373 | year = 2003 | volume = 2010 | pmid = 12804462 | doi = 10.1002/14651858.CD003373 | pmc = 7387360 }}</ref> Mammographic screening for breast cancer uses [[X-ray]]s to examine the breast for any uncharacteristic masses or lumps. During a screening, the breast is compressed and a technician takes photos from multiple angles. A general mammogram takes photos of the entire breast, while a diagnostic mammogram focuses on a specific lump or area of concern.<ref>{{cite web |title = Breast Cancer and Mammograms |url = http://www.webmd.com/breast-cancer/guide/mammograms |work = WebMD |access-date = 24 December 2012 |url-status = live |archive-url = https://web.archive.org/web/20121228104148/http://www.webmd.com/breast-cancer/guide/mammograms |archive-date = 28 December 2012 |df = dmy-all }}</ref>
A number of national bodies recommend breast cancer screening. For the average woman, the [[U.S. Preventive Services Task Force]] and [[American College of Physicians]] recommends mammography every two years in women between the ages of 50 and 74,<ref name=USPSTFScreen2016 /><ref>{{cite journal | vauthors = Qaseem A, Lin JS, Mustafa RA, Horwitch CA, Wilt TJ | title = Screening for Breast Cancer in Average-Risk Women: A Guidance Statement From the American College of Physicians | journal = Annals of Internal Medicine | volume = 170 | issue = 8 | pages = 547–560 | date = April 2019 | pmid = 30959525 | doi = 10.7326/M18-2147 | doi-access = free }}</ref> the [[Council of Europe]] recommends mammography between 50 and 69 with most programs using a 2-year frequency,<ref>{{cite journal | vauthors = Biesheuvel C, Weigel S, Heindel W | title = Mammography Screening: Evidence, History and Current Practice in Germany and Other European Countries | journal = Breast Care | volume = 6 | issue = 2 | pages = 104–109 | year = 2011 | pmid = 21673820 | pmc = 3104900 | doi = 10.1159/000327493 }}</ref> while the European Commission recommends mammography from 45 to 75 every 2 to 3 years,<ref>{{cite journal | vauthors = Schünemann HJ, Lerda D, Quinn C, Follmann M, Alonso-Coello P, Rossi PG, Lebeau A, Nyström L, Broeders M, Ioannidou-Mouzaka L, Duffy SW, Borisch B, Fitzpatrick P, Hofvind S, Castells X, Giordano L, Canelo-Aybar C, Warman S, Mansel R, Sardanelli F, Parmelli E, Gräwingholt A, Saz-Parkinson Z | display-authors = 6 | title = Breast Cancer Screening and Diagnosis: A Synopsis of the European Breast Guidelines | journal = Annals of Internal Medicine | volume = 172 | issue = 1 | pages = 46–56 | date = January 2020 | pmid = 31766052 | doi = 10.7326/M19-2125 | doi-access = free }}</ref> and in Canada screening is recommended between the ages of 50 and 74 at a frequency of 2 to 3 years.<ref>{{cite journal | vauthors = Tonelli M, Connor Gorber S, Joffres M, Dickinson J, Singh H, Lewin G, Birtwhistle R, Fitzpatrick-Lewis D, Hodgson N, Ciliska D, Gauld M, Liu YY | display-authors = 6 | title = Recommendations on screening for breast cancer in average-risk women aged 40–74 years | journal = CMAJ | volume = 183 | issue = 17 | pages = 1991–2001 | date = November 2011 | pmid = 22106103 | pmc = 3225421 | doi = 10.1503/cmaj.110334 }}</ref> The American Cancer Society also endorses that women ages 40 and older receive mammograms annually.<ref>{{cite journal | vauthors = Moss S | title = Should women under 50 be screened for breast cancer? | journal = British Journal of Cancer | volume = 91 | issue = 3 | pages = 413–417 | date = August 2004 | pmid = 15213718 | pmc = 2409834 | doi = 10.1038/sj.bjc.6601966 }}</ref> These task force reports point out that in addition to unnecessary surgery and anxiety, the risks of more frequent mammograms include a small but significant increase in breast cancer induced by radiation.<ref>{{cite web |url = http://www.ahrq.gov/clinic/3rduspstf/breastCancer/brcanrr.htm#ref31 |title = Breast Cancer: Screening |work = United States Preventive Services Task Force |url-status = dead |archive-url = https://web.archive.org/web/20130616040709/http://www.ahrq.gov/clinic/3rduspstf/breastcancer/brcanrr.htm |archive-date = 16 June 2013 }}</ref>
The [[Cochrane collaboration]] (2013) states that the best quality evidence neither demonstrates a reduction in cancer specific, nor a reduction in all cause mortality from screening mammography.<ref name="Got2013" /> When less rigorous trials are added to the analysis there is a reduction in mortality due to breast cancer of 0.05% (a decrease of 1 in 2000 deaths from breast cancer over 10 years or a relative decrease of 15% from breast cancer).<ref name=Got2013 /> Screening over 10 years results in a 30% increase in rates of over-diagnosis and over-treatment (3 to 14 per 1000) and more than half will have at least one falsely positive test.<ref name=Got2013 /><ref>{{cite journal | vauthors = Welch HG, Passow HJ | title = Quantifying the benefits and harms of screening mammography | journal = JAMA Internal Medicine | volume = 174 | issue = 3 | pages = 448–54 | date = March 2014 | pmid = 24380095 | doi = 10.1001/jamainternmed.2013.13635 }}</ref> This has resulted in the view that it is not clear whether mammography screening does more good or harm.<ref name=Got2013 /> Cochrane states that, due to recent improvements in breast cancer treatment, and the risks of false positives from breast cancer screening leading to unnecessary treatment, "it therefore no longer seems beneficial to attend for breast cancer screening" at any age.<ref>{{cite web |url = http://nordic.cochrane.org/screening-breast-cancer-mammography |title = Screening for breast cancer with mammography |publisher = Cochrane Nordic |date = 27 August 2015 |access-date = 15 October 2015 |url-status = live |archive-url = https://web.archive.org/web/20151029161343/http://nordic.cochrane.org/screening-breast-cancer-mammography |archive-date = 29 October 2015 |df = dmy-all }}</ref> Whether MRI as a screening method has greater harms or benefits when compared to standard mammography is not known.<ref>{{cite journal | title = Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement | journal = Annals of Internal Medicine | volume = 151 | issue = 10 | pages = 716–26, W-236 | date = November 2009 | pmid = 19920272 | doi = 10.7326/0003-4819-151-10-200911170-00008 | url = http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm | url-status = dead | access-date = 24 December 2012 | archive-url = https://web.archive.org/web/20130102015424/http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm | df = dmy-all | archive-date = 2 January 2013 | author1 = US Preventive Services Task Force }}</ref><ref>{{cite journal | title = Magnetic Resonance Imaging as an Adjunct to Mammography for Breast Cancer Screening in Women at Less Than High Risk for Breast Cancer: A Health Technology Assessment | journal = Ontario Health Technology Assessment Series | volume = 16 | issue = 20 | pages = 1–30 | date = 1 November 2016 | pmid = 27990198 | pmc = 5156844 }}</ref>
== Prevention ==
=== Lifestyle ===
Women can reduce their risk of breast cancer by maintaining a healthy weight, reducing [[alcohol use]], increasing physical activity, and [[breast-feeding]].<ref name="WCRF2007">{{Cite web|url=https://www.cancer.org/cancer/breast-cancer/risk-and-prevention/lifestyle-related-breast-cancer-risk-factors.html|title=Lifestyle-related Breast Cancer Risk Factors|website=www.cancer.org|access-date=18 April 2018}}</ref> These modifications might prevent 38% of breast cancers in the US, 42% in the UK, 28% in Brazil, and 20% in China.<ref name=WCRF2007 /> The benefits with moderate exercise such as brisk walking are seen at all age groups including postmenopausal women.<ref name=WCRF2007 /><ref>{{cite journal | vauthors = Eliassen AH, Hankinson SE, Rosner B, Holmes MD, Willett WC | title = Physical activity and risk of breast cancer among postmenopausal women | journal = Archives of Internal Medicine | volume = 170 | issue = 19 | pages = 1758–64 | date = October 2010 | pmid = 20975025 | pmc = 3142573 | doi = 10.1001/archinternmed.2010.363 }}</ref> High levels of physical activity reduce the risk of breast cancer by about 14%.<ref name="BMJ2016">{{cite journal | vauthors = Kyu HH, Bachman VF, Alexander LT, Mumford JE, Afshin A, Estep K, Veerman JL, Delwiche K, Iannarone ML, Moyer ML, Cercy K, Vos T, Murray CJ, Forouzanfar MH | display-authors = 6 | title = Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013 | journal = BMJ | volume = 354 | pages = i3857 | date = August 2016 | pmid = 27510511 | pmc = 4979358 | doi = 10.1136/bmj.i3857 }}</ref> Strategies that encourage regular physical activity and reduce obesity could also have other benefits, such as reduced risks of cardiovascular disease and diabetes.<ref name=Hay2013 /> A study that included data from 130,957 women of European ancestry found “strong evidence that greater levels of physical activity and less sedentary time are likely to reduce breast cancer risk, with results generally consistent across breast cancer subtypes”.<ref>{{Cite news |title=New study finds 'strong evidence' that exercise cuts breast cancer risk |language=en-GB |work=belfasttelegraph |url=https://www.belfasttelegraph.co.uk/news/uk/new-study-finds-strong-evidence-that-exercise-cuts-breast-cancer-risk-41967524.html |access-date=2022-09-07 |issn=0307-1235}}</ref>
The [[American Cancer Society]] and the [[American Society of Clinical Oncology]] advised in 2016 that people should eat a diet high in vegetables, fruits, whole grains, and legumes.<ref>{{cite journal | vauthors = Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA | display-authors = 6 | title = American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline | journal = CA: A Cancer Journal for Clinicians | volume = 66 | issue = 1 | pages = 43–73 | date = January 2016 | pmid = 26641959 | doi = 10.3322/caac.21319 | doi-access = free }}</ref> High intake of citrus fruit has been associated with a 10% reduction in the risk of breast cancer.<ref>{{cite journal | vauthors = Song JK, Bae JM | title = Citrus fruit intake and breast cancer risk: a quantitative systematic review | journal = Journal of Breast Cancer | volume = 16 | issue = 1 | pages = 72–6 | date = March 2013 | pmid = 23593085 | pmc = 3625773 | doi = 10.4048/jbc.2013.16.1.72 }}</ref> Marine [[omega-3 polyunsaturated fatty acids]] appear to reduce the risk.<ref name="pmid23814120">{{cite journal | vauthors = Zheng JS, Hu XJ, Zhao YM, Yang J, Li D | title = Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies | journal = BMJ | volume = 346 | pages = f3706 | date = June 2013 | pmid = 23814120 | doi = 10.1136/bmj.f3706 | doi-access = free }}</ref> High consumption of [[soy]]-based foods may reduce risk.<ref>{{cite journal | vauthors = Wu AH, Yu MC, Tseng CC, Pike MC | title = Epidemiology of soy exposures and breast cancer risk | journal = British Journal of Cancer | volume = 98 | issue = 1 | pages = 9–14 | date = January 2008 | pmid = 18182974 | pmc = 2359677 | doi = 10.1038/sj.bjc.6604145 }}</ref>
=== Pre-emptive surgery ===
Removal of both breasts before any cancer has been diagnosed or any suspicious lump or other lesion has appeared (a procedure known as "prophylactic bilateral [[preventive mastectomy|mastectomy]]" or "risk reducing mastectomy") may be considered in women with BRCA1 and BRCA2 mutations, which are associated with a substantially heightened risk for an eventual diagnosis of breast cancer.<ref>{{cite journal | vauthors = Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, Petty PM, Sellers TA, Johnson JL, McDonnell SK, Frost MH, Jenkins RB | display-authors = 6 | title = Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer | journal = The New England Journal of Medicine | volume = 340 | issue = 2 | pages = 77–84 | date = January 1999 | pmid = 9887158 | doi = 10.1056/NEJM199901143400201 }}</ref><ref>{{cite journal | vauthors = Meijers-Heijboer H, van Geel B, van Putten WL, Henzen-Logmans SC, Seynaeve C, Menke-Pluymers MB, Bartels CC, Verhoog LC, van den Ouweland AM, Niermeijer MF, Brekelmans CT, Klijn JG | display-authors = 6 | title = Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation | journal = The New England Journal of Medicine | volume = 345 | issue = 3 | pages = 159–64 | date = July 2001 | pmid = 11463009 | doi = 10.1056/NEJM200107193450301 | url = https://pure.eur.nl/ws/files/46620151/11463009.pdf }}</ref> Evidence is not strong enough to support this procedure in anyone but women at the highest risk.<ref name=":1">{{cite journal | vauthors = Carbine NE, Lostumbo L, Wallace J, Ko H | title = Risk-reducing mastectomy for the prevention of primary breast cancer | journal = The Cochrane Database of Systematic Reviews | volume = 4 | pages = CD002748 | date = April 2018 | pmid = 29620792 | pmc = 6494635 | doi = 10.1002/14651858.cd002748.pub4 }}</ref> BRCA testing is recommended in those with a high family risk after genetic counseling. It is not recommended routinely.<ref name="Risk assessment, genetic counseling">{{cite journal | vauthors = Moyer VA | title = Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement | journal = Annals of Internal Medicine | volume = 160 | issue = 4 | pages = 271–81 | date = February 2014 | pmid = 24366376 | doi = 10.7326/M13-2747 | doi-access = free }}</ref> This is because there are many forms of changes in BRCA genes, ranging from harmless [[Gene polymorphism|polymorphisms]] to obviously dangerous [[frameshift mutations]].<ref name="Risk assessment, genetic counseling"/> The effect of most of the identifiable changes in the genes is uncertain. Testing in an average-risk person is particularly likely to return one of these indeterminate, useless results. Removing the second breast in a person who has breast cancer (contralateral risk‐reducing mastectomy or CRRM) may reduce the risk of cancer in the second breast, however, it is unclear if removing the second breast in those who have breast cancer improves survival.<ref name=":1" />
=== Medications ===
The [[selective estrogen receptor modulators]] reduce the risk of breast cancer but increase the risk of [[thromboembolism]] and [[endometrial cancer]].<ref name=Nelson2013 /> There is no overall change in the risk of death.<ref name="Nelson2013">{{cite journal | vauthors = Nelson HD, Smith ME, Griffin JC, Fu R | title = Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force | journal = Annals of Internal Medicine | volume = 158 | issue = 8 | pages = 604–14 | date = April 2013 | pmid = 23588749 | doi = 10.7326/0003-4819-158-8-201304160-00005 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S, DeCensi A, Dowsett M, Forbes JF, Ford L, LaCroix AZ, Mershon J, Mitlak BH, Powles T, Veronesi U, Vogel V, Wickerham DL | display-authors = 6 | title = Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data | journal = Lancet | volume = 381 | issue = 9880 | pages = 1827–34 | date = May 2013 | pmid = 23639488 | pmc = 3671272 | doi = 10.1016/S0140-6736(13)60140-3 }}</ref> They are thus not recommended for the prevention of breast cancer in women at average risk but it is recommended they be offered for those at high risk and over the age of 35.<ref>{{cite journal | vauthors = Owens DK, Davidson KW, Krist AH, Barry MJ, Cabana M, Caughey AB, Doubeni CA, Epling JW, Kubik M, Landefeld CS, Mangione CM, Pbert L, Silverstein M, Tseng CW, Wong JB | display-authors = 6 | title = Medication Use to Reduce Risk of Breast Cancer: US Preventive Services Task Force Recommendation Statement | journal = JAMA | volume = 322 | issue = 9 | pages = 857–867 | date = September 2019 | pmid = 31479144 | doi = 10.1001/jama.2019.11885 | doi-access = free }}</ref> The benefit of breast cancer reduction continues for at least five years after stopping a course of treatment with these medications.<ref>{{cite journal | vauthors = Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S, DeCensi A, Dowsett M, Forbes JF, Ford L, LaCroix AZ, Mershon J, Mitlak BH, Powles T, Veronesi U, Vogel V, Wickerham DL | display-authors = 6 | title = Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data | journal = Lancet | volume = 381 | issue = 9880 | pages = 1827–34 | date = May 2013 | pmid = 23639488 | pmc = 3671272 | doi = 10.1016/S0140-6736(13)60140-3 | url = }}</ref> [[Aromatase inhibitor]]s (such as exemestane and anasatrozole) may be more effective than selective estrogen receptor modulators (such as tamoxifen) at reducing breast cancer risk and they are not associated with an increased risk of endometrial cancer and thromboembolism.<ref>{{cite journal | vauthors = Mocellin S, Goodwin A, Pasquali S | title = Risk-reducing medications for primary breast cancer: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 4 | pages = CD012191 | date = April 2019 | pmid = 31032883 | pmc = 6487387 | doi = 10.1002/14651858.cd012191.pub2 }}</ref>
== Management ==
{{Main|Breast cancer management}}
The management of breast cancer depends on various factors, including the [[Breast cancer classification#Stage|stage]] of the cancer and the person's age. Treatments are more aggressive when the cancer is more advanced or there is a higher risk of recurrence of the cancer following treatment.
Breast cancer is usually treated with surgery, which may be followed by chemotherapy or radiation therapy, or both. A multidisciplinary approach is preferable.<ref>{{cite journal | vauthors = Saini KS, Taylor C, Ramirez AJ, Palmieri C, Gunnarsson U, Schmoll HJ, Dolci SM, Ghenne C, Metzger-Filho O, Skrzypski M, Paesmans M, Ameye L, Piccart-Gebhart MJ, de Azambuja E | display-authors = 6 | title = Role of the multidisciplinary team in breast cancer management: results from a large international survey involving 39 countries | journal = Annals of Oncology | volume = 23 | issue = 4 | pages = 853–9 | date = April 2012 | pmid = 21821551 | doi = 10.1093/annonc/mdr352 | doi-access = free }}</ref> Hormone receptor-positive cancers are often treated with hormone-blocking therapy over courses of several years. Monoclonal antibodies, or other [[immune-modulating]] treatments, may be administered in certain cases of metastatic and other advanced stages of breast cancer. Although this range of treatment is still being studied.<ref>{{cite journal | vauthors = Khalil DN, Smith EL, Brentjens RJ, Wolchok JD | title = The future of cancer treatment: immunomodulation, CARs and combination immunotherapy | journal = Nature Reviews. Clinical Oncology | volume = 13 | issue = 5 | pages = 273–90 | date = May 2016 | pmid = 26977780 | pmc = 5551685 | doi = 10.1038/nrclinonc.2016.25 }}</ref>
=== Surgery ===
[[File:Mastectomie 02.jpg|thumb|Chest after right breast [[mastectomy]]]]
Surgery involves the physical removal of the tumor, typically along with some of the surrounding tissue. One or more lymph nodes may be biopsied during the surgery; increasingly the lymph node sampling is performed by a [[sentinel lymph node]] biopsy.
Standard surgeries include:
* [[Mastectomy]]: Removal of the whole breast.
* [[Quadrantectomy]]: Removal of one-quarter of the breast.
* [[Lumpectomy]]: Removal of a small part of the breast.
Once the tumor has been removed, if the person desires, [[breast reconstruction surgery]], a type of [[plastic surgery]], may then be performed to improve the aesthetic appearance of the treated site.
Alternatively, women use [[breast prostheses]] to simulate a breast under clothing, or choose a flat chest. [[Nipple prosthesis]] can be used at any time following the mastectomy.
=== Medication ===
Medications used after and in addition to surgery are called [[Adjuvant cancer therapy|adjuvant therapy]]. Chemotherapy or other types of therapy prior to surgery are called [[neoadjuvant therapy]]. [[Aspirin]] may reduce mortality from breast cancer when used with other treatments.<ref>{{cite journal | vauthors = Leite AM, Macedo AV, Jorge AJ, Martins WA | title = Antiplatelet Therapy in Breast Cancer Patients Using Hormonal Therapy: Myths, Evidence and Potentialities – Systematic Review | journal = Arquivos Brasileiros de Cardiologia | volume = 111 | issue = 2 | pages = 205–212 | date = August 2018 | pmid = 30183988 | pmc = 6122903 | doi = 10.5935/abc.20180138 }}</ref><ref>{{cite journal | vauthors = Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE | title = Aspirin intake and survival after breast cancer | journal = Journal of Clinical Oncology | volume = 28 | issue = 9 | pages = 1467–72 | date = March 2010 | pmid = 20159825 | pmc = 2849768 | doi = 10.1200/JCO.2009.22.7918 }}</ref>
There are currently three main groups of medications used for adjuvant breast cancer treatment: hormone-blocking agents, chemotherapy, and monoclonal antibodies.
====Hormonal therapy====
Some breast cancers require estrogen to continue growing. They can be identified by the presence of estrogen receptors (ER+) and progesterone receptors (PR+) on their surface (sometimes referred to together as hormone receptors). These ER+ cancers can be treated with drugs that either block the receptors, e.g. [[tamoxifen]], or alternatively block the production of estrogen with an [[aromatase inhibitor]], e.g. [[anastrozole]]<ref>{{cite journal | vauthors = Bao T, Rudek MA |s2cid = 1802863 |title = The Clinical Pharmacology of Anastrozole |journal = European Oncology & Haematology |volume = 7 |issue = 2 |pages = 106–8 |year = 2011 |doi = 10.17925/EOH.2011.07.02.106 |df = dmy-all }}</ref> or [[letrozole]]. The use of tamoxifen is recommended for 10 years.<ref>{{cite journal | vauthors = Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Rowden D, Solky AJ, Stearns V, Winer EP, Griggs JJ | display-authors = 6 | title = Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update | journal = Journal of Clinical Oncology | volume = 32 | issue = 21 | pages = 2255–69 | date = July 2014 | pmid = 24868023 | pmc = 4876310 | doi = 10.1200/JCO.2013.54.2258 }}</ref> Tamoxifen increases the risk of [[Vaginal bleeding|postmenopausal bleeding]], [[endometrial polyp]]s, [[hyperplasia]], and [[endometrial cancer]]; using tamoxifen with an [[intrauterine system]] releasing [[levonorgestrel]] might increase vaginal bleeding after 1 to 2 years, but reduces somewhat endometrial polyps and hyperplasia, but not necessarily endometrial cancer.<ref>{{Cite journal|vauthors=Romero SA, Young K, Hickey M, Su HI|date=21 December 2020|title=Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen|journal=Cochrane Database Syst Rev|volume=12|issue=2|pages=CD007245|doi=10.1002/14651858.CD007245.pub4|pmid=33348436|pmc=8092675}}</ref> Letrozole is recommended for five years.
Aromatase inhibitors are only suitable for women after menopause; however, in this group, they appear better than tamoxifen.<ref>{{cite journal | title = Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials | journal = Lancet | volume = 386 | issue = 10001 | pages = 1341–1352 | date = October 2015 | pmid = 26211827 | doi = 10.1016/S0140-6736(15)61074-1 | author1 = Early Breast Cancer Trialists' Collaborative Group (EBCTCG) | doi-access = free }}</ref> This is because the active aromatase in postmenopausal women is different from the prevalent form in premenopausal women, and therefore these agents are ineffective in inhibiting the predominant aromatase of premenopausal women.<ref>{{cite journal | vauthors = Petit T, Dufour P, Tannock I | title = A critical evaluation of the role of aromatase inhibitors as adjuvant therapy for postmenopausal women with breast cancer | journal = Endocrine-Related Cancer | volume = 18 | issue = 3 | pages = R79-89 | date = June 2011 | pmid = 21502311 | doi = 10.1530/ERC-10-0162 | doi-access = free }}</ref> Aromatase inhibitors should not be given to premenopausal women with intact ovarian function (unless they are also on treatment to stop their [[ovaries]] from working).<ref>{{cite web |url = http://www.uptodate.com/contents/treatment-of-metastatic-breast-cancer-beyond-the-basics |title = Treatment of metastatic breast cancer |website = www.uptodate.com |access-date = 4 September 2017 |url-status = live |archive-url = https://web.archive.org/web/20170904202736/http://www.uptodate.com/contents/treatment-of-metastatic-breast-cancer-beyond-the-basics?source=search_result&search=letrozole&selectedTitle=4~6 |archive-date = 4 September 2017 |df = dmy-all }}</ref> [[CDK inhibitor]]s can be used in combination with [[Goserelin|endocrine]] or aromatase therapy.<ref>{{Cite web|url=http://ascopost.com/issues/october-25-2016/combination-of-ribociclib-and-letrozole-is-a-home-run-in-advanced-breast-cancer/|title=Combination of Ribociclib and Letrozole Is a Home Run in Advanced Breast Cancer – The ASCO Post|website=ascopost.com|access-date=31 January 2019}}</ref>
====Chemotherapy====
[[Chemotherapy]] is predominantly used for cases of breast cancer in stages 2–4, and is particularly beneficial in estrogen receptor-negative (ER-) disease. The chemotherapy medications are administered in combinations, usually for periods of 3–6 months. One of the most common regimens, known as "AC", combines [[cyclophosphamide]] with [[doxorubicin]]. Sometimes a [[taxane]] drug, such as [[docetaxel]], is added, and the regime is then known as "CAT". Another common treatment is cyclophosphamide, [[methotrexate]], and [[fluorouracil]] (or "CMF"). Most chemotherapy medications work by destroying fast-growing and/or fast-replicating cancer cells, either by causing DNA damage upon replication or by other mechanisms. However, the medications also damage fast-growing normal cells, which may cause serious side effects. Damage to the heart muscle is the most dangerous complication of doxorubicin, for example.{{citation needed|date=March 2020}}
====Monoclonal antibodies====
[[Trastuzumab]], a monoclonal antibody to HER2, has improved the five-year disease free survival of stage 1–3 HER2-positive breast cancers to about 87% (overall survival 95%).<ref>{{cite journal | vauthors = Jahanzeb M | title = Adjuvant trastuzumab therapy for HER2-positive breast cancer | journal = Clinical Breast Cancer | volume = 8 | issue = 4 | pages = 324–33 | date = August 2008 | pmid = 18757259 | doi = 10.3816/CBC.2008.n.037 }}</ref> Between 25% and 30% of breast cancers [[overexpress]] the HER2 gene or its protein product,<ref>{{cite web |title = Entrez Gene: ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) |url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2064 |access-date = 17 November 2015 |url-status = live |archive-url = https://web.archive.org/web/20091026055528/http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2064 |archive-date = 26 October 2009 |df = dmy-all }}</ref> and overexpression of HER2 in breast cancer is associated with increased disease recurrence and worse prognosis. Trastuzumab, however, is very expensive, and its use may cause serious side effects (approximately 2% of people who receive it develop significant heart damage).<ref>{{cite web |url = http://www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp |title = Herceptin (trastuzumab) Adjuvant HER2+ Breast Cancer Therapy Pivotal Studies and Efficacy Data |publisher = Herceptin.com |access-date = 8 May 2010 |url-status = dead |archive-url = https://web.archive.org/web/20100406014305/http://www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp |archive-date = 6 April 2010 |df = dmy-all }}</ref> Another antibody [[pertuzumab]] prevents HER2 dimerization and is recommended together with [[Trastuzumab emtansine|trastuzumab]] and chemotherapy in severe disease.<ref>{{Cite web|url=https://www.breastcancer.org/research-news/new-guidelines-to-treat-advanced-her2-pos|title=New ASCO Guidelines on Treating Advanced-Stage HER2-Positive Breast Cancer|website=Breastcancer.org |date=4 October 2016 |access-date=31 January 2019}}</ref><ref>{{cite journal | vauthors = Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L | display-authors = 6 | title = Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 | journal = The New England Journal of Medicine | volume = 344 | issue = 11 | pages = 783–92 | date = March 2001 | pmid = 11248153 | doi = 10.1056/NEJM200103153441101 }}</ref>
=== Radiation ===
[[File:Diagram showing how you have internal radiotherapy for breast cancer CRUK 159.svg|thumb|right|Internal radiotherapy for breast cancer]]
[[Radiotherapy]] is given after surgery to the region of the tumor bed and regional lymph nodes, to destroy microscopic tumor cells that may have escaped surgery. When given intraoperatively as [[targeted intraoperative radiotherapy]], it may also have a beneficial effect on tumor microenvironment.<ref>{{cite journal |vauthors = Massarut S, Baldassare G, Belleti B, Reccanello S, D'Andrea S, Ezio C, Perin T, Roncadin M, Vaidya JS |title = Intraoperative radiotherapy impairs breast cancer cell motility induced by surgical wound fluid |journal = J Clin Oncol |volume = 24 |issue = 18S |page = 10611 |year = 2006 |url = http://www.asco.org/ASCOv2/Meetings/Abstracts?vmview=abst_detail_view&confID=40&abstractID=34291 |df = dmy-all |doi = 10.1200/jco.2006.24.18_suppl.10611 |access-date = 9 June 2010 |url-status = dead |archive-url = https://web.archive.org/web/20120112122626/http://www.asco.org/ASCOv2/Meetings/Abstracts?vmview=abst_detail_view&confID=40&abstractID=34291 |archive-date = 12 January 2012}}</ref><ref>{{cite journal | vauthors = Belletti B, Vaidya JS, D'Andrea S, Entschladen F, Roncadin M, Lovat F, Berton S, Perin T, Candiani E, Reccanello S, Veronesi A, Canzonieri V, Trovò MG, Zaenker KS, Colombatti A, Baldassarre G, Massarut S | display-authors = 6 | title = Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding | journal = Clinical Cancer Research | volume = 14 | issue = 5 | pages = 1325–32 | date = March 2008 | pmid = 18316551 | doi = 10.1158/1078-0432.CCR-07-4453 | doi-access = free }}</ref> Radiation therapy can be delivered as [[external beam radiotherapy]] or as [[brachytherapy]] (internal radiotherapy). Conventionally radiotherapy is given ''after'' the operation for breast cancer. Radiation can also be given at the time of operation on the breast cancer. Radiation can reduce the risk of recurrence by 50–66% (1/2 – 2/3 reduction of risk) when delivered in the correct dose<ref>{{cite web |url = http://www.breastcancer.org/treatment/radiation |title = Radiation Therapy |work = Breastcancer.org |access-date = 17 November 2015 |url-status = live |archive-url = https://web.archive.org/web/20151117193610/http://www.breastcancer.org/treatment/radiation |archive-date = 17 November 2015 |df = dmy-all }}</ref> and is considered essential when breast cancer is treated by removing only the lump (Lumpectomy or Wide local excision). In early breast cancer, partial breast irradiation does not give the same cancer control in the breast as treating the whole breast and may cause worse side effects.<ref>{{cite journal|vauthors=Hickey BE, Lehman M|date=August 30, 2021|title=Partial breast irradiation versus whole breast radiotherapy for early breast cancer|journal=The Cochrane Database of Systematic Reviews|volume=2021|issue=8|pages=CD007077|doi=10.1002/14651858.CD007077.pub4|pmid=34459500|pmc=8406917}}</ref>
=== Follow-up care ===
Care after primary breast cancer treatment, otherwise called 'follow-up care', can be intensive involving regular laboratory tests in asymptomatic people to try to achieve earlier detection of possible metastases. A review has found that follow-up programs involving regular physical examinations and yearly mammography alone are as effective as more intensive programs consisting of laboratory tests in terms of early detection of recurrence, overall survival and quality of life.<ref>{{cite journal | vauthors = Moschetti I, Cinquini M, Lambertini M, Levaggi A, Liberati A | title = Follow-up strategies for women treated for early breast cancer | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD001768 | date = May 2016 | volume = 2016 | pmid = 27230946 | doi = 10.1002/14651858.cd001768.pub3 | pmc = 7073405 }}</ref>
Multidisciplinary rehabilitation programmes, often including exercise, education and psychological help, may produce short-term improvements in functional ability, psychosocial adjustment and social participation in people with breast cancer.<ref>{{cite journal | vauthors = Khan F, Amatya B, Ng L, Demetrios M, Zhang NY, Turner-Stokes L | title = Multidisciplinary rehabilitation for follow-up of women treated for breast cancer | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD009553 | date = December 2012 | issue = 3 | pmid = 23235677 | doi = 10.1002/14651858.cd009553.pub2 | pmc = 8078577 }}</ref>
Upper limb problems such as shoulder and arm pain, weakness and restricted movement are a common side effect after radiotherapy or breast cancer surgery.<ref>{{cite journal | vauthors = Lee TS, Kilbreath SL, Refshauge KM, Herbert RD, Beith JM | title = Prognosis of the upper limb following surgery and radiation for breast cancer | journal = Breast Cancer Research and Treatment | volume = 110 | issue = 1 | pages = 19–37 | date = July 2008 | pmid = 17899373 | doi = 10.1007/s10549-007-9710-9 | s2cid = 24976113 }}</ref> According to research in the UK, an exercise programme started 7-10 days after surgery can reduce upper limb problems.<ref>{{Cite journal |date=2022-09-26 |title=Exercise programme improves arm function and pain after breast cancer surgery |url=https://evidence.nihr.ac.uk/alert/exercise-programme-improves-arm-function-pain-after-breast-cancer-surgery/ |journal=NIHR Evidence |type=Plain English summary |language=en |publisher=National Institute for Health and Care Research |doi=10.3310/nihrevidence_53632|s2cid=252562000 }}</ref><ref>{{cite journal | vauthors = Bruce J, Mazuquin B, Mistry P, Rees S, Canaway A, Hossain A, Williamson E, Padfield EJ, Lall R, Richmond H, Chowdhury L, Lait C, Petrou S, Booth K, Lamb SE, Vidya R, Thompson AM | display-authors = 6 | title = Exercise to prevent shoulder problems after breast cancer surgery: the PROSPER RCT | journal = Health Technology Assessment | volume = 26 | issue = 15 | pages = 1–124 | date = February 2022 | pmid = 35220995 | doi = 10.3310/JKNZ2003 | s2cid = 247157545 }}</ref>
== Prognosis ==
[[File:Breast reconstruction 15.jpg|thumb|Breasts after double mastectomy followed by nipple-sparing reconstruction with implants]]
[[File:RecurrentbreastCA1.gif|thumb|An extreme example of an advanced recurrent breast cancer with an ulcerating axillary mass]]
=== Prognostic factors ===
The [[Breast cancer classification#Stage|stage]] of the breast cancer is the most important component of traditional classification methods of breast cancer, because it has a greater effect on the prognosis than the other considerations. Staging takes into consideration size, local involvement, lymph node status and whether metastatic disease is present. The higher the stage at diagnosis, the poorer the prognosis. The stage is raised by the invasiveness of disease to lymph nodes, chest wall, skin or beyond, and the aggressiveness of the cancer cells. The stage is lowered by the presence of cancer-free zones and close-to-normal cell behaviour (grading). Size is not a factor in staging unless the cancer is invasive. For example, ductal carcinoma in situ (DCIS) involving the entire breast will still be stage zero and consequently an excellent prognosis with a 10-year disease free survival of about 98%.<ref>{{cite web |url = http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html |title = Breast Cancer: Breast Disorders: Merck Manual Professional |publisher = Merck.com |access-date = 8 May 2010 |url-status = live |archive-url = https://web.archive.org/web/20111110075702/http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html |archive-date = 10 November 2011 |df = dmy-all }}</ref>
* Stage 1 cancers (and DCIS, LCIS) have an excellent prognosis and are generally treated with lumpectomy and sometimes radiation.<ref>{{cite web |url = http://www.stopcancerfund.org/wp/wp-content/uploads/2009/12/booklet04bc.pdf |title = Surgery Choices for Women with Early Stage Breast Cancer |publisher = National Cancer Institute and the National Research Center for Women & Families |date = August 2004 |url-status = dead |archive-url = https://web.archive.org/web/20130813054115/http://www.stopcancerfund.org/wp/wp-content/uploads/2009/12/booklet04bc.pdf |archive-date = 13 August 2013 }}</ref>
* Stage 2 and 3 cancers with a progressively poorer prognosis and greater risk of recurrence are generally treated with surgery (lumpectomy or mastectomy with or without [[Lymphadenectomy|lymph node removal]]), chemotherapy (plus [[trastuzumab]] for HER2+ cancers) and sometimes radiation (particularly following large cancers, multiple positive nodes or lumpectomy).{{medcn|date=May 2018}}
* Stage 4, metastatic cancer, (i.e. spread to distant sites) has a poor prognosis and is managed by various combination of all treatments from surgery, radiation, chemotherapy and targeted therapies. Ten-year survival rate is 5% without treatment and 10% with optimal treatment.<ref>{{cite web |url = http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html |title = Breast Cancer: Breast Disorders: Merck Manual Professional |publisher = Merck.com |access-date = 14 November 2010 |url-status = live |archive-url = https://web.archive.org/web/20111110075702/http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html |archive-date = 10 November 2011 |df = dmy-all }}</ref>
[[Breast cancer classification#Grade|The breast cancer grade]] is assessed by comparison of the breast cancer cells to normal breast cells. The closer to normal the cancer cells are, the slower their growth and the better the prognosis. If cells are not well differentiated, they will appear immature, will divide more rapidly, and will tend to spread. Well differentiated is given a grade of 1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4 (depending upon the scale used). The most widely used grading system is the Nottingham scheme.<ref>{{cite journal | vauthors = Elston CW, Ellis IO | title = Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up | journal = Histopathology | volume = 19 | issue = 5 | pages = 403–10 | date = November 1991 | pmid = 1757079 | doi = 10.1111/j.1365-2559.1991.tb00229.x | s2cid = 17622089 }}</ref>
Younger women with an age of less than 40 years or women over 80 years tend to have a poorer prognosis than post-menopausal women due to several factors. Their breasts may change with their menstrual cycles, they may be nursing infants, and they may be unaware of changes in their breasts. Therefore, younger women are usually at a more advanced stage when diagnosed. There may also be biological factors contributing to a higher risk of disease recurrence for younger women with breast cancer.<ref>{{cite journal | vauthors = Peppercorn J |title = Breast Cancer in Women Under 40 |journal = Oncology |volume = 23 |issue = 6 |pages = 465–74 |year = 2009 |url = http://www.cancernetwork.com/cme/article/10165/1413886 |url-status = live |archive-url = https://web.archive.org/web/20090616191104/http://www.cancernetwork.com/cme/article/10165/1413886 |archive-date = 16 June 2009 |df = dmy-all |pmid = 19544685 }}</ref>
=== Psychological aspects ===
Not all people with breast cancer experience their illness in the same manner. Factors such as age can have a significant impact on the way a person copes with a breast cancer diagnosis. Premenopausal women with estrogen-receptor positive breast cancer must confront the issues of early [[menopause]] induced by many of the chemotherapy regimens used to treat their breast cancer, especially those that use hormones to counteract ovarian function.<ref>{{cite journal | vauthors = Pritchard KI |title = Ovarian Suppression/Ablation in Premenopausal ER-Positive Breast Cancer Patients |journal = Oncology |volume = 23 |issue = 1 |year = 2009 |url = http://www.cancernetwork.com/display/article/10165/1366719?pageNumber=1 |url-status = live |archive-url = https://web.archive.org/web/20090705230857/http://www.cancernetwork.com/display/article/10165/1366719?pageNumber=1 |archive-date = 5 July 2009 |df = dmy-all }}</ref>
In women with non-metastatic breast cancer, psychological interventions such as [[cognitive behavioral therapy]] can have positive effects on outcomes such as anxiety, depression and mood disturbance.<ref>{{cite journal | vauthors = Jassim GA, Whitford DL, Hickey A, Carter B | title = Psychological interventions for women with non-metastatic breast cancer | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD008729 | date = May 2015 | pmid = 26017383 | doi = 10.1002/14651858.cd008729.pub2 }}</ref> Physical activity interventions may also have beneficial effects on health related quality of life, anxiety, fitness and physical activity in women with breast cancer following adjuvant therapy.<ref>{{cite journal | vauthors = Lahart IM, Metsios GS, Nevill AM, Carmichael AR | title = Physical activity for women with breast cancer after adjuvant therapy | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD011292 | date = January 2018 | pmid = 29376559 | pmc = 6491330 | doi = 10.1002/14651858.cd011292.pub2 }}</ref>
== Epidemiology ==
{{Main|Epidemiology of breast cancer}}
[[File:Breast cancer world map - Death - WHO2004.svg|thumb|upright=1.25|[[Age adjustment|Age-standardized]] death from breast cancer per 100,000 inhabitants in 2004<ref>{{cite web|url=https://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html|title=WHO Disease and injury country estimates|year=2009|work=World Health Organization|access-date=11 November 2009|archive-url= https://web.archive.org/web/20091111101009/http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html|archive-date=11 November 2009|url-status=live}}</ref>
{{Col-begin}}
{{Col-break}}
{{legend|#b3b3b3|no data}}
{{legend|#ffff65|<2}}
{{legend|#fff200|2–4}}
{{legend|#ffdc00|4–6}}
{{legend|#ffc600|6–8}}
{{legend|#ffb000|8–10}}
{{legend|#ff9a00|10–12}}
{{Col-break}}
{{legend|#ff8400|12–14}}
{{legend|#ff6e00|14–16}}
{{legend|#ff5800|16–18}}
{{legend|#ff4200|18–20}}
{{legend|#ff2c00|20–22}}
{{legend|#cb0000|>22}}
{{col-end}} ]]
Worldwide, breast cancer is the most-common invasive cancer in women.<ref name=Malone2015 /> Along with lung cancer, breast cancer is the most commonly diagnosed cancer, with 2.09 million cases each in 2018.<ref>{{cite web|url=https://www.who.int/news-room/fact-sheets/detail/cancer| title=Cancer| website=World Health Organization| date=12 September 2018 | access-date=16 July 2020}}</ref> Breast cancer affects 1 in 7 (14%) of women worldwide.<ref name=genetics2019>{{cite journal |vauthors=Balasubramanian R, Rolph R, Morgan C, Hamed H |title=Genetics of breast cancer: management strategies and risk-reducing surgery. |journal=Br J Hosp Med (Lond) |volume=80 |issue=12 |pages=720–725 |date=2019 |pmid= 31822191 |doi=10.12968/hmed.2019.80.12.720|s2cid=209314404 }}</ref> (The most common form of cancer is non-invasive [[Skin neoplasm|non-melanoma skin cancer]]; non-invasive cancers are generally easily cured, cause very few deaths, and are routinely excluded from cancer statistics.) Breast cancer comprises 22.9% of invasive cancers in women<ref name="IARC GLOBOCAN 2008">{{cite web |publisher = [[International Agency for Research on Cancer]] |year = 2008 |title = World Cancer Report |url = http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/ |access-date = 26 February 2011 |url-status = dead |archive-url = https://web.archive.org/web/20111231111259/http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/ |archive-date = 31 December 2011 |df = dmy-all }} (cancer statistics often exclude non-melanoma skin cancers such as [[basal-cell carcinoma]], which are common but rarely fatal)</ref> and 16% of all female cancers.<ref>{{cite web |url =https://www.who.int/cancer/detection/breastcancer/en/index1.html |title = Breast cancer: prevention and control |work = World Health Organization |url-status = dead |archive-url = https://web.archive.org/web/20150906121739/http://www.who.int/cancer/detection/breastcancer/en/index1.html |archive-date = 6 September 2015 }}</ref> In 2012, it comprised 25.2% of cancers diagnosed in women, making it the most-common female cancer.<ref>{{cite book |title = World Cancer Report 2014 |publisher = International Agency for Research on Cancer, World Health Organization |date = 2014 |isbn = 978-92-832-0432-9 }}</ref>
In 2008, breast cancer caused 458,503 deaths worldwide (13.7% of cancer deaths in women and 6.0% of all cancer deaths for men and women together).<ref name="IARC GLOBOCAN 2008" /> Lung cancer, the second most-common cause of cancer-related deaths in women, caused 12.8% of cancer deaths in women (18.2% of all cancer deaths for men and women together).<ref name="IARC GLOBOCAN 2008" />
The incidence of breast cancer varies greatly around the world: it is lowest in less-developed countries and greatest in the more-developed countries. In the twelve world regions, the annual age-standardized [[incidence rate]]s per 100,000 women are as follows: 18 in Eastern Asia, 22 in South Central Asia and sub-Saharan Africa, 26 in South-Eastern Asia, 26, 28 in North Africa and Western Asia, 42 in South and Central America, 42, 49 in Eastern Europe, 56 in Southern Europe, 73 in Northern Europe, 74 in Oceania, 78 in Western Europe, and 90 in North America.<ref>{{Cite web|url=https://www.scribd.com/doc/2350813/World-Cancer-Report-2003-Stuart-e-Kleihues-WHO-e-IARC|archiveurl=https://web.archive.org/web/20081020000016/http://www.scribd.com/doc/2350813/World-Cancer-Report-2003-Stuart-e-Kleihues-WHO-e-IARC|url-status=dead|title=Stewart B. W. and Kleihues P. (Eds): World Cancer Report. IARCPress. Lyon 2003|archivedate=20 October 2008}}</ref> Metastatic breast cancer affects between 19% (United States) and 50% (parts of Africa) of women with breast cancer.<ref>{{cite book | veditors = Wyld L, Markopoulos C, Leidenius M, Senkus-Konefka E |title=Breast cancer management for surgeons : a European multidisciplinary textbook |date=2018 |publisher=Springer |isbn=978-3-319-56671-9 |page=580}}</ref>
The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly attributed to the modern lifestyles.<ref name=indy>{{Cite news | vauthors = Laurance J |title = Breast cancer cases rise 80% since Seventies |work = [[The Independent]] |date = 29 September 2006 |url = https://www.independent.co.uk/life-style/health-and-wellbeing/health-news/breast-cancer-cases-rise-80-since-seventies-417990.html |location = London |access-date = 9 October 2006 |url-status = dead |archive-url = https://web.archive.org/web/20080425022457/http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/breast-cancer-cases-rise-80-since-seventies-417990.html |archive-date = 25 April 2008 }}</ref><ref>{{cite web |title = Breast Cancer: Statistics on Incidence, Survival, and Screening |publisher = Imaginis Corporation |year = 2006 |url = http://imaginis.com/breasthealth/statistics.asp |access-date = 9 October 2006 |url-status = live |archive-url = https://web.archive.org/web/20061024120910/http://www.imaginis.com/breasthealth/statistics.asp |archive-date = 24 October 2006 |df = dmy-all }}</ref> Breast cancer is strongly related to age with only 5% of all breast cancers occurring in women under 40 years old.<ref>[http://www.webmd.com/breast-cancer/guide/breast-cancer-young-women Breast Cancer: Breast Cancer in Young Women] {{webarchive|url=https://web.archive.org/web/20090910015335/http://www.webmd.com/breast-cancer/guide/breast-cancer-young-women |date=10 September 2009 }} WebMD. Retrieved 9 September 2009</ref> There were more than 41,000 newly diagnosed cases of breast cancer registered in England in 2011, around 80% of these cases were in women age 50 or older.<ref>[http://www.ons.gov.uk/ons/rel/vsob1/cancer-statistics-registrations--england--series-mb1-/no--42--2011/sty-breast-cancer-survival.html Nearly 85% of women diagnosed with breast cancer now survive for 5 year or more] {{webarchive|url=https://web.archive.org/web/20131105085823/http://www.ons.gov.uk/ons/rel/vsob1/cancer-statistics-registrations--england--series-mb1-/no--42--2011/sty-breast-cancer-survival.html |date=5 November 2013 }} Office for National Statistics, 2013</ref> Based on U.S. statistics in 2015 there were 2.8 million women affected by breast cancer.<ref name="Malone2015">{{cite journal | vauthors = McGuire A, Brown JA, Malone C, McLaughlin R, Kerin MJ | title = Effects of age on the detection and management of breast cancer | journal = Cancers | volume = 7 | issue = 2 | pages = 908–29 | date = May 2015 | pmid = 26010605 | pmc = 4491690 | doi = 10.3390/cancers7020815 | doi-access = free }}</ref> In the United States, the [[age adjustment|age-adjusted incidence]] of breast cancer per 100,000 women rose from around 102 cases per year in the 1970s to around 141 in the late-1990s, and has since fallen, holding steady around 125 since 2003. However, age-adjusted deaths from breast cancer per 100,000 women only rose slightly from 31.4 in 1975 to 33.2 in 1989 and have since declined steadily to 20.5 in 2014.<ref>[https://seer.cancer.gov/statfacts/html/breast.html Cancer Stat Facts: Female Breast Cancer], U.S. National Cancer Institute, accessed 16 February 2018</ref>
== Multiple primary tumours ==
<!--- Please note that the page Multi-centric breast cancer redirects to this section --->
[[File:Breast_quadrants_ABC.svg|thumb|Quadrants of breast.]]
Multiple primary tumours can arise in different sites (as opposed to a single tumour spreading). These tumours can occur in both breasts (bilateral tumours), in different quadrants of a single breast (multi-centric cancer), or separate tumours within a single breast quadrant (multi-focal cancer).<ref name =Coombs>{{cite journal | vauthors = Coombs NJ, Boyages J | title = Multifocal and multicentric breast cancer: does each focus matter? | journal = Journal of Clinical Oncology | volume = 23 | issue = 30 | pages = 7497–7502 | date = October 2005 | pmid = 16234516 | doi = 10.1200/JCO.2005.02.1147 }}</ref><ref name="Neri">{{cite journal | vauthors = Neri A, Marrelli D, Megha T, Bettarini F, Tacchini D, De Franco L, Roviello F | title = "Clinical significance of multifocal and multicentric breast cancers and choice of surgical treatment: a retrospective study on a series of 1158 cases" | journal = BMC Surgery | volume = 15 | pages = 1 | date = January 2015 | pmid = 25586679 | pmc = 4324662 | doi = 10.1186/1471-2482-15-1 }}</ref>
Incidence of multi-centric and multi-focal breast cancers (MMBC) is increasing, partly due to improving mammography technology.<ref name="Lang">{{cite journal | vauthors = Lang Z, Wu Y, Li C, Li X, Wang X, Qu G | title = Multifocal and Multicentric Breast Carcinoma: A Significantly More Aggressive Tumor than Unifocal Breast Cancer | journal = Anticancer Research | volume = 37 | issue = 8 | pages = 4593–4598 | date = August 2017 | pmid = 28739757 | doi = 10.21873/anticanres.11858 }}</ref> Incidence of MMBC is reported between 9 and 75% in high income countries, depending on criteria used.<ref name="Lang" /> For instance, China reported that only 2% of patients are defined as MMBC.<ref name="Lang" /> The reason for this difference is due to lack of uniformity in diagnosis.<ref name="Lang" /> Therefore, standardised method and criteria should be made in order to define the incidence of MMBC correctly.<ref name="Lang" />
Mutations in [[tumour suppressor gene]]s such as [[BRCA mutation|BRCA1 and BRCA2]], the [[PI3K/AKT/mTOR pathway]] and [[PTEN (gene)|PTEN]] can be related to formation of multiple primary breast cancers.<ref name="Narod">{{cite journal | vauthors = Narod SA | title = Bilateral breast cancers | journal = Nature Reviews. Clinical Oncology | volume = 11 | issue = 3 | pages = 157–166 | date = March 2014 | pmid = 24492834 | doi = 10.1038/nrclinonc.2014.3 | s2cid = 601112 }}</ref> Diagnosis occurs via the same modalities as other breast cancers.
[[Mastectomy]] is the standard surgical treatment for multi centric breast cancer patients.<ref>{{Cite web |title=Breast-conserving Surgery (Lumpectomy) {{!}} Treating Breast Cancer |url=https://www.cancer.org/cancer/breast-cancer/treatment/surgery-for-breast-cancer/breast-conserving-surgery-lumpectomy.html |access-date=2022-03-24 |website=www.cancer.org |language=en}}</ref> Double [[Lumpectomy|lumpectomies]], also labelled as breast conservative therapy (BCT), is an alternative and preferred surgical treatment to [[mastectomy]] for early stage multi centric breast cancer patients.<ref name="pubmed.ncbi.nlm.nih.gov">{{cite journal | vauthors = Kapoor NS, Chung A, Huynh K, Giuliano AE | title = Preliminary results: double lumpectomies for multicentric breast carcinoma | journal = The American Surgeon | volume = 78 | issue = 12 | pages = 1345–1348 | date = December 2012 | pmid = 23265123 | doi = 10.1177/000313481207801226 | s2cid = 26112023 }}</ref> The procedure of double lumpectomies involves the surgical ablation of the cancerous tumour foci and the surrounding breast tissues in different quadrant of the same breast.<ref name="pubmed.ncbi.nlm.nih.gov"/> The benefits of double lumpectomies are the avoidance of breast reconstruction surgery and minimal breast scarring. However, this surgical treatment is not preferable for patients with over two breast tumours within the same breast due to difficulty in removing all cancer cells.<ref name="ReferenceA"/> Patients with multiple primary breast tumours may receive treatments such as chemotherapy, radiotherapy and [[breast reconstruction surgery]]<ref>{{Cite web |title=Another Study Looks at Quality of Life After Preventive Mastectomy |url=https://www.breastcancer.org/research-news/quality-of-life-after-preventive-mastectomy |access-date=2022-03-24 |website=www.breastcancer.org}}</ref><ref name="ReferenceA">{{cite journal | vauthors = Nguyen QD, Tavana A, Sadruddin S, Chao C | title = Successful Lumpectomy in a Patient With Multicentric Breast Cancer | journal = Cureus | volume = 12 | issue = 8 | pages = e10072 | date = August 2020 | pmid = 32999790 | pmc = 7522052 | doi = 10.7759/cureus.10072 }}</ref> for the same indications as other breast cancer patients.
== History ==
[[File:Louis-Jacques Goussier Enzyklopädie Diderot Pl XXIX.jpg|thumb|Breast cancer surgery in 18th century]]
Because of its visibility, breast cancer was the form of cancer most often described in ancient documents.<ref name="Olson_2002">{{cite book | vauthors = Olson JS |title = Bathsheba's breast: women, cancer & history |publisher = The Johns Hopkins University Press |year = 2002 |isbn = 978-0-8018-6936-5}}</ref>{{rp|9–13}} Because autopsies were rare, cancers of the internal organs were essentially invisible to ancient medicine. Breast cancer, however, could be felt through the skin, and in its advanced state often developed into [[fungating lesion]]s: the tumor would become [[necrotic]] (die from the inside, causing the tumor to appear to break up) and [[Ulcer (dermatology)|ulcerate]] through the skin, weeping fetid, dark fluid.<ref name="Olson_2002" />{{rp|9–13}}
The oldest discovered evidence of breast cancer is from Egypt and dates back 4200 years, to the [[Sixth Dynasty]].<ref name="reuters">{{Cite news |url = http://in.reuters.com/article/egypt-antiquities-cancer-idINKBN0MK1ZW20150324 |title = Oldest evidence of breast cancer found in Egyptian skeleton |date = 24 March 2015 |access-date = 25 March 2015 |url-status = live |archive-url = https://web.archive.org/web/20150327023314/http://in.reuters.com/article/2015/03/24/egypt-antiquities-cancer-idINKBN0MK1ZW20150324 |archive-date = 27 March 2015 |df = dmy-all |newspaper = Reuters }}</ref> The study of a woman's remains from the necropolis of [[Qubbet el-Hawa]] showed the typical destructive damage due to [[metastatic]] spread.<ref name="reuters" /> The [[Edwin Smith Papyrus]] describes eight cases of tumors or ulcers of the breast that were treated by [[cauterization]]. The writing says about the disease, "There is no treatment."<ref>{{cite web |title = The History of Cancer |work = American Cancer Society |date = 25 March 2002 |url = http://www.cancer.org/docroot/CRI/content/CRI_2_6x_the_history_of_cancer_72.asp?sitearea=CRI |access-date = 9 October 2006 |url-status = dead |archive-url = https://web.archive.org/web/20061009011530/http://www.cancer.org/docroot/CRI/content/CRI_2_6x_the_history_of_cancer_72.asp?sitearea=CRI |archive-date = 9 October 2006 |df = dmy-all }}</ref> For centuries, physicians described similar cases in their practices, with the same conclusion. Ancient medicine, from the time of the Greeks through the 17th century, was based on [[humoralism]], and thus believed that breast cancer was generally caused by imbalances in the fundamental fluids that controlled the body, especially an excess of [[black bile]].<ref name="Olson_2002" />{{rp|32}} Alternatively it was seen as [[divine punishment]].<ref name="Yalom">{{cite book | vauthors = Yalom M |title = A history of the breast |publisher = Alfred A. Knopf |location = New York |year = 1997 |page = [https://archive.org/details/historyofbreast00yalo/page/234 234] |isbn = 978-0-679-43459-7 |url = https://archive.org/details/historyofbreast00yalo/page/234 }}</ref>
Mastectomy for breast cancer was performed at least as early as AD 548, when it was proposed by the court physician [[Aetios of Amida]] to [[Theodora (wife of Justinian I)|Theodora]].<ref name="Olson_2002" />{{rp|9–13}} It was not until doctors achieved greater understanding of the circulatory system in the 17th century that they could link breast cancer's spread to the [[lymph nodes]] in the armpit. In the early 18th century the French surgeon [[Jean Louis Petit]] performed total mastectomies that included removing the [[axillary lymph nodes]], as he recognized that this reduced recurrence.<ref name="Faguet 2015">{{cite book| vauthors = Faguet G |title=The Conquest of Cancer: A Distant Goal|date=2015|isbn=9789401791656|page=24|chapter=Chapter 2: An Historical Overview: From Prehistory to WWII. From Medieval Europe to World War II}}</ref> Petit's work built on the methods of the surgeon [[Bernard Peyrilhe]], who in the 17th century additionally removed the [[pectoralis major muscle|pectoral muscle]] underlying the breast, as he judged that this greatly improved the prognosis.<ref>{{cite book| vauthors = Kaartinen M |title=Breast cancer in the eighteenth century|date=2013|publisher=Pickering & Chatto|location=London|isbn=978-1-84893-364-4|page=53|chapter=Chapter 2: "But Sad Resources": Treating Cancer in the Eighteenth Century}}</ref> But poor results and the considerable risk to the patient meant that physicians did not share the opinion of surgeons such as [[Nicolaes Tulp]], who in the 17th century proclaimed "the sole remedy is a timely operation". The eminent surgeon [[Richard Wiseman (surgeon)|Richard Wiseman]] documented in the mid 17th century that following 12 mastectomies, two patients died during the operation, eight patients died shortly after the operation from progressive cancer and only two of the 12 patients were cured.<ref name="Winchester_2006">{{Cite book|title=Breast Cancer | vauthors = Winchester DJ, Winchester DP, Hudis CA, Norton L |publisher=PMPH-USA|year=2006|isbn= 9781550092721 }}</ref>{{rp|6}} Physicians were conservative in the treatment they prescribed in the early stages of breast cancer. Patients were treated with a mixture of [[Detoxification (alternative medicine)|detox purges]], [[blood letting]] and traditional remedies that were supposed to lower acidity, such as the alkaline [[arsenic]].<ref name = "de_Moulin_2013">{{Cite book|title=A short history of breast cancer | vauthors = de Moulin D |publisher=Springer Science & Business Media|year=2013|isbn= 9789401706018 }}</ref>{{rp|24}}
When in 1664 [[Anne of Austria]] was diagnosed with breast cancer, the initial treatment involved compresses saturated with [[Conium|hemlock]] juice. When the lumps increased the King's physician commenced a treatment with arsenic [[ointment]]s.<ref name = "de_Moulin_2013" />{{rp|25}} The royal patient died 1666 in atrocious pain.<ref name = "de_Moulin_2013" />{{rp|26}} Each failing treatment for breast cancer led to the search for new treatments, spurring a market in remedies that were advertised and sold by [[quackery|quacks]], [[herbalist]]s, [[chemist]]s and [[apothecaries]].<ref>{{Cite book|title=Pain and Emotion in Modern History | vauthors = Boddice RG |publisher=Springer|year=2014|isbn= 9781137372437|pages=24}}</ref> The lack of [[anesthesia]] and [[antiseptics]] made [[mastectomy]] a painful and dangerous ordeal.<ref name="Winchester_2006"/> In the 18th century, a wide variety of anatomical discoveries were accompanied by new theories about the cause and growth of breast cancer. The investigative surgeon [[John Hunter (surgeon)|John Hunter]] claimed that neural fluid generated breast cancer. Other surgeons proposed that milk within the [[mammary duct]]s led to cancerous growths. Theories about trauma to the breast as cause for [[malignant]] changes in breast tissue were advanced. The discovery of [[breast lump]]s and swellings fueled controversies about hard [[tumor]]s and whether lumps were benign stages of cancer. Medical opinion about necessary immediate treatment varied.<ref name="Winchester_2006" />{{rp|5}} The surgeon [[Benjamin Bell]] advocated removal of the entire breast, even when only a portion was affected.<ref>{{cite journal | vauthors = Macintyre IM | title = Scientific surgeon of the Enlightenment or 'plagiarist in everything': a reappraisal of Benjamin Bell (1749–1806) | journal = The Journal of the Royal College of Physicians of Edinburgh | volume = 41 | issue = 2 | pages = 174–81 | date = June 2011 | pmid = 21677925 | doi = 10.4997/JRCPE.2011.211 | doi-access = free }}{{open access}}</ref>
[[File:William Stewart Halsted, Surgical papers Wellcome L0004968.jpg|thumb|Radical mastectomy, Halsted's surgical papers]]
Breast cancer was uncommon until the 19th century, when improvements in sanitation and control of deadly [[infectious disease]]s resulted in dramatic increases in lifespan. Previously, most women had died too young to have developed breast cancer.<ref name="Aronowitz">{{cite book | vauthors = Aronowitz RA |title = Unnatural history: breast cancer and American society |publisher = Cambridge University Press |location = Cambridge, UK |year = 2007 |pages = [https://archive.org/details/unnaturalhistory00aron/page/22 22–24] |isbn = 978-0-521-82249-7 |url = https://archive.org/details/unnaturalhistory00aron/page/22 }}</ref> In 1878, an article in ''[[Scientific American]]'' described historical treatment by pressure intended to induce local ischemia in cases when surgical removal were not possible.<ref>{{Cite book|url=https://books.google.com/books?id=p4o9AQAAIAAJ|title=Scientific American, "The Treatment of Cancer by Pressure"|date=10 August 1878|publisher=Munn & Company|pages=86|language=en}}</ref> [[William Stewart Halsted]] started performing [[radical mastectomies]] in 1882, helped greatly by advances in general surgical technology, such as [[aseptic technique]] and anesthesia. The Halsted radical mastectomy often involved removing both breasts, associated lymph nodes, and the underlying chest muscles. This often led to long-term pain and disability, but was seen as necessary to prevent the cancer from recurring..<ref name="Olson_2002" />{{rp|102–106}} Before the advent of the Halsted radical mastectomy, 20-year survival rates were only 10%; Halsted's surgery raised that rate to 50%.<ref name="Olson_2002" />{{rp|1}}
[[Cancer staging|Breast cancer staging system]]s were developed in the 1920s and 1930s to determining the extent to which a cancer has developed by growing and spreading..<ref name="Olson_2002" />{{rp|102–106}} The first [[case-control]]led study on breast cancer epidemiology was done by [[Janet Lane-Claypon]], who published a comparative study in 1926 of 500 breast cancer cases and 500 controls of the same background and lifestyle for the British Ministry of Health.<ref name="isbn3-7643-6818-7">{{Cite book | vauthors = Morabia A |title = A History of Epidemiologic Methods and Concepts |publisher = Birkhauser |location = Boston |year = 2004 |pages = 301–302 |isbn = 978-3-7643-6818-0 |url = https://books.google.com/books?id=E-OZbEmPSTkC&pg=PA301 |access-date = 31 December 2007 }}</ref> Radical mastectomies remained the standard of care in the USA until the 1970s, but in Europe, breast-sparing procedures, often followed by [[radiation therapy]], were generally adopted in the 1950s..<ref name="Olson_2002" />{{rp|102–106}} In 1955 [[George Crile Jr.]] published ''Cancer and Common Sense'' arguing that cancer patients needed to understand available treatment options. Crile became a close friend of the environmentalist [[Rachel Carson]], who had undergone a Halsted radical mastectomy in 1960 to treat her malign breast cancer.<ref name = "Knopf-Newman_2004">{{Cite book|title=Beyond Slash, Burn, and Poison: Transforming Breast Cancer Stories Into Action | vauthors = Knopf-Newman MJ |publisher= Rutgers University Press|year=2004|isbn=9780813534718 }}</ref>{{rp|39–40}} The US oncologist [[Jerome Urban]] promoted superradical mastectomies, taking even more tissue, until 1963, when the ten-year survival rates proved equal to the less-damaging radical mastectomy.<ref name="Olson_2002" />{{rp|102–106}} Carson died in 1964 and Crile went on to published a wide variety of articles, both in the popular press and in medical journals, challenging the widespread used of the Halsted radical mastectomy. In 1973 Crile published ''What Women Should Know About the Breast Cancer Controversy''. When in 1974 [[Betty Ford]] was diagnosed with breast cancer, the options for treating breast cancer were openly discussed in the press.<ref name = "Knopf-Newman_2004" />{{rp|58}} During the 1970s, a new understanding of [[metastasis]] led to perceiving cancer as a systemic illness as well as a localized one, and more sparing procedures were developed that proved equally effective.<ref name="Lax">{{cite book | vauthors = Lacroix M |title = A Concise History of Breast Cancer |publisher = Nova Science Publishers |location = USA |year = 2011 |pages = 59–68 |isbn = 978-1-61122-305-7 }}</ref>
In the 1980s and 1990s, thousands of women who had successfully completed standard treatment then demanded and received high-dose [[bone marrow transplant]]s, thinking this would lead to better long-term survival. However, it proved completely ineffective, and 15–20% of women died because of the brutal treatment.<ref name="Sulik_2010">{{cite book | vauthors = Sulik GA |title = Pink Ribbon Blues: How Breast Cancer Culture Undermines Women's Health |url = https://archive.org/details/pinkribbonbluesh0000suli |url-access = registration |publisher = Oxford University Press |location = USA |year = 2010 |isbn = 978-0-19-974045-1 |oclc = 535493589 }}</ref>{{rp|200–203}} The 1995 reports from the [[Nurses' Health Study]] and the 2002 conclusions of the [[Women's Health Initiative]] trial conclusively proved that [[Hormone replacement therapy (menopause)|hormone replacement therapy]] significantly increased the incidence of breast cancer.<ref name="Sulik_2010" />
== Society and culture ==
{{See also|Breast cancer awareness|List of people with breast cancer}}
Before the 20th century, breast cancer was feared and discussed in hushed tones, as if it were shameful. As little could be safely done with primitive surgical techniques, women tended to suffer silently rather than seeking care.{{citation needed|date=June 2022}} When surgery advanced, and long-term survival rates improved, women began [[raising awareness]] of the disease and the possibility of successful treatment. The "Women's Field Army", run by the American Society for the Control of Cancer (later the [[American Cancer Society]]) during the 1930s and 1940s was one of the first organized campaigns. In 1952, the first peer-to-peer [[support group]], called "Reach to Recovery", began providing post-mastectomy, in-hospital visits from women who had survived breast cancer.<ref name="Sulik_2010" />{{rp|37–38}}
The [[breast cancer movement]] of the 1980s and 1990s developed out of the larger [[feminist movement]]s and [[Women's health movement in the United States|women's health movement]] of the 20th century.<ref name="Sulik_2010" />{{rp|4}} This series of political and educational campaigns, partly inspired by the politically and socially effective AIDS awareness campaigns, resulted in the widespread acceptance of second opinions before surgery, less invasive surgical procedures, support groups, and other advances in care.<ref>{{cite web |url = http://www.crcfl.net/content/view/history-of-breast-cancer-advocacy.html |title = History of Breast Cancer Advocacy | vauthors = Riter B |publisher = Cancer Resource Center of the Finger Lakes |access-date = 29 June 2013 |url-status = dead |archive-url = https://web.archive.org/web/20130623074930/http://www.crcfl.net/content/view/history-of-breast-cancer-advocacy.html |archive-date = 23 June 2013 |df = dmy-all }}</ref>
=== Pink ribbon ===
[[File:Pink ribbon.svg|upright|thumb|The [[pink ribbon]] is a symbol to show support for breast cancer awareness.]]
{{Main|Pink ribbon}}
A [[pink ribbon]] is the most prominent symbol of breast cancer awareness. Pink ribbons, which can be made inexpensively, are sometimes sold as fundraisers, much like [[Poppy day#Poppies|poppies on Remembrance Day]]. They may be worn to honor those who have been diagnosed with breast cancer, or to identify products that the manufacturer would like to sell to consumers that are interested in breast cancer.<ref name="Sulik_2010" />{{rp|27–72}} In the 1990s breast cancer awareness campaigns were launched by US based corporations. As part of these [[cause related marketing]] campaigns corporations donated to a variety of breast cancer initiatives for every pink ribbon product that was purchased.<ref name = "Klawiter_2008">{{cite book | vauthors = Klawiter M |title = The Biopolitics of Breast Cancer: Changing Cultures of Disease and Activism |publisher = University of Minnesota Press |year = 2008 |isbn = 9780816651078 }}</ref>>{{rp|132–133}} ''[[The Wall Street Journal]]'' noted "that the strong emotions provoked by breast cancer translate to a company's [[bottom line]]". While many US corporations donated to existing breast cancer initiatives others such as [[Avon Products|Avon]] established their own breast cancer foundations on the back of pink ribbon products.<ref name = "Klawiter_2008" />{{rp|135–136}}
Wearing or displaying a pink ribbon has been criticized by the opponents of this practice as a kind of [[slacktivism]], because it has no practical positive effect. It has also been criticized as [[hypocrisy]], because some people wear the pink ribbon to show good will towards women with breast cancer, but then oppose these women's practical goals, like [[patient rights]] and [[anti-pollution legislation]].<ref name="Sulik_2010" />{{rp|366–368}}<ref>{{cite web | vauthors = Landeman A |date = 11 June 2008 |url = http://www.prwatch.org/node/7436 |title = Pinkwashing: Can Shopping Cure Breast Cancer? |publisher = [[Center for Media and Democracy]] |url-status = live |archive-url = https://web.archive.org/web/20110605122507/http://www.prwatch.org/node/7436 |archive-date = 5 June 2011 |df = dmy-all }}</ref> Critics say that the feel-good nature of pink ribbons and pink consumption distracts society from the lack of progress on preventing and curing breast cancer.<ref name="Sulik_2010" />{{rp|365–366}} It is also criticized for reinforcing gender stereotypes and [[objectifying]] women and their breasts.<<ref name="Sulik_2010" />{{rp|372–374}} In 2002 [[Breast Cancer Action]] launched the "Think Before You Pink" campaign against [[Pinkwashing (breast cancer)|pinkwashing]] to target businesses that have co-opted the pink campaign to promote products that cause breast cancer, such as alcoholic beverages.<ref>[https://www.ctvnews.ca/breast-cancer-month-overshadowed-by-pinkwashing-1.561275 Breast cancer month overshadowed by 'pinkwashing'] {{webarchive|url=https://web.archive.org/web/20101012151918/http://ottawa.ctv.ca/servlet/an/local/CTVNews/20101008/pinkwashing-pink-ribbon-101009/20101009/?hub=OttawaHome |date=12 October 2010 }} 9 October 2010, Angela Mulholland, CTV.ca News</ref>
=== Breast cancer culture ===
In her 2006 book ''Pink Ribbons, Inc.: Breast Cancer and the Politics of Philanthropy'' Samantha King claimed that breast cancer has been transformed from a serious disease and individual tragedy to a market-driven industry of survivorship and corporate sales pitch.<ref name= "King_2006">{{cite book | vauthors = King S |title=Pink ribbons, inc.: breast cancer and the politics of philanthropy |publisher=University of Minnesota Press |location=Minneapolis |year=2006 |isbn=0-8166-4898-0}}</ref> In 2010 Gayle Sulik argued that the primary purposes or goals of breast cancer culture are to maintain breast cancer's dominance as the pre-eminent women's health issue, to promote the appearance that society is doing something effective about breast cancer, and to sustain and expand the social, political, and financial power of breast cancer activists.<ref name="Sulik_2010" />{{rp|57}} In the same year [[Barbara Ehrenreich]] published an opinion piece in ''[[Harper's Magazine]]'', lamenting that in breast cancer culture, breast cancer therapy is viewed as a [[rite of passage]] rather than a disease. To fit into this mold, the woman with breast cancer needs to normalize and feminize her appearance, and minimize the disruption that her health issues cause anyone else. Anger, sadness, and negativity must be silenced. As with most cultural models, people who conform to the model are given social status, in this case as [[cancer survivor]]s. Women who reject the model are shunned, punished and shamed. The culture is criticized for treating adult women like little girls, as evidenced by "baby" toys such as pink [[teddy bear]]s given to adult women.<ref name=Ehrenreich>{{Cite news | vauthors = Ehrenreich B |title = Welcome to Cancerland |newspaper = Harper's Magazine |date = November 2001 |url = http://www.barbaraehrenreich.com/cancerland.htm |url-status = dead |archive-url = https://web.archive.org/web/20101120135605/http://barbaraehrenreich.com/cancerland.htm |archive-date = 20 November 2010 }}</ref>
=== Emphasis ===
In 2009 the US science journalist [[Christie Aschwanden]] criticized that the emphasis on breast cancer screening may be harming women by subjecting them to unnecessary radiation, biopsies, and surgery. One-third of diagnosed breast cancers might recede on their own.<ref name=Ave>{{cite news |title = The Trouble with Mammograms |date = 17 August 2009 | vauthors = Aschwanden C |newspaper =[[Los Angeles Times]] |url = https://articles.latimes.com/2009/aug/17/health/he-breast-overdiagnosis17 |url-status = live |archive-url = https://web.archive.org/web/20101204073704/http://articles.latimes.com/2009/aug/17/health/he-breast-overdiagnosis17 |archive-date = 4 December 2010 |df = dmy-all }}</ref> Screening mammography efficiently finds non-life-threatening, asymptomatic breast cancers and precancers, even while overlooking serious cancers. According to the cancer researcher [[H. Gilbert Welch]] screening mammography has taken the "brain-dead approach that says the best test is the one that finds the most cancers" rather than the one that finds dangerous cancers.<ref name=Ave />
In 2002 it was noted that as a result of breast cancer's high visibility, the statistical results can be misinterpreted, such as the claim that one in eight women will be diagnosed with breast cancer during their lives – a claim that depends on the unrealistic assumption that no woman will die of any other disease before the age of 95.<ref name="Olson_2002" />{{rp|199–200}} By 2010 the breast cancer survival rate in Europe was 91% at one years and 65% at five years. In the USA the five-year survival rate for localized breast cancer was 96.8%, while in cases of [[metastases]] it was only 20.6%. Because the prognosis for breast cancer was at this stage relatively favorable, compared to the prognosis for other cancers, breast cancer as cause of death among women was 13.9% of all cancer deaths. The second most common cause of death from cancer in women was lung cancer, the most common cancer worldwide for men and women. The improved survival rate made breast cancer the most prevalent cancer in the world. In 2010 an estimated 3.6 million women worldwide have had a breast cancer diagnosis in the past five years, while only 1.4 million male or female survivors from lung cancer were alive.<ref>{{cite book | vauthors = Olopade OI, Falkson CI |title = Breast Cancer in Women of African Descent |publisher = Springer Science & Business Media|year = 2010 |pages = 5 |isbn = 9781402036644}}</ref>
== Health disparities in breast cancer ==
There are ethnic disparities in the mortality rates for breast cancer as well as in breast cancer treatment. Breast cancer is the most prevalent cancer affecting women of every ethnic group in the United States. Breast cancer incidence among black women aged 45 and older is higher than that of white women in the same age group. White women aged 60–84 have higher incidence rates of breast cancer than Black women. Despite this, Black women at every age are more likely to succumb to breast cancer.<ref name="Health and Racial Disparity in Brea">{{cite journal | vauthors = Yedjou CG, Sims JN, Miele L, Noubissi F, Lowe L, Fonseca DD, Alo RA, Payton M, Tchounwou PB | display-authors = 6 | title = Health and Racial Disparity in Breast Cancer | journal = Advances in Experimental Medicine and Biology | volume = 1152 | pages = 31–49 | date = 3 January 2020 | pmid = 31456178 | pmc = 6941147 | doi = 10.1007/978-3-030-20301-6_3 | isbn = 978-3-030-20300-9 }}</ref>
Breast cancer treatment has improved greatly in recent years, but black women are still less likely to obtain treatment compared to white women.<ref name="Health and Racial Disparity in Brea"/> Risk factors such as socioeconomic status, late-stage, or breast cancer at diagnosis, genetic differences in tumor subtypes, differences in health care access all contribute to these disparities. Socioeconomic determinants affecting the disparity in breast cancer illness include poverty, culture, as well as social injustice. In Hispanic women, the incidence of breast cancer is lower than in non-Hispanic women but is often diagnosed at a later stage than white women with larger tumors.
Black women are usually diagnosed with breast cancer at a younger age than white women. The median age of diagnosis for Black women is 59, in comparison to 62 in White women. The incidence of breast cancer in Black women has increased by 0.4% per year since 1975 and 1.5% per year among Asian/Pacific Islander women since 1992. Incidence rates were stable for non-Hispanic White, Hispanics, and Native women. The five-year survival rate is noted to be 81% in Black women and 92% in White women. Chinese and Japanese women have the highest survival rates.<ref name="Health and Racial Disparity in Brea"/>
Poverty is a major driver for disparities related to breast cancer. Low-income women are less likely to undergo breast cancer screening and thus are more likely to have a late-stage diagnosis.<ref name="Health and Racial Disparity in Brea"/> Ensuring women of all ethnic groups receive equitable health care{{Clarify|date=January 2022}} can positively affect these disparities.{{Citation needed|date=January 2022}}
== Pregnancy ==
Pregnancy at an early age decreases the risk of developing breast cancer later in life.<ref name=Preg2019/> The risk of breast cancer also declines with the number of children a woman has.<ref name=Preg2019>{{cite web | url =https://www.cancer.gov/about-cancer/causes-prevention/risk/hormones/reproductive-history-fact-sheet#are-any-pregnancy-related-factors-associated-with-a-lower-risk-of-breast-cancer |title=Reproductive History and Cancer Risk |publisher=[[National Cancer Institute]] |date=30 November 2016 | access-date =22 August 2019}}</ref> Breast cancer then becomes more common in the 5 or 10 years following pregnancy but then becomes less common than among the general population.<ref>{{cite journal | vauthors = Azim HA, Santoro L, Russell-Edu W, Pentheroudakis G, Pavlidis N, Peccatori FA | title = Prognosis of pregnancy-associated breast cancer: a meta-analysis of 30 studies | journal = Cancer Treatment Reviews | volume = 38 | issue = 7 | pages = 834–42 | date = November 2012 | pmid = 22785217 | doi = 10.1016/j.ctrv.2012.06.004 }}</ref> These cancers are known as postpartum breast cancer and have worse outcomes including an increased risk of distant spread of disease and mortality.<ref>{{cite journal | vauthors = Schedin P | title = Pregnancy-associated breast cancer and metastasis | journal = Nature Reviews. Cancer | volume = 6 | issue = 4 | pages = 281–91 | date = April 2006 | pmid = 16557280 | doi = 10.1038/nrc1839 | s2cid = 9085879 }}</ref> Other cancers found during or shortly after pregnancy appear at approximately the same rate as other cancers in women of a similar age.<ref name=yarbro />
Diagnosing new cancer in a pregnant woman is difficult, in part because any symptoms are commonly assumed to be a normal discomfort associated with pregnancy.<ref name=yarbro /> As a result, cancer is typically discovered at a somewhat later stage than average in many pregnant or recently pregnant women. Some imaging procedures, such as [[MRI]]s (magnetic resonance imaging), [[CT scan]]s, ultrasounds, and [[mammogram]]s with fetal shielding are considered safe during pregnancy; some others, such as [[PET scan]]s are not.<ref name=yarbro />
Treatment is generally the same as for non-pregnant women.<ref name=yarbro /> However, radiation is normally avoided during pregnancy, especially if the fetal dose might exceed 100 cGy. In some cases, some or all treatments are postponed until after birth if the cancer is diagnosed late in the pregnancy. Early deliveries to speed the start of treatment are not uncommon. Surgery is generally considered safe during pregnancy, but some other treatments, especially certain chemotherapy drugs given during the [[first trimester]], increase the risk of [[birth defect]]s and pregnancy loss (spontaneous abortions and stillbirths).<ref name=yarbro /> Elective abortions are not required and do not improve the likelihood of the mother surviving or being cured.<ref name=yarbro />
Radiation treatments may interfere with the mother's ability to breastfeed her baby because it reduces the ability of that breast to produce milk and increases the risk of [[mastitis]]. Also, when chemotherapy is being given after birth, many of the drugs pass through breast milk to the baby, which could harm the baby.<ref name="yarbro">{{cite book |title = Cancer nursing: principles and practice | veditors = Yarbro CH, Wujcik D, Gobel BH |edition = 7th |publisher = Jones & Bartlett Publishers |year = 2011 |isbn = 978-1-4496-1829-2 |pages = 901–905 }}</ref>
Regarding future pregnancy among breast [[cancer survivor]]s, there is often fear of cancer recurrence.<ref name="Goncalves2013">{{cite journal | vauthors = Gonçalves V, Sehovic I, Quinn G | title = Childbearing attitudes and decisions of young breast cancer survivors: a systematic review | journal = Human Reproduction Update | volume = 20 | issue = 2 | pages = 279–92 | year = 2013 | pmid = 24077938 | pmc = 3922144 | doi = 10.1093/humupd/dmt039 }}</ref> On the other hand, many still regard pregnancy and parenthood to represent normality, happiness and life fulfillment.<ref name=Goncalves2013 />
== Hormones ==
=== Birth control ===
In breast cancer survivors, non-hormonal [[birth control]] methods such as the [[Copper IUDs|copper intrauterine device (IUD)]] should be used as first-line options.<ref>{{cite journal | vauthors = Patel A, Schwarz EB | title = Cancer and contraception. Release date May 2012. SFP Guideline #20121 | language = en | journal = Contraception | volume = 86 | issue = 3 | pages = 191–8 | date = September 2012 | pmid = 22682881 | doi = 10.1016/j.contraception.2012.05.008 }}</ref> [[Progestogen]]-based methods such as [[depot medroxyprogesterone acetate]], [[IUD with progestogen]] or [[progestogen only pill]]s have a poorly investigated but possible increased risk of cancer recurrence, but may be used if positive effects outweigh this possible risk.<ref>{{cite journal | vauthors = McNaught J, Reid RL | title = Progesterone-only and non-hormonal contraception in the breast cancer survivor: Joint Review and Committee Opinion of the Society of Obstetricians and Gynaecologists of Canada and the Society of Gynecologic Oncologists of Canada | journal = Journal of Obstetrics and Gynaecology Canada | volume = 28 | issue = 7 | pages = 616–626 | date = July 2006 | pmid = 16924781 | doi = 10.1016/S1701-2163(16)32195-8 }}</ref>
=== Menopausal hormone replacement ===
In breast cancer survivors, it is recommended to first consider non-hormonal options for [[menopausal]] effects, such as [[bisphosphonate]]s or [[selective estrogen receptor modulator]]s (SERMs) for osteoporosis, and [[vaginal estrogen]] for local symptoms. Observational studies of systemic [[Hormone replacement therapy (menopause)|hormone replacement therapy]] after breast cancer are generally reassuring. If hormone replacement is necessary after breast cancer, estrogen-only therapy or estrogen therapy with an [[intrauterine device with progestogen]] may be safer options than combined systemic therapy.<ref>[https://archive.today/20160407214503/https://www.ranzcog.edu.au/doc/management-of-the-menopause-after-breast-cancer.html Management of the menopause after breast cancer], from the [[Royal Australian and New Zealand College of Obstetricians and Gynaecologists]]. College Statement C-Gyn 15. 1st Endorsed: February 2003. Current: November 2011. Review: November 2014</ref>
== Research ==
Treatments are being evaluated in clinical trials. This includes individual drugs, combinations of drugs, and surgical and radiation techniques Investigations include new types of [[targeted therapy]],<ref>{{cite journal | vauthors = Venur VA, Leone JP | title = Targeted Therapies for Brain Metastases from Breast Cancer | journal = International Journal of Molecular Sciences | volume = 17 | issue = 9 | pages = 1543 | date = September 2016 | pmid = 27649142 | pmc = 5037817 | doi = 10.3390/ijms17091543 | df = dmy-all | doi-access = free }}</ref> [[cancer vaccine]]s, [[oncolytic virotherapy]],<ref>{{cite journal | vauthors = Suryawanshi YR, Zhang T, Essani K | title = Oncolytic viruses: emerging options for the treatment of breast cancer | journal = Medical Oncology | volume = 34 | issue = 3 | pages = 43 | date = March 2017 | pmid = 28185165 | doi = 10.1007/s12032-017-0899-0 | s2cid = 44562857 }}</ref> [[gene therapy]]<ref>{{cite journal | vauthors = Obermiller PS, Tait DL, Holt JT | title = Gene therapy for carcinoma of the breast: Therapeutic genetic correction strategies | journal = Breast Cancer Research | volume = 2 | issue = 1 | pages = 28–31 | year = 1999 | pmid = 11250690 | pmc = 521211 | doi = 10.1186/bcr26 }}</ref><ref>{{cite journal | vauthors = Roth JA, Swisher SG, Meyn RE | title = p53 tumor suppressor gene therapy for cancer | journal = Oncology | volume = 13 | issue = 10 Suppl 5 | pages = 148–54 | date = October 1999 | pmid = 10550840 }}</ref> and [[immunotherapy]].<ref>{{cite journal | vauthors = Yu LY, Tang J, Zhang CM, Zeng WJ, Yan H, Li MP, Chen XP | title = New Immunotherapy Strategies in Breast Cancer | journal = International Journal of Environmental Research and Public Health | volume = 14 | issue = 1 | pages = 68 | date = January 2017 | pmid = 28085094 | pmc = 5295319 | doi = 10.3390/ijerph14010068 | df = dmy-all | doi-access = free }}</ref>
The latest research is reported annually at scientific meetings such as that of the [[American Society of Clinical Oncology]], San Antonio Breast Cancer Symposium,<ref>[http://www.sabcs.org/EnduringMaterials/Index.asp San Antonio Breast Cancer Symposium] {{webarchive|url=https://web.archive.org/web/20100516171511/http://www.sabcs.org/EnduringMaterials/Index.asp |date=16 May 2010 }} Abstracts, newsletters, and other reports of the meeting.</ref> and the St. Gallen Oncology Conference in St. Gallen, Switzerland.<ref>{{cite journal | vauthors = Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thürlimann B, Senn HJ | title = Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009 | journal = Annals of Oncology | volume = 20 | issue = 8 | pages = 1319–29 | date = August 2009 | pmid = 19535820 | pmc = 2720818 | doi = 10.1093/annonc/mdp322 }}</ref> These studies are reviewed by professional societies and other organizations, and formulated into guidelines for specific treatment groups and risk category.
[[Fenretinide]], a [[retinoid]], is also being studied as a way to reduce the risk of breast cancer.<ref>{{Cite news |url = http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-new-research |title = What's new in breast cancer research and treatment? |work = Cancer |access-date = 17 November 2015 |url-status = live |archive-url = https://web.archive.org/web/20151112202807/http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-new-research |archive-date = 12 November 2015 |df = dmy-all }}</ref><ref>{{cite news |url = http://www.hindawi.com/journals/bmri/2012/172897/ |title = Fenretinide (4-HPR): A Preventive Chance for Women at Genetic and Familial Risk? |work = hindawi |access-date = 17 November 2015 |url-status = live |archive-url = https://web.archive.org/web/20151117181548/http://www.hindawi.com/journals/bmri/2012/172897/ |archive-date = 17 November 2015 |df = dmy-all}}</ref> In particular, combinations of [[ribociclib]] plus endocrine therapy have been the subject of clinical trials.<ref name="pmid29457921">{{cite journal | vauthors = Burris HA | title = Ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer | journal = Expert Review of Anticancer Therapy | volume = 18 | issue = 3 | pages = 201–213 | date = March 2018 | pmid = 29457921 | doi = 10.1080/14737140.2018.1435275| s2cid = 3425945 }}</ref>
A 2019 review found moderate certainty evidence that giving people [[antibiotic]]s before breast cancer surgery helped to prevent [[Perioperative mortality|surgical site infection (SSI)]]. Further study is required to determine the most effective antibiotic protocol and use in women undergoing immediate breast reconstruction.<ref>{{cite journal | vauthors = Gallagher M, Jones DJ, Bell-Syer SV | title = Prophylactic antibiotics to prevent surgical site infection after breast cancer surgery | journal = The Cochrane Database of Systematic Reviews | volume = 9 | pages = CD005360 | date = September 2019 | pmid = 31557310 | pmc = 6953223 | doi = 10.1002/14651858.CD005360.pub5 | collaboration = Cochrane Wounds Group}}</ref>
=== Cryoablation ===
As of 2014 [[cryoablation]] is being studied to see if it could be a substitute for a lumpectomy in small cancers.<ref>{{cite journal | vauthors = Sabel MS | title = Nonsurgical ablation of breast cancer: future options for small breast tumors | journal = Surgical Oncology Clinics of North America | volume = 23 | issue = 3 | pages = 593–608 | date = July 2014 | pmid = 24882353 | doi = 10.1016/j.soc.2014.03.009}}</ref> There is tentative evidence in those with tumors less than 2 centimeters.<ref name=Rou2014 /> It may also be used in those in who surgery is not possible.<ref name="Rou2014">{{cite journal | vauthors = Roubidoux MA, Yang W, Stafford RJ | title = Image-guided ablation in breast cancer treatment | journal = Techniques in Vascular and Interventional Radiology | volume = 17 | issue = 1 | pages = 49–54 | date = March 2014 | pmid = 24636331 | doi = 10.1053/j.tvir.2013.12.008}}</ref> Another review states that cryoablation looks promising for early breast cancer of small size.<ref>{{cite journal | vauthors = Fornage BD, Hwang RF | title = Current status of imaging-guided percutaneous ablation of breast cancer | journal = AJR. American Journal of Roentgenology | volume = 203 | issue = 2 | pages = 442–8 | date = August 2014 | pmid = 25055283 | doi = 10.2214/AJR.13.11600}}</ref>
=== Breast cancer cell lines ===
{{See also|List of breast cancer cell lines}}
Part of the current knowledge on breast carcinomas is based on [[in vivo]] and [[in vitro]] studies performed with [[cell lines]] derived from breast cancers. These provide an unlimited source of homogenous self-replicating material, free of contaminating [[stroma (animal tissue)|stromal]] cells, and often easily cultured in simple standard [[growth medium|media]]. The first breast cancer cell line described, [[BT-20 (cell line)|BT-20]], was established in 1958. Since then, and despite sustained work in this area, the number of permanent lines obtained has been strikingly low (about 100). Indeed, attempts to culture breast cancer cell lines from primary tumors have been largely unsuccessful. This poor efficiency was often due to technical difficulties associated with the extraction of viable tumor cells from their surrounding stroma. Most of the available breast cancer cell lines issued from metastatic tumors, mainly from [[pleural effusion]]s. Effusions provided generally large numbers of dissociated, viable tumor cells with little or no contamination by [[fibroblasts]] and other tumor stroma cells.
Many of the currently used BCC lines were established in the late 1970s. A very few of them, namely [[MCF-7]], [[T-47D]], [[MDA-MB-231]] and [[SK-BR-3]], account for more than two-thirds of all abstracts reporting studies on mentioned breast cancer cell lines, as concluded from a [[Medline]]-based survey.
=== Molecular markers ===
==== Metabolic markers ====
Clinically, the most useful metabolic markers in breast cancer are the estrogen and progesterone receptors that are used to predict response to hormone therapy. New or potentially new markers for breast cancer include BRCA1 and BRCA2<ref name="pmid11522269">{{cite journal | vauthors = Duffy MJ | title = Biochemical markers in breast cancer: which ones are clinically useful? | journal = Clinical Biochemistry | volume = 34 | issue = 5 | pages = 347–52 | date = July 2001 | pmid = 11522269 | doi = 10.1016/s0009-9120(00)00201-0}}</ref> to identify people at high risk of developing breast cancer, [[HER-2]],{{medcn|date=May 2018}} and [[Stearoyl-CoA desaturase-1|SCD1]], for predicting response to therapeutic regimens, and [[urokinase plasminogen activator]], PA1-1 and [[Stearoyl-CoA desaturase-1|SCD1]] for assessing prognosis.{{medcn|date=May 2018}}
== Other animals ==
* [[Mammary tumor]] for breast cancer in other animals
* [[Mouse models of breast cancer metastasis]]
== See also ==
*[[Male breast cancer]]
*[[Breast Cancer Research and Treatment]], a scientific journal
== References ==
{{Reflist}}
== External links ==
{{Medical resources
| eMedicine_mult = {{eMedicine2|med|3287}} {{eMedicine2|radio|115}} {{eMedicine2|plastic|521}}
| DiseasesDB = 1598
| ICD10 = {{ICD10|C|50||c|50}}
| ICD9 = {{ICD9|174}}-{{ICD9|175}},{{ICD9|V10.3}}
| ICDO={{ICDO|8502|3}}
| OMIM = 114480
| MedlinePlus = 000913
| eMedicineSubj = med
| eMedicineTopic = 2808
| MeshID = D001943
}}
{{Library resources box |by=no |onlinebooks=no |others=yes lcheading=Breast cancer}}
* {{curlie|Health/Conditions_and_Diseases/Cancer/Breast/}}
{{Subject bar |portal1= Biology |portal2= Medicine |commons= y |commons-search= Breast cancer |n= y |wikt= y|b= y |q= y |s= y |v= n |voy= n }}
{{Breast cancer types}}
{{Authority control}}
[[Category:Breast cancer| ]]
[[Category:Hereditary cancers]]
[[Category:Human female endocrine system]]
[[Category:Wikipedia medicine articles ready to translate]]' |
New page wikitext, after the edit (new_wikitext) | '{{Short description|Cancer that originates in mammary glands}}
{{pp-pc1}}
{{Use dmy dates|date=June 2021}}
{{Infobox medical condition (new)
| name = Breast cancer
| image = Breast Cancer.png
| caption = An illustration of breast cancer
| field = [[Oncology]]
| symptoms = A lump in a breast, a change in breast shape, dimpling of the skin, fluid from the [[nipple]], a newly inverted nipple, a red scaly patch of skin on the breast<ref name=NCI2014Pt/>
| complications =
| onset =
| duration =
| causes =
| risks = Being female, [[obesity]], lack of exercise, alcohol, [[hormone replacement therapy]] during [[menopause]], [[ionizing radiation]], early age at [[menarche|first menstruation]], having childrenst Cancer |url = http://seer.cancer.gov/statfacts/html/breast.html |website = NCI |access-date = 18 June 2014 |url-status = live |archive-url = https://web.archive.org/web/20140703030149/http://seer.cancer.gov/statfacts/html/breast.html |archive-date = 3 July 2014 |df = dmy-all }}</ref><ref name=UK2013Prog>{{cite web |title = Cancer Survival in England: Patients Diagnosed 2007–2011 and Followed up to 2012 |url = http://www.ons.gov.uk/ons/dcp171778_333318.pdf |website = Office for National Statistics |access-date = 29 June 2014 |date = 29 October 2013 |url-status = live |archive-url = https://web.archive.org/web/20141129124915/http://www.ons.gov.uk/ons/dcp171778_333318.pdf |archive-date = 29 November 2014 |df = dmy-all }}</ref> In developing countries, five-year survival rates are lower.<ref name=WCR2014 /> Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases.<ref name="WCR2014Epi">{{cite book |title = World Cancer Report 2014 |date = 2014 |publisher = World Health Organization |isbn = 978-92-832-0429-9 |pages = Chapter 1.1 }}</ref> In 2018, it resulted in 2 million new cases and 627,000 deaths.<ref name=Bra2018>{{cite journal | vauthors = Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A | title = Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries | journal = CA: A Cancer Journal for Clinicians | volume = 68 | issue = 6 | pages = 394–424 | date = November 2018 | pmid = 30207593 | doi = 10.3322/caac.21492 | s2cid = 52188256 | doi-access = free}}</ref> It is more common in developed countries<ref name=WCR2014 /> and is more than 100 times more common in women than [[Male breast cancer|in men]].<ref name=WCR2008 /><ref>{{cite web |title = Male Breast Cancer Treatment |publisher = [[National Cancer Institute]] |year = 2014 |url = http://www.cancer.gov/cancertopics/pdq/treatment/malebreast/HealthProfessional |access-date = 29 June 2014 |url-status = live |archive-url = https://web.archive.org/web/20140704182515/http://www.cancer.gov/cancertopics/pdq/treatment/malebreast/HealthProfessional |archive-date = 4 July 2014 |df = dmy-all }}</ref>
{{TOC limit|3}}
== Signs and symptoms ==
[[File:Breast cancer.jpg|thumb|Breast cancer showing an inverted nipple, lump, and skin dimpling]]
[[File:En Breast cancer illustrations.png|thumb|Early signs of possible breast cancer]]
Breast cancer most commonly presents as a [[breast lump|lump]] that feels different from the rest of the breast tissue. More than 80% of cases are discovered when a person detects such a lump with the fingertips.<ref name="merck">{{cite web |author = Merck Manual of Diagnosis and Therapy |date = February 2003 |title = Breast Disorders: Breast Cancer |url = http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/breast_cancer.html |access-date = 5 February 2008 |url-status = live |archive-url = https://web.archive.org/web/20111002141649/http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/breast_cancer.html |archive-date = 2 October 2011 |df = dmy-all |author-link = Merck Manual of Diagnosis and Therapy }}</ref> The earliest breast cancers, however, are detected by a [[mammogram]].<ref name="acs cancer facts 2007" /><ref>{{cite journal | vauthors = Boyd NF, Guo H, Martin LJ, Sun L, Stone J, Fishell E, Jong RA, Hislop G, Chiarelli A, Minkin S, Yaffe MJ | display-authors = 6 | title = Mammographic density and the risk and detection of breast cancer | journal = The New England Journal of Medicine | volume = 356 | issue = 3 | pages = 227–36 | date = January 2007 | pmid = 17229950 | doi = 10.1056/NEJMoa062790 | s2cid = 13831558 }}</ref> Lumps found in lymph nodes located in the armpits<ref name="merck" /> may also indicate breast cancer.
Indications of breast cancer other than a lump may include thickening different from the other breast tissue, one breast becoming larger or lower, a nipple changing position or shape or becoming inverted, skin puckering or dimpling, a rash on or around a nipple, discharge from nipple/s, constant pain in part of the breast or armpit and swelling beneath the armpit or around the collarbone.<ref>{{cite journal | vauthors = Watson M |title = Assessment of suspected cancer |journal = InnoAiT |volume = 1 |issue = 2 |pages = 94–107 |year = 2008 |doi = 10.1093/innovait/inn001 |s2cid = 71908359 }}</ref> Pain ("[[mastodynia]]") is an unreliable tool in determining the presence or absence of breast cancer, but may be indicative of other [[breast health]] issues.<ref name="merck" /><ref name="acs cancer facts 2007">{{cite web |author = American Cancer Society |year = 2007 |title = Cancer Facts & Figures 2007 |url = http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf |access-date = 26 April 2007 |archive-url = https://web.archive.org/web/20070410025934/http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf |archive-date = 10 April 2007 }}</ref><ref name="eMed">{{Cite web|website=eMedicine|date=23 August 2006|title=Breast Cancer Evaluation|url=http://www.emedicine.com/med/TOPIC3287.HTM|access-date=5 February 2008|url-status=dead|archive-url=https://web.archive.org/web/20080212070431/http://www.emedicine.com/med/TOPIC3287.HTM|archive-date=12 February 2008}}</ref>
Another symptom complex of breast cancer is [[Paget's disease of the breast]]. This syndrome presents as skin changes resembling eczema; such as redness, discoloration or mild flaking of the nipple skin. As Paget's disease of the breast advances, symptoms may include tingling, itching, increased sensitivity, burning, and pain. There may also be discharge from the nipple. Approximately half the women diagnosed with Paget's disease of the breast also have a lump in the breast.<ref>{{cite journal | vauthors = Ashikari R, Park K, Huvos AG, Urban JA | title = Paget's disease of the breast | journal = Cancer | volume = 26 | issue = 3 | pages = 680–5 | date = September 1970 | pmid = 4318756 | doi = 10.1002/1097-0142(197009)26:3<680::aid-cncr2820260329>3.0.co;2-p | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kollmorgen DR, Varanasi JS, Edge SB, Carson WE | title = Paget's disease of the breast: a 33-year experience | journal = Journal of the American College of Surgeons | volume = 187 | issue = 2 | pages = 171–7 | date = August 1998 | pmid = 9704964 | doi = 10.1016/S1072-7515(98)00143-4 }}</ref>
[[Inflammatory Breast Cancer|Inflammatory breast cancer]] is a rare (only seen in less than 5% of breast cancer diagnosis) yet aggressive form of breast cancer characterized by the swollen, red areas formed on the top of the breast. The visual effects of inflammatory breast cancer is a result of a blockage of lymph vessels by cancer cells. This type of breast cancer is seen in more commonly diagnosed in younger ages, obese women and African American women. As inflammatory breast cancer does not present as a lump there can sometimes be a delay in diagnosis.<ref>{{cite journal | vauthors = Kleer CG, van Golen KL, Merajver SD | title = Molecular biology of breast cancer metastasis. Inflammatory breast cancer: clinical syndrome and molecular determinants | journal = Breast Cancer Research | volume = 2 | issue = 6 | pages = 423–9 | date = 1 December 2000 | pmid = 11250736 | pmc = 138665 | doi = 10.1186/bcr89 }}</ref>
[[Mammary secretory carcinoma]] (MSC) is a rare form of the [[secretory carcinoma]]s that occurs exclusively in the breast.<ref name="pmid34282256">{{cite journal | vauthors = Gong P, Xia C, Yang Y, Lei W, Yang W, Yu J, Ji Y, Ren L, Ye F | title = Clinicopathologic profiling and oncologic outcomes of secretory carcinoma of the breast | journal = Scientific Reports | volume = 11 | issue = 1 | pages = 14738 | date = July 2021 | pmid = 34282256 | pmc = 8289843 | doi = 10.1038/s41598-021-94351-w | bibcode = 2021NatSR..1114738G | url = }}</ref> It usually develops in adults but in a significant percentage of cases also affects children:<ref name="pmid35156343">{{cite journal | vauthors = Carretero-Barrio I, Santón A, Caniego Casas T, López Miranda E, Reguero-Callejas ME, Pérez-Mies B, Benito A, Palacios J | title = Cytological and molecular characterization of secretory breast carcinoma | journal = Diagnostic Cytopathology | volume = 50| issue = 7| pages = E174–E180| date = February 2022 | pmid = 35156343 | doi = 10.1002/dc.24945 | pmc = 9303577 | s2cid = 246813006 | url = }}</ref> MSC accounts for 80% of all childhood breast cancers.<ref name="pmid34243852">{{cite journal | vauthors = Knaus ME, Grabowksi JE | title = Pediatric Breast Masses: An Overview of the Subtypes, Workup, Imaging, and Management | journal = Advances in Pediatrics | volume = 68 | issue = | pages = 195–209 | date = August 2021 | pmid = 34243852 | doi = 10.1016/j.yapd.2021.05.006 | s2cid = 235786044 | url = }}</ref> MSC lesions are typically slow growing, painless, small [[Invasive carcinoma of no special type|ductal breast tumors]] that have invaded the tissue around their [[Lactiferous duct|ducts]] of origin, often spread to [[sentinel lymph nodes]] and/or [[axillary lymph nodes]], but rarely metastasized to distant tissues.<ref name="pmid35106856">{{cite journal | vauthors = Loo SK, Yates ME, Yang S, Oesterreich S, Lee AV, Wang XS | title = Fusion-associated carcinomas of the breast: Diagnostic, prognostic, and therapeutic significance | journal = Genes, Chromosomes & Cancer | volume = 61 | issue = 5 | pages = 261–273 | date = May 2022 | pmid = 35106856 | pmc = 8930468 | doi = 10.1002/gcc.23029 | url = }}</ref> These tumors typically have distinctive microscopic features and tumor cells that carry a balanced [[genetic translocation]] in which part of the ''[[NTRK3]]'' gene is fused to part of the ''[[ETV6]]'' gene<ref name="pmid34277491">{{cite journal | vauthors = Banerjee N, Banerjee D, Choudhary N | title = Secretory carcinoma of the breast, commonly exhibits the features of low grade, triple negative breast carcinoma- A Case report with updated review of literature | journal = Autopsy & Case Reports | volume = 11 | issue = | pages = e2020227 | date = 2021 | pmid = 34277491 | pmc = 8101654 | doi = 10.4322/acr.2020.227 | url = }}</ref> to form a [[fusion gene]], ''[[ETV6-NTRK3 gene fusion|ETV6-NTRK3]]''. This fusion gene encodes a [[chimeric protein]] termed ETV6-NTRK3. The NTRK3 part of ETV6-NTRK3 protein has up-regulated [[tyrosine kinase]] activity that stimulates two [[cell signaling|signaling]] pathways, the [[PI3K/AKT/mTOR pathway|PI3K/AKT/mTOR]] and [[MAPK/ERK pathway]]s, which promote cell proliferation and survival and thereby may contribute to the development of MSC.<ref name="pmid35156343"/> Conservative surgery, modified radical mastectomy, and radical mastectomy have been the most frequent procedures used to treat adults, while simple mastectomy, local excision with [[sentinel lymph node]] biopsy, and complete axillary dissection have been recommended to treat children with MSC.<ref name="pmid31119054">{{cite journal | vauthors = Li L, Wu N, Li F, Li L, Wei L, Liu J | title = Clinicopathologic and molecular characteristics of 44 patients with pure secretory breast carcinoma | journal = Cancer Biology & Medicine | volume = 16 | issue = 1 | pages = 139–146 | date = February 2019 | pmid = 31119054 | pmc = 6528460 | doi = 10.20892/j.issn.2095-3941.2018.0035 | url = }}</ref> In all cases, long-term, e.g. >20 years, follow-up examinations are recommended.<ref name="pmid34282256"/><ref name="pmid34277491"/> The relatively rare cases of MSC that have metastasized to distant tissues have shown little or no responses to chemotherapy and radiotherapy. Three patients with metastatic disease had good partial responses to [[Entrectinib]], a drug that inhibits the tyrosine kinase activity of the ETV6-NTRK3 fusion protein.<ref name="pmid34176200">{{cite journal | vauthors = Mortensen L, Ordulu Z, Dagogo-Jack I, Bossuyt V, Winters L, Taghian A, Smith BL, Ellisen LW, Kiedrowski LA, Lennerz JK, Bardia A, Spring LM | title = Locally Recurrent Secretory Carcinoma of the Breast with NTRK3 Gene Fusion | journal = The Oncologist | volume = 26 | issue = 10 | pages = 818–824 | date = October 2021 | pmid = 34176200 | pmc = 8488779 | doi = 10.1002/onco.13880 | url = }}</ref> Because of its slow growth and low rate of metastasis to distant tissues, individuals with MSC have had 20 year survival rates of 93.16%.<ref name="pmid34282256"/>
In rare cases, what initially appears as a [[fibroadenoma]] (hard, movable non-cancerous lump) could in fact be a [[phyllodes tumor]]. Phyllodes tumors are formed within the [[Stroma (tissue)|stroma]] (connective tissue) of the breast and contain glandular as well as stromal tissue. Phyllodes tumors are not staged in the usual sense; they are classified on the basis of their appearance under the microscope as benign, borderline or malignant.<ref name="phyllodes-tumor">{{cite web |author = answers.com |title = Oncology Encyclopedia: Cystosarcoma Phyllodes |website = [[Answers.com]] |url = http://www.answers.com/topic/phyllodes-tumor |access-date = 10 August 2010 |url-status = live |archive-url = https://web.archive.org/web/20100908032727/http://www.answers.com/topic/phyllodes-tumor |archive-date = 8 September 2010 |df = dmy-all }}</ref>
Malignant tumors can result in metastatic tumors – secondary tumors (originating from the primary tumor) that spread beyond the site of origination. The symptoms caused by metastatic breast cancer will depend on the location of metastasis. Common sites of metastasis include bone, liver, lung, and brain.<ref name="pmid17158753">{{cite journal | vauthors = Lacroix M | title = Significance, detection and markers of disseminated breast cancer cells | journal = Endocrine-Related Cancer | volume = 13 | issue = 4 | pages = 1033–67 | date = December 2006 | pmid = 17158753 | doi = 10.1677/ERC-06-0001 | doi-access = free }}</ref> When cancer has reached such an invasive state, it is categorized as a stage 4 cancer, cancers of this state are often fatal.<ref>{{cite web |title=Stage 4 :: The National Breast Cancer Foundation |url=https://www.nationalbreastcancer.org/breast-cancer-stage-4 |website=www.nationalbreastcancer.org }}</ref> Common symptoms of stage 4 cancer include unexplained weight loss, bone and joint pain, jaundice and neurological symptoms. These symptoms are called [[non-specific symptoms]] because they could be manifestations of many other illnesses.<ref name="nci metastatic">{{cite web |author = National Cancer Institute |date = 1 September 2004 |title = Metastatic Cancer: Questions and Answers |url = http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic |access-date = 6 February 2008 |url-status = live |archive-url = https://web.archive.org/web/20080827093333/http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic |archive-date = 27 August 2008 |df = dmy-all |author-link = National Cancer Institute }}</ref> Rarely breast cancer can spread to exceedingly uncommon sites such as peripancreatic lymph nodes causing biliary obstruction leading to diagnostic difficulties.<ref>{{cite journal | vauthors = Perera N, Fernando N, Perera R | title = Metastatic breast cancer spread to peripancreatic lymph nodes causing biliary obstruction | journal = The Breast Journal | volume = 26 | issue = 3 | pages = 511–13 | date = March 2020 | doi = 10.1111/tbj.13531 | pmid = 31538691 | doi-access = free }}</ref>
[[File:Brust Computertomographie mit Kontrastmittel Tumor.jpg|alt=Tumor in the breast visualized by Breast-CT|thumb|403x403px|Tumor in the breast visualized by Breast-Computertomography (Breast-CT)]]
Most symptoms of breast disorders, including most lumps, do not turn out to represent underlying breast cancer. Less than 20% of lumps, for example, are cancerous,<ref>{{cite book|title=Interpreting Signs and Symptoms|url={{google books |plainurl=y |id=PcARTQwHLpIC|page=99}}|year=2007|publisher=Lippincott Williams & Wilkins|isbn=978-1-58255-668-0|pages=99–}}</ref> and [[benign breast disease]]s such as [[mastitis]] and [[fibroadenoma]] of the breast are more common causes of breast disorder symptoms.<ref name="merck breasts">{{cite web |author = Merck Manual of Diagnosis and Therapy |date = February 2003 |title = Breast Disorders: Overview of Breast Disorders |url = http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/overview_of_breast_disorders.html |access-date = 5 February 2008 |url-status = live |archive-url = https://web.archive.org/web/20111003004918/http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/overview_of_breast_disorders.html |archive-date = 3 October 2011 |df = dmy-all |author-link = Merck Manual of Diagnosis and Therapy }}</ref>
== Risk factors ==
{{Main|Risk factors of breast cancer}}
Risk factors can be divided into two categories:
* ''modifiable'' risk factors (things that people can change themselves, such as consumption of alcoholic beverages), and
* ''fixed'' risk factors (things that cannot be changed, such as age and physiological sex).<ref name="Hay2013">{{cite journal|vauthors=Hayes J, Richardson A, Frampton C|date=November 2013|title=Population attributable risks for modifiable lifestyle factors and breast cancer in New Zealand women|journal=Internal Medicine Journal|volume=43|issue=11|pages=1198–204|doi=10.1111/imj.12256|pmid=23910051|s2cid=23237732}}</ref>
The primary risk factors for breast cancer are being female and older age.<ref>{{Cite book |vauthors = Reeder JG, Vogel VG |chapter = Breast cancer prevention |volume = 141 |pages = 149–64 |year = 2008 |pmid = 18274088 |doi = 10.1007/978-0-387-73161-2_10 |series = Cancer Treatment and Research |isbn = 978-0-387-73160-5 |title = Advances in Breast Cancer Management, Second Edition }}</ref> Other potential risk factors include genetics,<ref name="Am I at risk">{{cite web |title = Am I at risk? |url = http://www.breastcancercare.org.uk/breast-cancer-information/breast-awareness/am-i-risk/risk |publisher = Breast Cancer Care |access-date = 22 October 2013 |url-status = live |archive-url = https://web.archive.org/web/20131025074635/http://www.breastcancercare.org.uk/breast-cancer-information/breast-awareness/am-i-risk/risk |archive-date = 25 October 2013 |df = dmy-all |date = 23 February 2018 }}</ref> lack of childbearing or lack of breastfeeding,<ref>{{cite journal | author = Collaborative Group on Hormonal Factors in Breast Cancer | title = Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease | journal = Lancet | volume = 360 | issue = 9328 | pages = 187–95 | date = July 2002 | pmid = 12133652 | doi = 10.1016/S0140-6736(02)09454-0 | s2cid = 25250519 }}</ref> higher levels of certain hormones,<ref>{{cite journal | vauthors = Yager JD, Davidson NE | title = Estrogen carcinogenesis in breast cancer | journal = The New England Journal of Medicine | volume = 354 | issue = 3 | pages = 270–82 | date = January 2006 | pmid = 16421368 | doi = 10.1056/NEJMra050776 }}</ref><ref>{{cite web |url = http://www.center4research.org/hormone-therapy-menopause/ |title = Hormone Therapy and Menopause |publisher = National Research Center for Women & Families |vauthors = Mazzucco A, Santoro E, DeSoto, M, Hong Lee J |date = February 2009 }}</ref> certain dietary patterns, and obesity. One study indicates that exposure to light pollution is a risk factor for the development of breast cancer.<ref>{{cite book | vauthors = Haim A, Portnov BP |title=Light Pollution as new risk factor for human Breast and Prostate Cancers |date=2013 |publisher=Springer |location=Dordrecht |isbn=978-94-007-6220-6}}</ref>
If all adults maintained the healthiest possible lifestyles, including not drinking [[alcoholic beverages]], maintaining a healthy [[body composition]], never [[smoking]], eating [[Healthy diet|healthful food]], and other actions, then almost a quarter of breast cancer cases worldwide could be prevented.<ref name=":2">{{cite journal | vauthors = Zhang YB, Pan XF, Chen J, Cao A, Zhang YG, Xia L, Wang J, Li H, Liu G, Pan A | display-authors = 6 | title = Combined lifestyle factors, incident cancer, and cancer mortality: a systematic review and meta-analysis of prospective cohort studies | journal = British Journal of Cancer | volume = 122 | issue = 7 | pages = 1085–1093 | date = March 2020 | pmid = 32037402 | pmc = 7109112 | doi = 10.1038/s41416-020-0741-x }}</ref> The remaining three-quarters of breast cancer cases cannot be prevented through lifestyle changes.<ref name=":2" />
=== Lifestyle ===
{{See also|List of breast carcinogenic substances}}
[[File:NIH standard drink comparison.jpg|alt=Diagram of different sizes, showing how big a single serving of alcohol is for different types of alcoholic beverages|thumb|All types of [[alcoholic beverages]], including beer, wine, or liquor, cause breast cancer.]]
{{Image frame
| caption=Drinking alcohol, even at low levels, increases the risk of breast cancer<br/>{{legend|red| Additional risk from drinking<ref name="Choi"/><ref name="Bagnardi">{{cite journal | vauthors = Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V, Scotti L, Jenab M, Turati F, Pasquali E, Pelucchi C, Galeone C, Bellocco R, Negri E, Corrao G, Boffetta P, La Vecchia C | display-authors = 6 | title = Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis | journal = British Journal of Cancer | volume = 112 | issue = 3 | pages = 580–593 | date = February 2015 | pmid = 25422909 | pmc = 4453639 | doi = 10.1038/bjc.2014.579 }}</ref>}}
{{legend|pink| Original breast cancer risk ({{=}}100%)}}
| content = {{Graph:Chart|width=300|height=150
|xAxisTitle=Maximum drinks per day
|yAxisTitle=Risk
|legend=Legend
| y1Title=Risk due to drinking
| y2Title=Baseline
|type=stackedrect
| x=0,1,2,3,4+
| y1=0,9,13,23,60
| y2=100,100,100,100,100
|colors=red, pink}}
}}
[[Alcohol and breast cancer|Drinking alcoholic beverages increases the risk of breast cancer]], even among very light drinkers (women drinking less than half of one alcoholic drink per day).<ref name="Choi">{{cite journal | vauthors = Choi YJ, Myung SK, Lee JH | title = Light Alcohol Drinking and Risk of Cancer: A Meta-Analysis of Cohort Studies | journal = Cancer Research and Treatment | volume = 50 | issue = 2 | pages = 474–487 | date = April 2018 | pmid = 28546524 | pmc = 5912140 | doi = 10.4143/crt.2017.094 }}</ref> The risk is highest among heavy drinkers.<ref name="Shield">{{cite journal | vauthors = Shield KD, Soerjomataram I, Rehm J | title = Alcohol Use and Breast Cancer: A Critical Review | journal = Alcoholism, Clinical and Experimental Research | volume = 40 | issue = 6 | pages = 1166–1181 | date = June 2016 | pmid = 27130687 | doi = 10.1111/acer.13071 | quote = All levels of evidence showed a risk relationship between alcohol consumption and the risk of breast cancer, even at low levels of consumption. }}</ref> Globally, about one in 10 cases of breast cancer is caused by women drinking alcoholic beverages.<ref name="Shield" /> Drinking alcoholic beverages is among the most common modifiable risk factors.<ref>{{cite journal | vauthors = McDonald JA, Goyal A, Terry MB | title = Alcohol Intake and Breast Cancer Risk: Weighing the Overall Evidence | journal = Current Breast Cancer Reports | volume = 5 | issue = 3 | pages = 208–221 | date = September 2013 | pmid = 24265860 | pmc = 3832299 | doi = 10.1007/s12609-013-0114-z }}</ref>
The correlation between [[obesity]] and breast cancer is anything but linear. Studies show that those who rapidly gain weight in adulthood are at higher risk than those who have been overweight since childhood. Likewise excess fat in the midsection seems to induce a higher risk than excess weight carried in the lower body. This implies that the food one eats is of greater importance than one's [[Body mass index|BMI]].<ref>{{cite web|title=Lifestyle-related Breast Cancer Risk Factors|url=https://www.cancer.org/cancer/breast-cancer/risk-and-prevention/lifestyle-related-breast-cancer-risk-factors.html|website=www.cancer.org}}</ref> Dietary factors that may increase risk include a high-fat diet<ref>{{cite journal | vauthors = Blackburn GL, Wang KA | title = Dietary fat reduction and breast cancer outcome: results from the Women's Intervention Nutrition Study (WINS) | journal = The American Journal of Clinical Nutrition | volume = 86 | issue = 3 | pages = s878-81 | date = September 2007 | pmid = 18265482 | doi = 10.1093/ajcn/86.3.878S | doi-access = free }}</ref> and obesity-related [[Hypercholesterolemia|high cholesterol]] levels.<ref>BBC report [http://news.bbc.co.uk/1/hi/health/5171838.stm Weight link to breast cancer risk] {{webarchive|url=https://web.archive.org/web/20070313141518/http://news.bbc.co.uk/1/hi/health/5171838.stm |date=13 March 2007 }}</ref><ref>{{cite journal | vauthors = Kaiser J | title = Cancer. Cholesterol forges link between obesity and breast cancer | journal = Science | volume = 342 | issue = 6162 | pages = 1028 | date = November 2013 | pmid = 24288308 | doi = 10.1126/science.342.6162.1028 }}</ref> Dietary iodine deficiency may also play a role.<ref>{{cite journal | vauthors = Aceves C, Anguiano B, Delgado G | title = Is iodine a gatekeeper of the integrity of the mammary gland? | journal = Journal of Mammary Gland Biology and Neoplasia | volume = 10 | issue = 2 | pages = 189–96 | date = April 2005 | pmid = 16025225 | doi = 10.1007/s10911-005-5401-5 | s2cid = 16838840 }}</ref> Evidence for fiber is unclear. A 2015 review found that studies trying to link fiber intake with breast cancer produced mixed results.<ref>{{cite journal | vauthors = Mourouti N, Kontogianni MD, Papavagelis C, Panagiotakos DB | title = Diet and breast cancer: a systematic review | journal = International Journal of Food Sciences and Nutrition | volume = 66 | issue = 1 | pages = 1–42 | date = February 2015 | pmid = 25198160 | doi = 10.3109/09637486.2014.950207 | s2cid = 207498132 }}</ref> In 2016, a tentative association between low fiber intake during adolescence and breast cancer was observed.<ref>{{cite news | vauthors = Aubrey A |date = 1 February 2016 |title = A Diet High In Fiber May Help Protect Against Breast Cancer |url = https://www.npr.org/sections/thesalt/2016/02/01/464854395/a-diet-high-in-fiber-may-help-protect-against-breast-cancer |newspaper = [[NPR]] |access-date = 1 February 2016 |url-status = live |archive-url = https://web.archive.org/web/20160201114307/http://www.npr.org/sections/thesalt/2016/02/01/464854395/a-diet-high-in-fiber-may-help-protect-against-breast-cancer |archive-date = 1 February 2016 |df = dmy-all }}</ref>
[[Tobacco smoking|Smoking tobacco]] appears to increase the risk of breast cancer, with the greater the amount smoked and the earlier in life that smoking began, the higher the risk.<ref name="Smoking2011">{{cite journal | vauthors = Johnson KC, Miller AB, Collishaw NE, Palmer JR, Hammond SK, Salmon AG, Cantor KP, Miller MD, Boyd NF, Millar J, Turcotte F | display-authors = 6 | title = Active smoking and secondhand smoke increase breast cancer risk: the report of the Canadian Expert Panel on Tobacco Smoke and Breast Cancer Risk (2009) | journal = Tobacco Control | volume = 20 | issue = 1 | pages = e2 | date = January 2011 | pmid = 21148114 | doi = 10.1136/tc.2010.035931 | s2cid = 448229 }}</ref> In those who are long-term smokers, the relative risk is increased 35% to 50%.<ref name="Smoking2011" />
A lack of physical activity has been linked to about 10% of cases.<ref>{{cite journal | vauthors = Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT | title = Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy | journal = Lancet | volume = 380 | issue = 9838 | pages = 219–29 | date = July 2012 | pmid = 22818936 | pmc = 3645500 | doi = 10.1016/S0140-6736(12)61031-9 }}</ref> [[Sitting]] regularly for prolonged periods is associated with higher mortality from breast cancer. The risk is not negated by regular exercise, though it is lowered.<ref name="Biswas">{{cite journal | vauthors = Biswas A, Oh PI, Faulkner GE, Bajaj RR, Silver MA, Mitchell MS, Alter DA | title = Sedentary time and its association with risk for disease incidence, mortality, and hospitalization in adults: a systematic review and meta-analysis | journal = Annals of Internal Medicine | volume = 162 | issue = 2 | pages = 123–32 | date = January 2015 | pmid = 25599350 | doi = 10.7326/M14-1651 | s2cid = 7256176 }}</ref>
[[Hormone replacement therapy|Hormone therapy]] to treat [[menopause]] is also associated with an increased risk of breast cancer.<ref>{{cite journal | vauthors = | title = Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence | journal = Lancet | volume = 394 | issue = 10204 | pages = 1159–1168 | date = September 2019 | pmid = 31474332 | pmc = 6891893 | doi = 10.1016/S0140-6736(19)31709-X }}</ref> The use of [[hormonal birth control]] does not cause breast cancer for most women;<ref>{{cite journal | vauthors = Kanadys W, Barańska A, Malm M, Błaszczuk A, Polz-Dacewicz M, Janiszewska M, Jędrych M | title = Use of Oral Contraceptives as a Potential Risk Factor for Breast Cancer: A Systematic Review and Meta-Analysis of Case-Control Studies Up to 2010 | journal = International Journal of Environmental Research and Public Health | volume = 18 | issue = 9 | pages = 4638 | date = April 2021 | pmid = 33925599 | pmc = 8123798 | doi = 10.3390/ijerph18094638 | doi-access = free }}</ref> if it has an effect, it is small (on the order of 0.01% per user–year; comparable to the rate of [[maternal mortality in the United States]]<ref name=":0" />), temporary, and offset by the users' significantly reduced risk of ovarian and endometrial cancers.<ref name=":0">{{cite journal | vauthors = Chelmow D, Pearlman MD, Young A, Bozzuto L, Dayaratna S, Jeudy M, Kremer ME, Scott DM, O'Hara JS | display-authors = 6 | title = Executive Summary of the Early-Onset Breast Cancer Evidence Review Conference | journal = Obstetrics and Gynecology | volume = 135 | issue = 6 | pages = 1457–1478 | date = June 2020 | pmid = 32459439 | pmc = 7253192 | doi = 10.1097/AOG.0000000000003889 }}</ref> Among those with a family history of breast cancer, use of modern oral contraceptives does not appear to affect the risk of breast cancer.<ref>{{cite journal | vauthors = Gaffield ME, Culwell KR, Ravi A | title = Oral contraceptives and family history of breast cancer | journal = Contraception | volume = 80 | issue = 4 | pages = 372–380 | date = October 2009 | pmid = 19751860 | doi = 10.1016/j.contraception.2009.04.010 }}</ref> It is less certain whether hormonal contraceptives could increase the already high rates of breast cancer in women with mutations in the breast cancer susceptibility genes [[BRCA mutation|''BRCA1'' or ''BRCA2'']].<ref>{{cite journal | vauthors = Huber D, Seitz S, Kast K, Emons G, Ortmann O | title = Use of oral contraceptives in BRCA mutation carriers and risk for ovarian and breast cancer: a systematic review | journal = Archives of Gynecology and Obstetrics | volume = 301 | issue = 4 | pages = 875–884 | date = April 2020 | pmid = 32140806 | pmc = 8494665 | doi = 10.1007/s00404-020-05458-w }}</ref>
[[Breast feeding]] reduces the risk of several types of cancers, including breast cancer.<ref name=":3">{{cite journal | vauthors = Chowdhury R, Sinha B, Sankar MJ, Taneja S, Bhandari N, Rollins N, Bahl R, Martines J | display-authors = 6 | title = Breastfeeding and maternal health outcomes: a systematic review and meta-analysis | journal = Acta Paediatrica | volume = 104 | issue = 467 | pages = 96–113 | date = December 2015 | pmid = 26172878 | pmc = 4670483 | doi = 10.1111/apa.13102 }}</ref><ref>{{cite web|url=https://www.who.int/health-topics/breastfeeding#tab=tab_1|title=Breastfeeding|work= [[World Health Organization]]}}</ref><ref>{{cite web| url=https://www.cdc.gov/breastfeeding/faq/index.htm#benefits|title=Breastfeeding:Frequently Asked Questions (FAQs)|work= U.S. Center for disease control and prevention(CDC)|date=10 August 2021}}</ref><ref>{{cite journal | title = Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease | journal = Lancet | volume = 360 | issue = 9328 | pages = 187–195 | date = July 2002 | pmid = 12133652 | doi = 10.1016/S0140-6736(02)09454-0 | s2cid = 25250519 | author1 = Collaborative Group on Hormonal Factors in Breast Cancer }}</ref> In the 1980s, the [[abortion–breast cancer hypothesis]] posited that [[induced abortion]] increased the risk of developing breast cancer.<ref name="RUSSO_505">{{cite journal | vauthors = Russo J, Russo IH | title = Susceptibility of the mammary gland to carcinogenesis. II. Pregnancy interruption as a risk factor in tumor incidence | journal = The American Journal of Pathology | volume = 100 | issue = 2 | pages = 497–512 | date = August 1980 | pmid = 6773421 | pmc = 1903536 | quote = In contrast, abortion is associated with increased risk of carcinomas of the breast. The explanation for these epidemiologic findings is not known, but the parallelism between the DMBA-induced rat mammary carcinoma model and the human situation is striking. ... Abortion would interrupt this process, leaving in the gland undifferentiated structures like those observed in the rat mammary gland, which could render the gland again susceptible to carcinogenesis. }}</ref> This hypothesis was the subject of extensive scientific inquiry, which concluded that neither [[miscarriage]]s nor abortions are associated with a heightened risk for breast cancer.<ref>{{cite journal | vauthors = Beral V, Bull D, Doll R, Peto R, Reeves G | title = Breast cancer and abortion: collaborative reanalysis of data from 53 epidemiological studies, including 83?000 women with breast cancer from 16 countries | journal = Lancet | volume = 363 | issue = 9414 | pages = 1007–16 | date = March 2004 | pmid = 15051280 | doi = 10.1016/S0140-6736(04)15835-2 | s2cid = 20751083 }}</ref>
Other risk factors include [[radiation]]<ref name="acs bc facts 2005-6" /> and [[Circadian rhythm|circadian]] disruptions related to [[shift-work]]<ref>{{cite journal | vauthors = Wang XS, Armstrong ME, Cairns BJ, Key TJ, Travis RC | title = Shift work and chronic disease: the epidemiological evidence | journal = Occupational Medicine | volume = 61 | issue = 2 | pages = 78–89 | date = March 2011 | pmid = 21355031 | pmc = 3045028 | doi = 10.1093/occmed/kqr001 }}</ref> and routine late-night eating.<ref>{{cite journal | vauthors = Marinac CR, Nelson SH, Breen CI, Hartman SJ, Natarajan L, Pierce JP, Flatt SW, Sears DD, Patterson RE | display-authors = 6 | title = Prolonged Nightly Fasting and Breast Cancer Prognosis | journal = JAMA Oncology | volume = 2 | issue = 8 | pages = 1049–55 | date = August 2016 | pmid = 27032109 | pmc = 4982776 | doi = 10.1001/jamaoncol.2016.0164 }}</ref> A number of chemicals have also been linked, including [[polychlorinated biphenyls]], [[polycyclic aromatic hydrocarbons]], and [[organic solvents]]<ref>{{cite journal | vauthors = Brody JG, Rudel RA, Michels KB, Moysich KB, Bernstein L, Attfield KR, Gray S | title = Environmental pollutants, diet, physical activity, body size, and breast cancer: where do we stand in research to identify opportunities for prevention? | journal = Cancer | volume = 109 | issue = 12 Suppl | pages = 2627–34 | date = June 2007 | pmid = 17503444 | doi = 10.1002/cncr.22656 | s2cid = 34880415 }}</ref> Although the radiation from [[mammography]] is a low dose, it is estimated that yearly screening from 40 to 80 years of age will cause approximately 225 cases of fatal breast cancer per million women screened.<ref>{{cite journal | vauthors = Hendrick RE | title = Radiation doses and cancer risks from breast imaging studies | journal = Radiology | volume = 257 | issue = 1 | pages = 246–53 | date = October 2010 | pmid = 20736332 | doi = 10.1148/radiol.10100570 | doi-access = free }}</ref>
=== Genetics ===
Genetics is believed to be the primary cause of 5–10% of all cases.<ref name="Gage2012">{{cite journal | vauthors = Gage M, Wattendorf D, Henry LR | title = Translational advances regarding hereditary breast cancer syndromes | journal = Journal of Surgical Oncology | volume = 105 | issue = 5 | pages = 444–51 | date = April 2012 | pmid = 22441895 | doi = 10.1002/jso.21856 | s2cid = 3406636 }}</ref> Women whose mother was diagnosed before 50 have an increased risk of 1.7 and those whose mother was diagnosed at age 50 or after has an increased risk of 1.4.<ref>{{cite journal | vauthors = Colditz GA, Kaphingst KA, Hankinson SE, Rosner B | title = Family history and risk of breast cancer: nurses' health study | journal = Breast Cancer Research and Treatment | volume = 133 | issue = 3 | pages = 1097–104 | date = June 2012 | pmid = 22350789 | pmc = 3387322 | doi = 10.1007/s10549-012-1985-9 }}</ref> In those with zero, one or two affected relatives, the risk of breast cancer before the age of 80 is 7.8%, 13.3%, and 21.1% with a subsequent mortality from the disease of 2.3%, 4.2%, and 7.6% respectively.<ref>{{cite journal | title = Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease | journal = Lancet | volume = 358 | issue = 9291 | pages = 1389–99 | date = October 2001 | pmid = 11705483 | doi = 10.1016/S0140-6736(01)06524-2 | author1 = Collaborative Group on Hormonal Factors in Breast Cancer | s2cid = 24278814 }}</ref> In those with a first degree relative with the disease the risk of breast cancer between the age of 40 and 50 is double that of the general population.<ref>{{cite journal | vauthors = Nelson HD, Zakher B, Cantor A, Fu R, Griffin J, O'Meara ES, Buist DS, Kerlikowske K, van Ravesteyn NT, Trentham-Dietz A, Mandelblatt JS, Miglioretti DL | display-authors = 6 | title = Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis | journal = Annals of Internal Medicine | volume = 156 | issue = 9 | pages = 635–48 | date = May 2012 | pmid = 22547473 | pmc = 3561467 | doi = 10.7326/0003-4819-156-9-201205010-00006 }}</ref>
In less than 5% of cases, genetics plays a more significant role by causing a [[hereditary breast–ovarian cancer syndrome]].<ref name="Genetics2010">{{cite book | vauthors = Pasche B |title = Cancer Genetics (Cancer Treatment and Research) |publisher = Springer |location = Berlin |year = 2010 |pages = 19–20 |isbn = 978-1-4419-6032-0 }}</ref> This includes those who carry the [[BRCA mutation|''BRCA1'' and ''BRCA2'' gene mutation]].<ref name=Genetics2010 /> These mutations account for up to 90% of the total genetic influence with a risk of breast cancer of 60–80% in those affected.<ref name=Gage2012 /> Other significant mutations include ''p53'' ([[Li–Fraumeni syndrome]]), ''PTEN'' ([[Cowden syndrome]]), and ''STK11'' ([[Peutz–Jeghers syndrome]]), ''CHEK2'', ''ATM'', ''BRIP1'', and ''PALB2''.<ref name=Gage2012 /> In 2012, researchers said that there are four genetically distinct types of the breast cancer and that in each type, hallmark genetic changes lead to many cancers.<ref name=nyt23912>{{cite news | vauthors = Kolata G |title = Genetic Study Finds 4 Distinct Variations of Breast Cancer |url = https://www.nytimes.com/2012/09/24/health/study-finds-variations-of-breast-cancer.html |newspaper = The New York Times |date = 23 September 2012 |access-date = 23 September 2012 |url-status = live |archive-url = https://web.archive.org/web/20120924091105/http://www.nytimes.com/2012/09/24/health/study-finds-variations-of-breast-cancer.html |archive-date = 24 September 2012 |df = dmy-all }}</ref>
Other genetic predispositions include the density of the breast tissue and hormonal levels. Women with [[dense breast tissue]] are more likely to get tumors and are less likely to be diagnosed with breast cancer – because the dense tissue makes tumors less visible on mammograms. Furthermore, women with naturally high estrogen and progesterone levels are also at higher risk for tumor development.<ref>{{cite web |title=CDC – What Are the Risk Factors for Breast Cancer? |url=https://www.cdc.gov/cancer/breast/basic_info/risk_factors.htm |website=www.cdc.gov |date=14 December 2018}}</ref><ref>{{cite journal | vauthors = Tian JM, Ran B, Zhang CL, Yan DM, Li XH | title = Estrogen and progesterone promote breast cancer cell proliferation by inducing cyclin G1 expression | journal = Brazilian Journal of Medical and Biological Research | volume = 51 | issue = 3 | pages = 1–7 | date = January 2018 | pmid = 29513878 | pmc = 5912097 | doi = 10.1590/1414-431X20175612 | url = https://www.popline.org/node/328955 | access-date = 29 April 2019 | archive-date = 14 May 2017 | archive-url = https://web.archive.org/web/20170514183905/http://www.popline.org/node/328955 | url-status = dead }}</ref>
=== Medical conditions ===
Breast changes like [[atypical ductal hyperplasia]]<ref name="urlUnderstanding Breast Changes – National Cancer Institute">{{cite web |url = http://www.cancer.gov/cancertopics/understanding-breast-changes/page6#F8 |title = Understanding Breast Changes – National Cancer Institute |url-status = dead |archive-url = https://web.archive.org/web/20100527185336/http://www.cancer.gov/cancertopics/understanding-breast-changes/page6 |archive-date = 27 May 2010 }}</ref> and [[lobular carcinoma in situ|lobular carcinoma ''in situ'']],<ref>{{cite web |url = http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/page6 |title = Breast Cancer Treatment |publisher = National Cancer Institute |url-status = live |archive-url = https://web.archive.org/web/20150425224841/http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page6 |archive-date = 25 April 2015 |df = dmy-all |date = January 1980 }}</ref><ref name="pmid18562954">{{cite journal | vauthors = Afonso N, Bouwman D | title = Lobular carcinoma in situ | journal = European Journal of Cancer Prevention | volume = 17 | issue = 4 | pages = 312–6 | date = August 2008 | pmid = 18562954 | doi = 10.1097/CEJ.0b013e3282f75e5d | s2cid = 388045 }}</ref> found in benign breast conditions such as [[fibrocystic breast changes]], are correlated with an increased breast cancer risk.
[[Diabetes mellitus]] might also increase the risk of breast cancer.<ref name="pmid23709491">{{cite journal | vauthors = Anothaisintawee T, Wiratkapun C, Lerdsitthichai P, Kasamesup V, Wongwaisayawan S, Srinakarin J, Hirunpat S, Woodtichartpreecha P, Boonlikit S, Teerawattananon Y, Thakkinstian A | display-authors = 6 | title = Risk factors of breast cancer: a systematic review and meta-analysis | journal = Asia-Pacific Journal of Public Health | volume = 25 | issue = 5 | pages = 368–87 | date = September 2013 | pmid = 23709491 | doi = 10.1177/1010539513488795 | s2cid = 206616972 }}</ref> Autoimmune diseases such as [[lupus erythematosus]] seem also to increase the risk for the acquisition of breast cancer.<ref name="pmid21237645">{{cite journal | vauthors = Böhm I | title = Breast cancer in lupus | journal = Breast | volume = 20 | issue = 3 | pages = 288–90 | date = June 2011 | pmid = 21237645 | doi = 10.1016/j.breast.2010.12.005 | doi-access = free }}</ref>
The major causes of sporadic breast cancer are associated with hormone levels. Breast cancer is promoted by estrogen. This hormone activates the development of breast throughout puberty, menstrual cycles and pregnancy. The imbalance between estrogen and progesterone during the menstrual phases causes cell proliferation. Moreover, oxidative metabolites of estrogen can increase DNA damage and mutations. Repeated cycling and the impairment of repair process can transform a normal cell into pre-malignant and eventually malignant cell through mutation. During the premalignant stage, high proliferation of stromal cells can be activated by estrogen to support the development of breast cancer. During the ligand binding activation, the ER can regulate gene expression by interacting with estrogen response elements within the promotor of specific genes. The expression and activation of ER due to lack of estrogen can be stimulated by extracellular signals.<ref>{{cite journal | vauthors = Williams C, Lin CY | title = Oestrogen receptors in breast cancer: basic mechanisms and clinical implications | journal = Ecancermedicalscience | volume = 7 | pages = 370 | date = November 2013 | pmid = 24222786 | pmc = 3816846 | doi = 10.3332/ecancer.2013.370 }}</ref> Interestingly, the ER directly binding with the several proteins, including growth factor receptors, can promote the expression of genes related to cell growth and survival.<ref>{{cite journal | vauthors = Levin ER, Pietras RJ | title = Estrogen receptors outside the nucleus in breast cancer | journal = Breast Cancer Research and Treatment | volume = 108 | issue = 3 | pages = 351–361 | date = April 2008 | pmid = 17592774 | doi = 10.1007/s10549-007-9618-4 | s2cid = 11394158 }}</ref>
Raised [[prolactin]] levels in the blood are associated with increased risk of breast cancer.<ref>{{cite journal | vauthors = Wang M, Wu X, Chai F, Zhang Y, Jiang J | title = Plasma prolactin and breast cancer risk: a meta- analysis | journal = Scientific Reports | volume = 6 | pages = 25998 | date = May 2016 | pmid = 27184120 | pmc = 4869065 | doi = 10.1038/srep25998 | bibcode = 2016NatSR...625998W }}</ref> A meta-analysis of observational research with over two million individuals has suggested a moderate association of antipsychotic use with breast cancer, possibly mediated by prolactin-inducing properties of specific agents.<ref>{{cite journal | vauthors = Leung JC, Ng DW, Chu RY, Chan EW, Huang L, Lum DH, Chan EW, Smith DJ, Wong IC, Lai FT | display-authors = 6 | title = Association of antipsychotic use with breast cancer: a systematic review and meta-analysis of observational studies with over 2 million individuals | journal = Epidemiology and Psychiatric Sciences | volume = 31 | pages = e61 | date = September 2022 | pmid = 36059215 | pmc = 9483823 | doi = 10.1017/S2045796022000476 }}</ref>
== Pathophysiology ==
{{See also|Carcinogenesis}}
[[File:Lobules and ducts of the breast.jpg|thumb|[[Lactiferous duct|Ducts]] and lobules, the main locations of breast cancers]]
[[File:Signal transduction pathways.svg|thumb|Overview of signal transduction pathways involved in [[apoptosis|programmed cell death]]. Mutations leading to loss of this ability can lead to cancer formation.]]
Breast cancer, like other [[cancers]], occurs because of an interaction between an environmental (external) factor and a genetically susceptible host. Normal cells divide as many times as needed and stop. They attach to other cells and stay in place in tissues. Cells become cancerous when they lose their ability to stop dividing, to attach to other cells, to stay where they belong, and to die at the proper time.
Normal cells will self-destruct ([[apoptosis|programmed cell death]]) when they are no longer needed. Until then, cells are protected from programmed death by several protein clusters and pathways. One of the protective pathways is the [[PI3K]]/[[AKT]] pathway; another is the [[Ras (protein)|RAS]]/[[Mitogen-activated protein kinase kinase|MEK]]/[[Extracellular signal-regulated kinases|ERK]] pathway. Sometimes the genes along these protective pathways are mutated in a way that turns them permanently "on", rendering the cell incapable of self-destructing when it is no longer needed. This is one of the steps that causes cancer in combination with other mutations. Normally, the [[PTEN (gene)|PTEN]] protein turns off the PI3K/AKT pathway when the cell is ready for programmed cell death. In some breast cancers, the gene for the PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the "on" position, and the cancer cell does not self-destruct.<ref>{{cite conference | vauthors = Lee A, Arteaga C |title = 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium |book-title = Sunday Morning Year-End Review |date = 14 December 2009 |url = http://www.sabcs.org/Newsletter/Docs/SABCS_2009_Issue5.pdf |url-status = dead |archive-url = https://web.archive.org/web/20130813021816/http://www.sabcs.org/Newsletter/Docs/SABCS_2009_Issue5.pdf |archive-date = 13 August 2013 }}</ref>
Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure.<ref name="pmid16675129">{{cite journal | vauthors = Cavalieri E, Chakravarti D, Guttenplan J, Hart E, Ingle J, Jankowiak R, Muti P, Rogan E, Russo J, Santen R, Sutter T | display-authors = 6 | title = Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer| volume = 1766 | issue = 1 | pages = 63–78 | date = August 2006 | pmid = 16675129 | doi = 10.1016/j.bbcan.2006.03.001 }}</ref> Additionally, G-protein coupled [[estrogen receptor]]s have been associated with various cancers of the female reproductive system including breast cancer.<ref>{{cite journal | vauthors = Filardo EJ | title = A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 176 | pages = 38–48 | date = February 2018 | pmid = 28595943 | doi = 10.1016/j.jsbmb.2017.05.005 | s2cid = 19644829 }}</ref>
Abnormal [[growth factor]] signaling in the interaction between [[stromal cell]]s and [[epithelial cell]]s can facilitate malignant cell growth.<ref name="pmid12817994">{{cite journal | vauthors = Haslam SZ, Woodward TL | title = Host microenvironment in breast cancer development: epithelial-cell-stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland | journal = Breast Cancer Research | volume = 5 | issue = 4 | pages = 208–15 | date = June 2003 | pmid = 12817994 | pmc = 165024 | doi = 10.1186/bcr615 }}</ref><ref>{{cite journal | vauthors = Wiseman BS, Werb Z | title = Stromal effects on mammary gland development and breast cancer | journal = Science | volume = 296 | issue = 5570 | pages = 1046–9 | date = May 2002 | pmid = 12004111 | pmc = 2788989 | doi = 10.1126/science.1067431 | bibcode = 2002Sci...296.1046W }}</ref> In breast adipose tissue, overexpression of leptin leads to increased cell proliferation and cancer.<ref name="pmid20889333">{{cite journal | vauthors = Jardé T, Perrier S, Vasson MP, Caldefie-Chézet F | title = Molecular mechanisms of leptin and adiponectin in breast cancer | journal = European Journal of Cancer | volume = 47 | issue = 1 | pages = 33–43 | date = January 2011 | pmid = 20889333 | doi = 10.1016/j.ejca.2010.09.005 }}</ref>
In the United States, 10 to 20 percent of women with breast cancer or [[ovarian cancer]] have a first- or second-degree relative with one of these diseases. Men with breast cancer have an even higher likelihood. The familial tendency to develop these cancers is called [[hereditary breast–ovarian cancer syndrome]]. The best known of these, the [[BRCA mutation|''BRCA'' mutations]], confer a lifetime risk of breast cancer of between 60 and 85 percent and a lifetime risk of ovarian cancer of between 15 and 40 percent. Some mutations associated with cancer, such as ''[[p53]]'', ''[[BRCA1]]'' and ''[[BRCA2]]'', occur in mechanisms to correct errors in [[DNA]]. These mutations are either inherited or acquired after birth. Presumably, they allow further mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant organs.<ref name="acs bc facts 2005-6">{{cite web |author = American Cancer Society |year = 2005 |title = Breast Cancer Facts & Figures 2005–2006 |url = http://www.cancer.org/downloads/STT/CAFF2005BrFacspdf2005.pdf |access-date = 26 April 2007 |archive-url = https://web.archive.org/web/20070613192148/http://www.cancer.org/downloads/STT/CAFF2005BrFacspdf2005.pdf |archive-date = 13 June 2007 }}</ref><ref>{{cite journal | vauthors = Dunning AM, Healey CS, Pharoah PD, Teare MD, Ponder BA, Easton DF | title = A systematic review of genetic polymorphisms and breast cancer risk | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 8 | issue = 10 | pages = 843–54 | date = October 1999 | pmid = 10548311 | url = http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10548311 }}</ref> However, there is strong evidence of residual risk variation that goes well beyond hereditary ''BRCA'' gene mutations between carrier families. This is caused by unobserved risk factors.<ref>{{cite journal | vauthors = Begg CB, Haile RW, Borg A, Malone KE, Concannon P, Thomas DC, Langholz B, Bernstein L, Olsen JH, Lynch CF, Anton-Culver H, Capanu M, Liang X, Hummer AJ, Sima C, Bernstein JL | display-authors = 6 | title = Variation of breast cancer risk among BRCA1/2 carriers | journal = JAMA | volume = 299 | issue = 2 | pages = 194–201 | date = January 2008 | pmid = 18182601 | pmc = 2714486 | doi = 10.1001/jama.2007.55-a }}</ref> This implicates environmental and other causes as triggers for breast cancers. The inherited mutation in ''BRCA1'' or ''BRCA2'' genes can interfere with repair of DNA cross links and DNA double strand breaks (known functions of the encoded protein).<ref>{{cite journal | vauthors = Patel KJ, Yu VP, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ, Colledge WH, Friedman LS, Ponder BA, Venkitaraman AR | display-authors = 6 | title = Involvement of Brca2 in DNA repair | journal = Molecular Cell | volume = 1 | issue = 3 | pages = 347–57 | date = February 1998 | pmid = 9660919 | doi = 10.1016/S1097-2765(00)80035-0 | doi-access = free }}</ref> These carcinogens cause DNA damage such as DNA cross links and double strand breaks that often require repairs by pathways containing BRCA1 and BRCA2.<ref>{{cite journal | vauthors = Marietta C, Thompson LH, Lamerdin JE, Brooks PJ | title = Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: implications for alcohol-related carcinogenesis | journal = Mutation Research | volume = 664 | issue = 1–2 | pages = 77–83 | date = May 2009 | pmid = 19428384 | pmc = 2807731 | doi = 10.1016/j.mrfmmm.2009.03.011 }}</ref><ref>{{cite journal | vauthors = Theruvathu JA, Jaruga P, Nath RG, Dizdaroglu M, Brooks PJ | title = Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde | journal = Nucleic Acids Research | volume = 33 | issue = 11 | pages = 3513–20 | year = 2005 | pmid = 15972793 | pmc = 1156964 | doi = 10.1093/nar/gki661 }}</ref> However, mutations in ''BRCA'' genes account for only 2 to 3 percent of all breast cancers.<ref>{{cite journal | vauthors = Wooster R, Weber BL | s2cid = 26602401 | title = Breast and ovarian cancer | journal = The New England Journal of Medicine | volume = 348 | issue = 23 | pages = 2339–47 | date = June 2003 | pmid = 12788999 | doi = 10.1056/NEJMra012284 }}</ref> Levin ''et al.'' say that cancer may not be inevitable for all carriers of ''BRCA1'' and ''BRCA2'' mutations.<ref name="Levin2012">{{cite journal | vauthors = Levin B, Lech D, Friedenson B | title = Evidence that BRCA1- or BRCA2-associated cancers are not inevitable | journal = Molecular Medicine | volume = 18 | issue = 9 | pages = 1327–37 | date = December 2012 | pmid = 22972572 | pmc = 3521784 | doi = 10.2119/molmed.2012.00280 }}</ref> About half of hereditary breast–ovarian cancer syndromes involve unknown genes. Furthermore, certain latent viruses, may decrease the expression of the ''BRCA1'' gene and increase the risk of breast tumors.<ref>{{cite journal | vauthors = Polansky H, Schwab H | title = How latent viruses cause breast cancer: An explanation based on the microcompetition model | journal = Bosnian Journal of Basic Medical Sciences | volume = 19 | issue = 3 | pages = 221–226 | date = August 2019 | pmid = 30579323 | pmc = 6716096 | doi = 10.17305/bjbms.2018.3950 }}</ref>
[[GATA-3]] directly controls the expression of estrogen receptor (ER) and other genes associated with epithelial differentiation, and the loss of GATA-3 leads to loss of differentiation and poor prognosis due to cancer cell invasion and metastasis.<ref>{{cite journal | vauthors = Kouros-Mehr H, Kim JW, Bechis SK, Werb Z | title = GATA-3 and the regulation of the mammary luminal cell fate | journal = Current Opinion in Cell Biology | volume = 20 | issue = 2 | pages = 164–70 | date = April 2008 | pmid = 18358709 | pmc = 2397451 | doi = 10.1016/j.ceb.2008.02.003 }}</ref>
== Diagnosis ==
Most types of breast cancer are easy to diagnose by microscopic analysis of a sample – or [[breast biopsy|biopsy]] [[abortion–breast cancer hypothesis|–]] of the affected area of the breast. Also, there are types of breast cancer that require specialized lab exams.
The two most commonly used screening methods, physical examination of the breasts by a healthcare provider and mammography, can offer an approximate likelihood that a lump is cancer, and may also detect some other lesions, such as a simple [[cyst]].<ref>{{cite journal | vauthors = Saslow D, Hannan J, Osuch J, Alciati MH, Baines C, Barton M, Bobo JK, Coleman C, Dolan M, Gaumer G, Kopans D, Kutner S, Lane DS, Lawson H, Meissner H, Moorman C, Pennypacker H, Pierce P, Sciandra E, Smith R, Coates R | display-authors = 6 | title = Clinical breast examination: practical recommendations for optimizing performance and reporting | journal = CA: A Cancer Journal for Clinicians | volume = 54 | issue = 6 | pages = 327–44 | year = 2004 | pmid = 15537576 | doi = 10.3322/canjclin.54.6.327 | doi-access = free }}</ref> When these examinations are inconclusive, a healthcare provider can remove a sample of the fluid in the lump for microscopic analysis (a procedure known as [[fine needle aspiration]], or fine needle aspiration and cytology, FNAC) to help establish the diagnosis. A needle aspiration can be performed in a healthcare provider's office or clinic. A local anesthetic may be used to numb the breast tissue to prevent pain during the procedure, but may not be necessary if the lump isn't beneath the skin. A finding of clear fluid makes the lump highly unlikely to be cancerous, but bloody fluid may be sent off for inspection under a microscope for cancerous cells. Together, physical examination of the breasts, mammography, and FNAC can be used to diagnose breast cancer with a good degree of accuracy.
Other options for biopsy include a [[core biopsy]] or [[vacuum-assisted breast biopsy]],<ref name="pmid20130983">{{cite journal | vauthors = Yu YH, Liang C, Yuan XZ | title = Diagnostic value of vacuum-assisted breast biopsy for breast carcinoma: a meta-analysis and systematic review | journal = Breast Cancer Research and Treatment | volume = 120 | issue = 2 | pages = 469–79 | date = April 2010 | pmid = 20130983 | doi = 10.1007/s10549-010-0750-1 | s2cid = 22685290 }}</ref> which are procedures in which a section of the breast lump is removed; or an [[excisional biopsy]], in which the entire lump is removed. Very often the results of physical examination by a healthcare provider, mammography, and additional tests that may be performed in special circumstances (such as imaging by [[medical ultrasonography|ultrasound]] or [[magnetic resonance imaging|MRI]]) are sufficient to warrant excisional biopsy as the definitive diagnostic and primary treatment method.<ref>{{cite journal | vauthors = Ferguson MJ | title = Multifocal invasive mucinous carcinoma of the breast | journal = Journal of Medical Radiation Sciences | volume = 67 | issue = 2 | pages = 155–158 | date = June 2020 | pmid = 31975569 | pmc = 7276192 | doi = 10.1002/jmrs.379 }}</ref>{{Primary source inline|date=July 2020}}
<gallery class="center">
File:Breast MRI T1W FSE ARC T2W FSE ARC T2W FSE IDEAL 09-arrow.jpg|MRI showing breast cancer
File:Breast cancer.JPG|Excised human [[breast]] [[tissue (biology)|tissue]], showing an irregular, dense, white [[wikt:stellate|stellate]] area of cancer 2 cm in diameter, within yellow fatty tissue
File:Invasive Ductal Carcinoma 40x.jpg|High-grade invasive ductal carcinoma, with minimal tubule formation, marked [[pleomorphism (cytology)|pleomorphism]], and prominent [[Breast cancer classification#Mitotic count|mitoses]], 40x field
File:Breast carcinoma in a lymph node.jpg|Micrograph showing a lymph node invaded by ductal breast carcinoma, with an extension of the tumor beyond the lymph node
File:Neuropilin-2 (Nrp2) expression in normal breast and breast carcinoma tissue.jpg|Neuropilin-2 expression in normal breast and breast carcinoma tissue
File:Mamma-CA.jpg|F-18 FDG PET/CT: A breast cancer metastasis to the right scapula
File:Needle Breast Biopsy.png|Needle breast biopsy
File:Manual compression elastography of invazive ductal carcinoma 00132.gif|Elastography shows stiff cancer tissue on ultrasound imaging.
File:Breast cancer ultrasound.jpg|Ultrasound image shows irregularly shaped mass of breast cancer.
File:Infiltrating breast carcinoma.jpg|Infiltrating (invasive) breast carcinoma
File:Mammo breast cancer wArrows.jpg|[[Mammograms]] showing a normal breast (left) and a breast with cancer (right)
</gallery>
=== Classification ===
{{Main|Breast cancer classification}}
Breast cancers are classified by several grading systems. Each of these influences the [[prognosis]] and can affect treatment response. Description of a breast cancer optimally includes all of these factors.
[[File:Pie chart of incidence and prognosis of histopathologic breast cancer types.png|thumb|upright=1.25|Histopathologic types of breast cancer, with relative incidences and prognoses]]
* '''Histopathology'''. Breast cancer is usually classified primarily by its [[Breast cancer classification#Histopathology|histological]] appearance. Most breast cancers are derived from the epithelium lining the ducts or lobules, and these cancers are classified as [[mammary ductal carcinoma|ductal]] or lobular carcinoma. ''Carcinoma in situ'' is growth of low-grade cancerous or precancerous cells within a particular tissue compartment such as the mammary duct without invasion of the surrounding tissue. In contrast, ''invasive carcinoma'' does not confine itself to the initial tissue compartment.<ref>{{cite book | vauthors = Kosir MA |date=July 2019|title=Merck Manual, Professional Edition|chapter-url=http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html|archive-url= https://web.archive.org/web/20111110075702/http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html|archive-date=10 November 2011|url-status=live|chapter=Ch. 253, Breast Cancer}}</ref>
* '''Grade'''. [[Breast cancer classification#Grade|Grading]] compares the appearance of the breast cancer cells to the appearance of normal breast tissue. Normal cells in an organ like the breast become differentiated, meaning that they take on specific shapes and forms that reflect their function as part of that organ. Cancerous cells lose that differentiation. In cancer, the cells that would normally line up in an orderly way to make up the milk ducts become disorganized. Cell division becomes uncontrolled. Cell nuclei become less uniform. Pathologists describe cells as well differentiated (low grade), moderately differentiated (intermediate grade), and poorly differentiated (high grade) as the cells progressively lose the features seen in normal breast cells. Poorly differentiated cancers (the ones whose tissue is least like normal breast tissue) have a worse prognosis.
* '''Stage'''. [[Breast cancer classification#Stage|Breast cancer staging]] using the [[Breast cancer classification#TNM system|TNM system]] is based on the size of the <u>t</u>umor ('''T'''), whether or not the tumor has spread to the [[lymph node|lymph]] <u>n</u>odes ('''N''') in the armpits, and whether the tumor has <u>m</u>etastasized ('''M''') (i.e. spread to a more distant part of the body). Larger size, nodal spread, and metastasis have a larger stage number and a worse prognosis. <br />The main stages are:
** Stage 0 is a pre-cancerous or marker condition, either [[ductal carcinoma in situ]] (DCIS) or [[lobular carcinoma in situ]] (LCIS).
** Stages 1–3 are within the breast or regional lymph nodes.
** Stage 4 is [[Metastatic breast cancer|'metastatic' cancer]] that has a less favorable prognosis since it has spread beyond the breast and regional lymph nodes.
<gallery>
File:Diagram showing stage T1 breast cancer CRUK 244.svg|Stage T1 breast cancer
File:Diagram showing stage T2 breast cancer CRUK 252.svg|Stage T2 breast cancer
File:Diagram showing stage T3 breast cancer CRUK 259.svg|Stage T3 breast cancer
File:Stage 4 of Breast Cancer.jpg|Metastatic or stage 4 breast cancer
</gallery>
:Where available, [[imaging studies]] may be employed as part of the staging process in select cases to look for signs of metastatic cancer. However, in cases of breast cancer with low risk for metastasis, the risks associated with [[Positron emission tomography|PET scans]], [[X-ray computed tomography|CT scans]], or [[Bone scintigraphy|bone scans]] outweigh the possible benefits, as these procedures expose the person to a substantial amount of potentially dangerous ionizing radiation.<ref name="ASCOfive">{{Citation |author1 = American Society of Clinical Oncology |author1-link = American Society of Clinical Oncology |title = Five Things Physicians and Patients Should Question |publisher = [[American Society of Clinical Oncology]] |work = Choosing Wisely: an initiative of the [[ABIM Foundation]] |url = http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf |access-date = 14 August 2012 |url-status = dead |archive-url = https://web.archive.org/web/20120731073425/http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf |archive-date = 31 July 2012 |df = dmy-all }}</ref><ref name="CarlsonBreast">{{cite journal | vauthors = Carlson RW, Allred DC, Anderson BO, Burstein HJ, Carter WB, Edge SB, Erban JK, Farrar WB, Goldstein LJ, Gradishar WJ, Hayes DF, Hudis CA, Jahanzeb M, Kiel K, Ljung BM, Marcom PK, Mayer IA, McCormick B, Nabell LM, Pierce LJ, Reed EC, Smith ML, Somlo G, Theriault RL, Topham NS, Ward JH, Winer EP, Wolff AC | display-authors = 6 | title = Breast cancer. Clinical practice guidelines in oncology | journal = Journal of the National Comprehensive Cancer Network | volume = 7 | issue = 2 | pages = 122–92 | date = February 2009 | pmid = 19200416 | doi = 10.6004/jnccn.2009.0012 | author29 = NCCN Breast Cancer Clinical Practice Guidelines Panel | doi-access = free }}</ref>
* '''Receptor status'''. Breast cancer cells have [[Breast cancer classification#Receptor status|receptors]] on their surface and in their [[cytoplasm]] and [[Cell nucleus|nucleus]]. Chemical messengers such as [[hormone]]s bind to [[receptor (biochemistry)|receptors]], and this causes changes in the cell. Breast cancer cells may or may not have three important receptors: [[estrogen receptor]] (ER), [[progesterone receptor]] (PR), and [[HER2/neu|HER2]]. <br />ER+ cancer cells (that is, cancer cells that have estrogen receptors) depend on estrogen for their growth, so they can be treated with drugs to block estrogen effects (e.g. [[tamoxifen]]), and generally have a better prognosis. Untreated, HER2+ breast cancers are generally more aggressive than HER2- breast cancers,<ref>{{cite book | vauthors = Kumar V, Abbas A |title = Robbins and Cotran Pathologic Basis of Disease |year = 2010 |publisher = Saunders, an imprint of Elsevier inc. |location = Philadelphia |isbn = 978-1-4160-3121-5 |page = 1090 }}</ref><ref name="sotirou">{{cite journal | vauthors = Sotiriou C, Pusztai L | title = Gene-expression signatures in breast cancer | journal = The New England Journal of Medicine | volume = 360 | issue = 8 | pages = 790–800 | date = February 2009 | pmid = 19228622 | doi = 10.1056/NEJMra0801289 }}</ref> but HER2+ cancer cells respond to drugs such as the [[monoclonal antibody]] [[trastuzumab]] (in combination with conventional chemotherapy), and this has improved the prognosis significantly.<ref>{{cite journal | vauthors = Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N | display-authors = 6 | title = Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer | journal = The New England Journal of Medicine | volume = 353 | issue = 16 | pages = 1673–84 | date = October 2005 | pmid = 16236738 | doi = 10.1056/NEJMoa052122 | s2cid = 9534884 }}</ref> Cells that do not have any of these three receptor types (estrogen receptors, progesterone receptors, or HER2) are called [[triple-negative breast cancer|triple-negative]], although they frequently do express receptors for other hormones, such as [[androgen receptor]] and [[prolactin receptor]].
* '''DNA assays'''. [[Breast cancer classification#DNA classification|DNA testing]] of various types including [[DNA microarray]]s have compared normal cells to breast cancer cells. The specific changes in a particular breast cancer can be used to classify the cancer in several ways, and may assist in choosing the most effective treatment for that DNA type.
<gallery>
File:Diagram showing stage 1A breast cancer CRUK 199.svg|Stage 1A breast cancer
File:Diagram showing stage 1B breast cancer CRUK 202.svg|Stage 1B breast cancer
File:Diagram 1 of 2 showing stage 2A breast cancer CRUK 003.svg|Stage 2A breast cancer
File:Diagram 2 of 2 showing stage 2A breast cancer CRUK 009.svg|Stage 2A breast cancer
File:Diagram 1 of 3 showing stage 2B breast cancer CRUK 006.svg|Stage 2B breast cancer
File:Diagram 2 of 3 showing stage 2B breast cancer CRUK 012.svg|Stage 2B breast cancer
File:Diagram 3 of 3 showing stage 2B breast cancer CRUK 015.svg|Stage 2B breast cancer
File:Diagram 1 of 3 showing stage 3A breast cancer CRUK 007.svg|Stage 3A breast cancer
File:Diagram 2 of 3 showing stage 3A breast cancer CRUK 013.svg|Stage 3A breast cancer
File:Diagram 3 of 3 showing stage 3A breast cancer CRUK 016.svg|Stage 3A breast cancer
File:Diagram 1 of 2 showing stage 3B breast cancer CRUK 004.svg|Stage 3B breast cancer
File:Diagram 2 of 2 showing stage 3B breast cancer CRUK 010.svg|Stage 3B breast cancer
File:Diagram showing stage 4 breast cancer CRUK 228.svg|Stage 4 breast cancer
</gallery>
== Screening ==
{{Main|Breast cancer screening}}
[[File:BreastScreen Aotearoa.JPG|thumb|A mobile breast cancer screening unit in New Zealand]]
Breast cancer screening refers to testing otherwise-healthy women for breast cancer in an attempt to achieve an earlier diagnosis under the assumption that early detection will improve outcomes. A number of screening tests have been employed including clinical and self [[breast exams]], [[mammography]], genetic screening, ultrasound, and magnetic resonance imaging.
A clinical or self breast exam involves feeling the breast for [[breast lump|lumps]] or other abnormalities. Clinical breast exams are performed by health care providers, while self-breast exams are performed by the person themselves.<ref>{{cite web |title = Screening |url = https://www.cdc.gov/cancer/breast/basic_info/screening.htm |work = Centers for Disease Control and Prevention |access-date = 17 November 2015 |url-status = live |archive-url = https://web.archive.org/web/20151118012201/http://www.cdc.gov/cancer/breast/basic_info/screening.htm |archive-date = 18 November 2015 |df = dmy-all |date = 11 September 2018 }}</ref> Evidence does not support the effectiveness of either type of breast exam, as by the time a lump is large enough to be found it is likely to have been growing for several years and thus soon be large enough to be found without an exam.<ref name=USPSTFScreen2009>{{cite web |title = Screening for Breast Cancer |url = http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm |work = US Preventive Services Task Force |date = December 2009 |access-date = 24 December 2012 |url-status = dead |archive-url = https://web.archive.org/web/20130102015424/http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm |archive-date = 2 January 2013 |df = dmy-all }}</ref><ref>{{cite journal | vauthors = Kösters JP, Gøtzsche PC | title = Regular self-examination or clinical examination for early detection of breast cancer | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD003373 | year = 2003 | volume = 2010 | pmid = 12804462 | doi = 10.1002/14651858.CD003373 | pmc = 7387360 }}</ref> Mammographic screening for breast cancer uses [[X-ray]]s to examine the breast for any uncharacteristic masses or lumps. During a screening, the breast is compressed and a technician takes photos from multiple angles. A general mammogram takes photos of the entire breast, while a diagnostic mammogram focuses on a specific lump or area of concern.<ref>{{cite web |title = Breast Cancer and Mammograms |url = http://www.webmd.com/breast-cancer/guide/mammograms |work = WebMD |access-date = 24 December 2012 |url-status = live |archive-url = https://web.archive.org/web/20121228104148/http://www.webmd.com/breast-cancer/guide/mammograms |archive-date = 28 December 2012 |df = dmy-all }}</ref>
A number of national bodies recommend breast cancer screening. For the average woman, the [[U.S. Preventive Services Task Force]] and [[American College of Physicians]] recommends mammography every two years in women between the ages of 50 and 74,<ref name=USPSTFScreen2016 /><ref>{{cite journal | vauthors = Qaseem A, Lin JS, Mustafa RA, Horwitch CA, Wilt TJ | title = Screening for Breast Cancer in Average-Risk Women: A Guidance Statement From the American College of Physicians | journal = Annals of Internal Medicine | volume = 170 | issue = 8 | pages = 547–560 | date = April 2019 | pmid = 30959525 | doi = 10.7326/M18-2147 | doi-access = free }}</ref> the [[Council of Europe]] recommends mammography between 50 and 69 with most programs using a 2-year frequency,<ref>{{cite journal | vauthors = Biesheuvel C, Weigel S, Heindel W | title = Mammography Screening: Evidence, History and Current Practice in Germany and Other European Countries | journal = Breast Care | volume = 6 | issue = 2 | pages = 104–109 | year = 2011 | pmid = 21673820 | pmc = 3104900 | doi = 10.1159/000327493 }}</ref> while the European Commission recommends mammography from 45 to 75 every 2 to 3 years,<ref>{{cite journal | vauthors = Schünemann HJ, Lerda D, Quinn C, Follmann M, Alonso-Coello P, Rossi PG, Lebeau A, Nyström L, Broeders M, Ioannidou-Mouzaka L, Duffy SW, Borisch B, Fitzpatrick P, Hofvind S, Castells X, Giordano L, Canelo-Aybar C, Warman S, Mansel R, Sardanelli F, Parmelli E, Gräwingholt A, Saz-Parkinson Z | display-authors = 6 | title = Breast Cancer Screening and Diagnosis: A Synopsis of the European Breast Guidelines | journal = Annals of Internal Medicine | volume = 172 | issue = 1 | pages = 46–56 | date = January 2020 | pmid = 31766052 | doi = 10.7326/M19-2125 | doi-access = free }}</ref> and in Canada screening is recommended between the ages of 50 and 74 at a frequency of 2 to 3 years.<ref>{{cite journal | vauthors = Tonelli M, Connor Gorber S, Joffres M, Dickinson J, Singh H, Lewin G, Birtwhistle R, Fitzpatrick-Lewis D, Hodgson N, Ciliska D, Gauld M, Liu YY | display-authors = 6 | title = Recommendations on screening for breast cancer in average-risk women aged 40–74 years | journal = CMAJ | volume = 183 | issue = 17 | pages = 1991–2001 | date = November 2011 | pmid = 22106103 | pmc = 3225421 | doi = 10.1503/cmaj.110334 }}</ref> The American Cancer Society also endorses that women ages 40 and older receive mammograms annually.<ref>{{cite journal | vauthors = Moss S | title = Should women under 50 be screened for breast cancer? | journal = British Journal of Cancer | volume = 91 | issue = 3 | pages = 413–417 | date = August 2004 | pmid = 15213718 | pmc = 2409834 | doi = 10.1038/sj.bjc.6601966 }}</ref> These task force reports point out that in addition to unnecessary surgery and anxiety, the risks of more frequent mammograms include a small but significant increase in breast cancer induced by radiation.<ref>{{cite web |url = http://www.ahrq.gov/clinic/3rduspstf/breastCancer/brcanrr.htm#ref31 |title = Breast Cancer: Screening |work = United States Preventive Services Task Force |url-status = dead |archive-url = https://web.archive.org/web/20130616040709/http://www.ahrq.gov/clinic/3rduspstf/breastcancer/brcanrr.htm |archive-date = 16 June 2013 }}</ref>
The [[Cochrane collaboration]] (2013) states that the best quality evidence neither demonstrates a reduction in cancer specific, nor a reduction in all cause mortality from screening mammography.<ref name="Got2013" /> When less rigorous trials are added to the analysis there is a reduction in mortality due to breast cancer of 0.05% (a decrease of 1 in 2000 deaths from breast cancer over 10 years or a relative decrease of 15% from breast cancer).<ref name=Got2013 /> Screening over 10 years results in a 30% increase in rates of over-diagnosis and over-treatment (3 to 14 per 1000) and more than half will have at least one falsely positive test.<ref name=Got2013 /><ref>{{cite journal | vauthors = Welch HG, Passow HJ | title = Quantifying the benefits and harms of screening mammography | journal = JAMA Internal Medicine | volume = 174 | issue = 3 | pages = 448–54 | date = March 2014 | pmid = 24380095 | doi = 10.1001/jamainternmed.2013.13635 }}</ref> This has resulted in the view that it is not clear whether mammography screening does more good or harm.<ref name=Got2013 /> Cochrane states that, due to recent improvements in breast cancer treatment, and the risks of false positives from breast cancer screening leading to unnecessary treatment, "it therefore no longer seems beneficial to attend for breast cancer screening" at any age.<ref>{{cite web |url = http://nordic.cochrane.org/screening-breast-cancer-mammography |title = Screening for breast cancer with mammography |publisher = Cochrane Nordic |date = 27 August 2015 |access-date = 15 October 2015 |url-status = live |archive-url = https://web.archive.org/web/20151029161343/http://nordic.cochrane.org/screening-breast-cancer-mammography |archive-date = 29 October 2015 |df = dmy-all }}</ref> Whether MRI as a screening method has greater harms or benefits when compared to standard mammography is not known.<ref>{{cite journal | title = Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement | journal = Annals of Internal Medicine | volume = 151 | issue = 10 | pages = 716–26, W-236 | date = November 2009 | pmid = 19920272 | doi = 10.7326/0003-4819-151-10-200911170-00008 | url = http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm | url-status = dead | access-date = 24 December 2012 | archive-url = https://web.archive.org/web/20130102015424/http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm | df = dmy-all | archive-date = 2 January 2013 | author1 = US Preventive Services Task Force }}</ref><ref>{{cite journal | title = Magnetic Resonance Imaging as an Adjunct to Mammography for Breast Cancer Screening in Women at Less Than High Risk for Breast Cancer: A Health Technology Assessment | journal = Ontario Health Technology Assessment Series | volume = 16 | issue = 20 | pages = 1–30 | date = 1 November 2016 | pmid = 27990198 | pmc = 5156844 }}</ref>
== Prevention ==
=== Lifestyle ===
Women can reduce their risk of breast cancer by maintaining a healthy weight, reducing [[alcohol use]], increasing physical activity, and [[breast-feeding]].<ref name="WCRF2007">{{Cite web|url=https://www.cancer.org/cancer/breast-cancer/risk-and-prevention/lifestyle-related-breast-cancer-risk-factors.html|title=Lifestyle-related Breast Cancer Risk Factors|website=www.cancer.org|access-date=18 April 2018}}</ref> These modifications might prevent 38% of breast cancers in the US, 42% in the UK, 28% in Brazil, and 20% in China.<ref name=WCRF2007 /> The benefits with moderate exercise such as brisk walking are seen at all age groups including postmenopausal women.<ref name=WCRF2007 /><ref>{{cite journal | vauthors = Eliassen AH, Hankinson SE, Rosner B, Holmes MD, Willett WC | title = Physical activity and risk of breast cancer among postmenopausal women | journal = Archives of Internal Medicine | volume = 170 | issue = 19 | pages = 1758–64 | date = October 2010 | pmid = 20975025 | pmc = 3142573 | doi = 10.1001/archinternmed.2010.363 }}</ref> High levels of physical activity reduce the risk of breast cancer by about 14%.<ref name="BMJ2016">{{cite journal | vauthors = Kyu HH, Bachman VF, Alexander LT, Mumford JE, Afshin A, Estep K, Veerman JL, Delwiche K, Iannarone ML, Moyer ML, Cercy K, Vos T, Murray CJ, Forouzanfar MH | display-authors = 6 | title = Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013 | journal = BMJ | volume = 354 | pages = i3857 | date = August 2016 | pmid = 27510511 | pmc = 4979358 | doi = 10.1136/bmj.i3857 }}</ref> Strategies that encourage regular physical activity and reduce obesity could also have other benefits, such as reduced risks of cardiovascular disease and diabetes.<ref name=Hay2013 /> A study that included data from 130,957 women of European ancestry found “strong evidence that greater levels of physical activity and less sedentary time are likely to reduce breast cancer risk, with results generally consistent across breast cancer subtypes”.<ref>{{Cite news |title=New study finds 'strong evidence' that exercise cuts breast cancer risk |language=en-GB |work=belfasttelegraph |url=https://www.belfasttelegraph.co.uk/news/uk/new-study-finds-strong-evidence-that-exercise-cuts-breast-cancer-risk-41967524.html |access-date=2022-09-07 |issn=0307-1235}}</ref>
The [[American Cancer Society]] and the [[American Society of Clinical Oncology]] advised in 2016 that people should eat a diet high in vegetables, fruits, whole grains, and legumes.<ref>{{cite journal | vauthors = Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA | display-authors = 6 | title = American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline | journal = CA: A Cancer Journal for Clinicians | volume = 66 | issue = 1 | pages = 43–73 | date = January 2016 | pmid = 26641959 | doi = 10.3322/caac.21319 | doi-access = free }}</ref> High intake of citrus fruit has been associated with a 10% reduction in the risk of breast cancer.<ref>{{cite journal | vauthors = Song JK, Bae JM | title = Citrus fruit intake and breast cancer risk: a quantitative systematic review | journal = Journal of Breast Cancer | volume = 16 | issue = 1 | pages = 72–6 | date = March 2013 | pmid = 23593085 | pmc = 3625773 | doi = 10.4048/jbc.2013.16.1.72 }}</ref> Marine [[omega-3 polyunsaturated fatty acids]] appear to reduce the risk.<ref name="pmid23814120">{{cite journal | vauthors = Zheng JS, Hu XJ, Zhao YM, Yang J, Li D | title = Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies | journal = BMJ | volume = 346 | pages = f3706 | date = June 2013 | pmid = 23814120 | doi = 10.1136/bmj.f3706 | doi-access = free }}</ref> High consumption of [[soy]]-based foods may reduce risk.<ref>{{cite journal | vauthors = Wu AH, Yu MC, Tseng CC, Pike MC | title = Epidemiology of soy exposures and breast cancer risk | journal = British Journal of Cancer | volume = 98 | issue = 1 | pages = 9–14 | date = January 2008 | pmid = 18182974 | pmc = 2359677 | doi = 10.1038/sj.bjc.6604145 }}</ref>
=== Pre-emptive surgery ===
Removal of both breasts before any cancer has been diagnosed or any suspicious lump or other lesion has appeared (a procedure known as "prophylactic bilateral [[preventive mastectomy|mastectomy]]" or "risk reducing mastectomy") may be considered in women with BRCA1 and BRCA2 mutations, which are associated with a substantially heightened risk for an eventual diagnosis of breast cancer.<ref>{{cite journal | vauthors = Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, Petty PM, Sellers TA, Johnson JL, McDonnell SK, Frost MH, Jenkins RB | display-authors = 6 | title = Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer | journal = The New England Journal of Medicine | volume = 340 | issue = 2 | pages = 77–84 | date = January 1999 | pmid = 9887158 | doi = 10.1056/NEJM199901143400201 }}</ref><ref>{{cite journal | vauthors = Meijers-Heijboer H, van Geel B, van Putten WL, Henzen-Logmans SC, Seynaeve C, Menke-Pluymers MB, Bartels CC, Verhoog LC, van den Ouweland AM, Niermeijer MF, Brekelmans CT, Klijn JG | display-authors = 6 | title = Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation | journal = The New England Journal of Medicine | volume = 345 | issue = 3 | pages = 159–64 | date = July 2001 | pmid = 11463009 | doi = 10.1056/NEJM200107193450301 | url = https://pure.eur.nl/ws/files/46620151/11463009.pdf }}</ref> Evidence is not strong enough to support this procedure in anyone but women at the highest risk.<ref name=":1">{{cite journal | vauthors = Carbine NE, Lostumbo L, Wallace J, Ko H | title = Risk-reducing mastectomy for the prevention of primary breast cancer | journal = The Cochrane Database of Systematic Reviews | volume = 4 | pages = CD002748 | date = April 2018 | pmid = 29620792 | pmc = 6494635 | doi = 10.1002/14651858.cd002748.pub4 }}</ref> BRCA testing is recommended in those with a high family risk after genetic counseling. It is not recommended routinely.<ref name="Risk assessment, genetic counseling">{{cite journal | vauthors = Moyer VA | title = Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement | journal = Annals of Internal Medicine | volume = 160 | issue = 4 | pages = 271–81 | date = February 2014 | pmid = 24366376 | doi = 10.7326/M13-2747 | doi-access = free }}</ref> This is because there are many forms of changes in BRCA genes, ranging from harmless [[Gene polymorphism|polymorphisms]] to obviously dangerous [[frameshift mutations]].<ref name="Risk assessment, genetic counseling"/> The effect of most of the identifiable changes in the genes is uncertain. Testing in an average-risk person is particularly likely to return one of these indeterminate, useless results. Removing the second breast in a person who has breast cancer (contralateral risk‐reducing mastectomy or CRRM) may reduce the risk of cancer in the second breast, however, it is unclear if removing the second breast in those who have breast cancer improves survival.<ref name=":1" />
=== Medications ===
The [[selective estrogen receptor modulators]] reduce the risk of breast cancer but increase the risk of [[thromboembolism]] and [[endometrial cancer]].<ref name=Nelson2013 /> There is no overall change in the risk of death.<ref name="Nelson2013">{{cite journal | vauthors = Nelson HD, Smith ME, Griffin JC, Fu R | title = Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force | journal = Annals of Internal Medicine | volume = 158 | issue = 8 | pages = 604–14 | date = April 2013 | pmid = 23588749 | doi = 10.7326/0003-4819-158-8-201304160-00005 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S, DeCensi A, Dowsett M, Forbes JF, Ford L, LaCroix AZ, Mershon J, Mitlak BH, Powles T, Veronesi U, Vogel V, Wickerham DL | display-authors = 6 | title = Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data | journal = Lancet | volume = 381 | issue = 9880 | pages = 1827–34 | date = May 2013 | pmid = 23639488 | pmc = 3671272 | doi = 10.1016/S0140-6736(13)60140-3 }}</ref> They are thus not recommended for the prevention of breast cancer in women at average risk but it is recommended they be offered for those at high risk and over the age of 35.<ref>{{cite journal | vauthors = Owens DK, Davidson KW, Krist AH, Barry MJ, Cabana M, Caughey AB, Doubeni CA, Epling JW, Kubik M, Landefeld CS, Mangione CM, Pbert L, Silverstein M, Tseng CW, Wong JB | display-authors = 6 | title = Medication Use to Reduce Risk of Breast Cancer: US Preventive Services Task Force Recommendation Statement | journal = JAMA | volume = 322 | issue = 9 | pages = 857–867 | date = September 2019 | pmid = 31479144 | doi = 10.1001/jama.2019.11885 | doi-access = free }}</ref> The benefit of breast cancer reduction continues for at least five years after stopping a course of treatment with these medications.<ref>{{cite journal | vauthors = Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S, DeCensi A, Dowsett M, Forbes JF, Ford L, LaCroix AZ, Mershon J, Mitlak BH, Powles T, Veronesi U, Vogel V, Wickerham DL | display-authors = 6 | title = Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data | journal = Lancet | volume = 381 | issue = 9880 | pages = 1827–34 | date = May 2013 | pmid = 23639488 | pmc = 3671272 | doi = 10.1016/S0140-6736(13)60140-3 | url = }}</ref> [[Aromatase inhibitor]]s (such as exemestane and anasatrozole) may be more effective than selective estrogen receptor modulators (such as tamoxifen) at reducing breast cancer risk and they are not associated with an increased risk of endometrial cancer and thromboembolism.<ref>{{cite journal | vauthors = Mocellin S, Goodwin A, Pasquali S | title = Risk-reducing medications for primary breast cancer: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 4 | pages = CD012191 | date = April 2019 | pmid = 31032883 | pmc = 6487387 | doi = 10.1002/14651858.cd012191.pub2 }}</ref>
== Management ==
{{Main|Breast cancer management}}
The management of breast cancer depends on various factors, including the [[Breast cancer classification#Stage|stage]] of the cancer and the person's age. Treatments are more aggressive when the cancer is more advanced or there is a higher risk of recurrence of the cancer following treatment.
Breast cancer is usually treated with surgery, which may be followed by chemotherapy or radiation therapy, or both. A multidisciplinary approach is preferable.<ref>{{cite journal | vauthors = Saini KS, Taylor C, Ramirez AJ, Palmieri C, Gunnarsson U, Schmoll HJ, Dolci SM, Ghenne C, Metzger-Filho O, Skrzypski M, Paesmans M, Ameye L, Piccart-Gebhart MJ, de Azambuja E | display-authors = 6 | title = Role of the multidisciplinary team in breast cancer management: results from a large international survey involving 39 countries | journal = Annals of Oncology | volume = 23 | issue = 4 | pages = 853–9 | date = April 2012 | pmid = 21821551 | doi = 10.1093/annonc/mdr352 | doi-access = free }}</ref> Hormone receptor-positive cancers are often treated with hormone-blocking therapy over courses of several years. Monoclonal antibodies, or other [[immune-modulating]] treatments, may be administered in certain cases of metastatic and other advanced stages of breast cancer. Although this range of treatment is still being studied.<ref>{{cite journal | vauthors = Khalil DN, Smith EL, Brentjens RJ, Wolchok JD | title = The future of cancer treatment: immunomodulation, CARs and combination immunotherapy | journal = Nature Reviews. Clinical Oncology | volume = 13 | issue = 5 | pages = 273–90 | date = May 2016 | pmid = 26977780 | pmc = 5551685 | doi = 10.1038/nrclinonc.2016.25 }}</ref>
=== Surgery ===
[[File:Mastectomie 02.jpg|thumb|Chest after right breast [[mastectomy]]]]
Surgery involves the physical removal of the tumor, typically along with some of the surrounding tissue. One or more lymph nodes may be biopsied during the surgery; increasingly the lymph node sampling is performed by a [[sentinel lymph node]] biopsy.
Standard surgeries include:
* [[Mastectomy]]: Removal of the whole breast.
* [[Quadrantectomy]]: Removal of one-quarter of the breast.
* [[Lumpectomy]]: Removal of a small part of the breast.
Once the tumor has been removed, if the person desires, [[breast reconstruction surgery]], a type of [[plastic surgery]], may then be performed to improve the aesthetic appearance of the treated site.
Alternatively, women use [[breast prostheses]] to simulate a breast under clothing, or choose a flat chest. [[Nipple prosthesis]] can be used at any time following the mastectomy.
=== Medication ===
Medications used after and in addition to surgery are called [[Adjuvant cancer therapy|adjuvant therapy]]. Chemotherapy or other types of therapy prior to surgery are called [[neoadjuvant therapy]]. [[Aspirin]] may reduce mortality from breast cancer when used with other treatments.<ref>{{cite journal | vauthors = Leite AM, Macedo AV, Jorge AJ, Martins WA | title = Antiplatelet Therapy in Breast Cancer Patients Using Hormonal Therapy: Myths, Evidence and Potentialities – Systematic Review | journal = Arquivos Brasileiros de Cardiologia | volume = 111 | issue = 2 | pages = 205–212 | date = August 2018 | pmid = 30183988 | pmc = 6122903 | doi = 10.5935/abc.20180138 }}</ref><ref>{{cite journal | vauthors = Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE | title = Aspirin intake and survival after breast cancer | journal = Journal of Clinical Oncology | volume = 28 | issue = 9 | pages = 1467–72 | date = March 2010 | pmid = 20159825 | pmc = 2849768 | doi = 10.1200/JCO.2009.22.7918 }}</ref>
There are currently three main groups of medications used for adjuvant breast cancer treatment: hormone-blocking agents, chemotherapy, and monoclonal antibodies.
====Hormonal therapy====
Some breast cancers require estrogen to continue growing. They can be identified by the presence of estrogen receptors (ER+) and progesterone receptors (PR+) on their surface (sometimes referred to together as hormone receptors). These ER+ cancers can be treated with drugs that either block the receptors, e.g. [[tamoxifen]], or alternatively block the production of estrogen with an [[aromatase inhibitor]], e.g. [[anastrozole]]<ref>{{cite journal | vauthors = Bao T, Rudek MA |s2cid = 1802863 |title = The Clinical Pharmacology of Anastrozole |journal = European Oncology & Haematology |volume = 7 |issue = 2 |pages = 106–8 |year = 2011 |doi = 10.17925/EOH.2011.07.02.106 |df = dmy-all }}</ref> or [[letrozole]]. The use of tamoxifen is recommended for 10 years.<ref>{{cite journal | vauthors = Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Rowden D, Solky AJ, Stearns V, Winer EP, Griggs JJ | display-authors = 6 | title = Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update | journal = Journal of Clinical Oncology | volume = 32 | issue = 21 | pages = 2255–69 | date = July 2014 | pmid = 24868023 | pmc = 4876310 | doi = 10.1200/JCO.2013.54.2258 }}</ref> Tamoxifen increases the risk of [[Vaginal bleeding|postmenopausal bleeding]], [[endometrial polyp]]s, [[hyperplasia]], and [[endometrial cancer]]; using tamoxifen with an [[intrauterine system]] releasing [[levonorgestrel]] might increase vaginal bleeding after 1 to 2 years, but reduces somewhat endometrial polyps and hyperplasia, but not necessarily endometrial cancer.<ref>{{Cite journal|vauthors=Romero SA, Young K, Hickey M, Su HI|date=21 December 2020|title=Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen|journal=Cochrane Database Syst Rev|volume=12|issue=2|pages=CD007245|doi=10.1002/14651858.CD007245.pub4|pmid=33348436|pmc=8092675}}</ref> Letrozole is recommended for five years.
Aromatase inhibitors are only suitable for women after menopause; however, in this group, they appear better than tamoxifen.<ref>{{cite journal | title = Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials | journal = Lancet | volume = 386 | issue = 10001 | pages = 1341–1352 | date = October 2015 | pmid = 26211827 | doi = 10.1016/S0140-6736(15)61074-1 | author1 = Early Breast Cancer Trialists' Collaborative Group (EBCTCG) | doi-access = free }}</ref> This is because the active aromatase in postmenopausal women is different from the prevalent form in premenopausal women, and therefore these agents are ineffective in inhibiting the predominant aromatase of premenopausal women.<ref>{{cite journal | vauthors = Petit T, Dufour P, Tannock I | title = A critical evaluation of the role of aromatase inhibitors as adjuvant therapy for postmenopausal women with breast cancer | journal = Endocrine-Related Cancer | volume = 18 | issue = 3 | pages = R79-89 | date = June 2011 | pmid = 21502311 | doi = 10.1530/ERC-10-0162 | doi-access = free }}</ref> Aromatase inhibitors should not be given to premenopausal women with intact ovarian function (unless they are also on treatment to stop their [[ovaries]] from working).<ref>{{cite web |url = http://www.uptodate.com/contents/treatment-of-metastatic-breast-cancer-beyond-the-basics |title = Treatment of metastatic breast cancer |website = www.uptodate.com |access-date = 4 September 2017 |url-status = live |archive-url = https://web.archive.org/web/20170904202736/http://www.uptodate.com/contents/treatment-of-metastatic-breast-cancer-beyond-the-basics?source=search_result&search=letrozole&selectedTitle=4~6 |archive-date = 4 September 2017 |df = dmy-all }}</ref> [[CDK inhibitor]]s can be used in combination with [[Goserelin|endocrine]] or aromatase therapy.<ref>{{Cite web|url=http://ascopost.com/issues/october-25-2016/combination-of-ribociclib-and-letrozole-is-a-home-run-in-advanced-breast-cancer/|title=Combination of Ribociclib and Letrozole Is a Home Run in Advanced Breast Cancer – The ASCO Post|website=ascopost.com|access-date=31 January 2019}}</ref>
====Chemotherapy====
[[Chemotherapy]] is predominantly used for cases of breast cancer in stages 2–4, and is particularly beneficial in estrogen receptor-negative (ER-) disease. The chemotherapy medications are administered in combinations, usually for periods of 3–6 months. One of the most common regimens, known as "AC", combines [[cyclophosphamide]] with [[doxorubicin]]. Sometimes a [[taxane]] drug, such as [[docetaxel]], is added, and the regime is then known as "CAT". Another common treatment is cyclophosphamide, [[methotrexate]], and [[fluorouracil]] (or "CMF"). Most chemotherapy medications work by destroying fast-growing and/or fast-replicating cancer cells, either by causing DNA damage upon replication or by other mechanisms. However, the medications also damage fast-growing normal cells, which may cause serious side effects. Damage to the heart muscle is the most dangerous complication of doxorubicin, for example.{{citation needed|date=March 2020}}
====Monoclonal antibodies====
[[Trastuzumab]], a monoclonal antibody to HER2, has improved the five-year disease free survival of stage 1–3 HER2-positive breast cancers to about 87% (overall survival 95%).<ref>{{cite journal | vauthors = Jahanzeb M | title = Adjuvant trastuzumab therapy for HER2-positive breast cancer | journal = Clinical Breast Cancer | volume = 8 | issue = 4 | pages = 324–33 | date = August 2008 | pmid = 18757259 | doi = 10.3816/CBC.2008.n.037 }}</ref> Between 25% and 30% of breast cancers [[overexpress]] the HER2 gene or its protein product,<ref>{{cite web |title = Entrez Gene: ERBB2 v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) |url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2064 |access-date = 17 November 2015 |url-status = live |archive-url = https://web.archive.org/web/20091026055528/http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2064 |archive-date = 26 October 2009 |df = dmy-all }}</ref> and overexpression of HER2 in breast cancer is associated with increased disease recurrence and worse prognosis. Trastuzumab, however, is very expensive, and its use may cause serious side effects (approximately 2% of people who receive it develop significant heart damage).<ref>{{cite web |url = http://www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp |title = Herceptin (trastuzumab) Adjuvant HER2+ Breast Cancer Therapy Pivotal Studies and Efficacy Data |publisher = Herceptin.com |access-date = 8 May 2010 |url-status = dead |archive-url = https://web.archive.org/web/20100406014305/http://www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp |archive-date = 6 April 2010 |df = dmy-all }}</ref> Another antibody [[pertuzumab]] prevents HER2 dimerization and is recommended together with [[Trastuzumab emtansine|trastuzumab]] and chemotherapy in severe disease.<ref>{{Cite web|url=https://www.breastcancer.org/research-news/new-guidelines-to-treat-advanced-her2-pos|title=New ASCO Guidelines on Treating Advanced-Stage HER2-Positive Breast Cancer|website=Breastcancer.org |date=4 October 2016 |access-date=31 January 2019}}</ref><ref>{{cite journal | vauthors = Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L | display-authors = 6 | title = Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 | journal = The New England Journal of Medicine | volume = 344 | issue = 11 | pages = 783–92 | date = March 2001 | pmid = 11248153 | doi = 10.1056/NEJM200103153441101 }}</ref>
=== Radiation ===
[[File:Diagram showing how you have internal radiotherapy for breast cancer CRUK 159.svg|thumb|right|Internal radiotherapy for breast cancer]]
[[Radiotherapy]] is given after surgery to the region of the tumor bed and regional lymph nodes, to destroy microscopic tumor cells that may have escaped surgery. When given intraoperatively as [[targeted intraoperative radiotherapy]], it may also have a beneficial effect on tumor microenvironment.<ref>{{cite journal |vauthors = Massarut S, Baldassare G, Belleti B, Reccanello S, D'Andrea S, Ezio C, Perin T, Roncadin M, Vaidya JS |title = Intraoperative radiotherapy impairs breast cancer cell motility induced by surgical wound fluid |journal = J Clin Oncol |volume = 24 |issue = 18S |page = 10611 |year = 2006 |url = http://www.asco.org/ASCOv2/Meetings/Abstracts?vmview=abst_detail_view&confID=40&abstractID=34291 |df = dmy-all |doi = 10.1200/jco.2006.24.18_suppl.10611 |access-date = 9 June 2010 |url-status = dead |archive-url = https://web.archive.org/web/20120112122626/http://www.asco.org/ASCOv2/Meetings/Abstracts?vmview=abst_detail_view&confID=40&abstractID=34291 |archive-date = 12 January 2012}}</ref><ref>{{cite journal | vauthors = Belletti B, Vaidya JS, D'Andrea S, Entschladen F, Roncadin M, Lovat F, Berton S, Perin T, Candiani E, Reccanello S, Veronesi A, Canzonieri V, Trovò MG, Zaenker KS, Colombatti A, Baldassarre G, Massarut S | display-authors = 6 | title = Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding | journal = Clinical Cancer Research | volume = 14 | issue = 5 | pages = 1325–32 | date = March 2008 | pmid = 18316551 | doi = 10.1158/1078-0432.CCR-07-4453 | doi-access = free }}</ref> Radiation therapy can be delivered as [[external beam radiotherapy]] or as [[brachytherapy]] (internal radiotherapy). Conventionally radiotherapy is given ''after'' the operation for breast cancer. Radiation can also be given at the time of operation on the breast cancer. Radiation can reduce the risk of recurrence by 50–66% (1/2 – 2/3 reduction of risk) when delivered in the correct dose<ref>{{cite web |url = http://www.breastcancer.org/treatment/radiation |title = Radiation Therapy |work = Breastcancer.org |access-date = 17 November 2015 |url-status = live |archive-url = https://web.archive.org/web/20151117193610/http://www.breastcancer.org/treatment/radiation |archive-date = 17 November 2015 |df = dmy-all }}</ref> and is considered essential when breast cancer is treated by removing only the lump (Lumpectomy or Wide local excision). In early breast cancer, partial breast irradiation does not give the same cancer control in the breast as treating the whole breast and may cause worse side effects.<ref>{{cite journal|vauthors=Hickey BE, Lehman M|date=August 30, 2021|title=Partial breast irradiation versus whole breast radiotherapy for early breast cancer|journal=The Cochrane Database of Systematic Reviews|volume=2021|issue=8|pages=CD007077|doi=10.1002/14651858.CD007077.pub4|pmid=34459500|pmc=8406917}}</ref>
=== Follow-up care ===
Care after primary breast cancer treatment, otherwise called 'follow-up care', can be intensive involving regular laboratory tests in asymptomatic people to try to achieve earlier detection of possible metastases. A review has found that follow-up programs involving regular physical examinations and yearly mammography alone are as effective as more intensive programs consisting of laboratory tests in terms of early detection of recurrence, overall survival and quality of life.<ref>{{cite journal | vauthors = Moschetti I, Cinquini M, Lambertini M, Levaggi A, Liberati A | title = Follow-up strategies for women treated for early breast cancer | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD001768 | date = May 2016 | volume = 2016 | pmid = 27230946 | doi = 10.1002/14651858.cd001768.pub3 | pmc = 7073405 }}</ref>
Multidisciplinary rehabilitation programmes, often including exercise, education and psychological help, may produce short-term improvements in functional ability, psychosocial adjustment and social participation in people with breast cancer.<ref>{{cite journal | vauthors = Khan F, Amatya B, Ng L, Demetrios M, Zhang NY, Turner-Stokes L | title = Multidisciplinary rehabilitation for follow-up of women treated for breast cancer | journal = The Cochrane Database of Systematic Reviews | volume = 12 | pages = CD009553 | date = December 2012 | issue = 3 | pmid = 23235677 | doi = 10.1002/14651858.cd009553.pub2 | pmc = 8078577 }}</ref>
Upper limb problems such as shoulder and arm pain, weakness and restricted movement are a common side effect after radiotherapy or breast cancer surgery.<ref>{{cite journal | vauthors = Lee TS, Kilbreath SL, Refshauge KM, Herbert RD, Beith JM | title = Prognosis of the upper limb following surgery and radiation for breast cancer | journal = Breast Cancer Research and Treatment | volume = 110 | issue = 1 | pages = 19–37 | date = July 2008 | pmid = 17899373 | doi = 10.1007/s10549-007-9710-9 | s2cid = 24976113 }}</ref> According to research in the UK, an exercise programme started 7-10 days after surgery can reduce upper limb problems.<ref>{{Cite journal |date=2022-09-26 |title=Exercise programme improves arm function and pain after breast cancer surgery |url=https://evidence.nihr.ac.uk/alert/exercise-programme-improves-arm-function-pain-after-breast-cancer-surgery/ |journal=NIHR Evidence |type=Plain English summary |language=en |publisher=National Institute for Health and Care Research |doi=10.3310/nihrevidence_53632|s2cid=252562000 }}</ref><ref>{{cite journal | vauthors = Bruce J, Mazuquin B, Mistry P, Rees S, Canaway A, Hossain A, Williamson E, Padfield EJ, Lall R, Richmond H, Chowdhury L, Lait C, Petrou S, Booth K, Lamb SE, Vidya R, Thompson AM | display-authors = 6 | title = Exercise to prevent shoulder problems after breast cancer surgery: the PROSPER RCT | journal = Health Technology Assessment | volume = 26 | issue = 15 | pages = 1–124 | date = February 2022 | pmid = 35220995 | doi = 10.3310/JKNZ2003 | s2cid = 247157545 }}</ref>
== Prognosis ==
[[File:Breast reconstruction 15.jpg|thumb|Breasts after double mastectomy followed by nipple-sparing reconstruction with implants]]
[[File:RecurrentbreastCA1.gif|thumb|An extreme example of an advanced recurrent breast cancer with an ulcerating axillary mass]]
=== Prognostic factors ===
The [[Breast cancer classification#Stage|stage]] of the breast cancer is the most important component of traditional classification methods of breast cancer, because it has a greater effect on the prognosis than the other considerations. Staging takes into consideration size, local involvement, lymph node status and whether metastatic disease is present. The higher the stage at diagnosis, the poorer the prognosis. The stage is raised by the invasiveness of disease to lymph nodes, chest wall, skin or beyond, and the aggressiveness of the cancer cells. The stage is lowered by the presence of cancer-free zones and close-to-normal cell behaviour (grading). Size is not a factor in staging unless the cancer is invasive. For example, ductal carcinoma in situ (DCIS) involving the entire breast will still be stage zero and consequently an excellent prognosis with a 10-year disease free survival of about 98%.<ref>{{cite web |url = http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html |title = Breast Cancer: Breast Disorders: Merck Manual Professional |publisher = Merck.com |access-date = 8 May 2010 |url-status = live |archive-url = https://web.archive.org/web/20111110075702/http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html |archive-date = 10 November 2011 |df = dmy-all }}</ref>
* Stage 1 cancers (and DCIS, LCIS) have an excellent prognosis and are generally treated with lumpectomy and sometimes radiation.<ref>{{cite web |url = http://www.stopcancerfund.org/wp/wp-content/uploads/2009/12/booklet04bc.pdf |title = Surgery Choices for Women with Early Stage Breast Cancer |publisher = National Cancer Institute and the National Research Center for Women & Families |date = August 2004 |url-status = dead |archive-url = https://web.archive.org/web/20130813054115/http://www.stopcancerfund.org/wp/wp-content/uploads/2009/12/booklet04bc.pdf |archive-date = 13 August 2013 }}</ref>
* Stage 2 and 3 cancers with a progressively poorer prognosis and greater risk of recurrence are generally treated with surgery (lumpectomy or mastectomy with or without [[Lymphadenectomy|lymph node removal]]), chemotherapy (plus [[trastuzumab]] for HER2+ cancers) and sometimes radiation (particularly following large cancers, multiple positive nodes or lumpectomy).{{medcn|date=May 2018}}
* Stage 4, metastatic cancer, (i.e. spread to distant sites) has a poor prognosis and is managed by various combination of all treatments from surgery, radiation, chemotherapy and targeted therapies. Ten-year survival rate is 5% without treatment and 10% with optimal treatment.<ref>{{cite web |url = http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html |title = Breast Cancer: Breast Disorders: Merck Manual Professional |publisher = Merck.com |access-date = 14 November 2010 |url-status = live |archive-url = https://web.archive.org/web/20111110075702/http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html |archive-date = 10 November 2011 |df = dmy-all }}</ref>
[[Breast cancer classification#Grade|The breast cancer grade]] is assessed by comparison of the breast cancer cells to normal breast cells. The closer to normal the cancer cells are, the slower their growth and the better the prognosis. If cells are not well differentiated, they will appear immature, will divide more rapidly, and will tend to spread. Well differentiated is given a grade of 1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4 (depending upon the scale used). The most widely used grading system is the Nottingham scheme.<ref>{{cite journal | vauthors = Elston CW, Ellis IO | title = Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up | journal = Histopathology | volume = 19 | issue = 5 | pages = 403–10 | date = November 1991 | pmid = 1757079 | doi = 10.1111/j.1365-2559.1991.tb00229.x | s2cid = 17622089 }}</ref>
Younger women with an age of less than 40 years or women over 80 years tend to have a poorer prognosis than post-menopausal women due to several factors. Their breasts may change with their menstrual cycles, they may be nursing infants, and they may be unaware of changes in their breasts. Therefore, younger women are usually at a more advanced stage when diagnosed. There may also be biological factors contributing to a higher risk of disease recurrence for younger women with breast cancer.<ref>{{cite journal | vauthors = Peppercorn J |title = Breast Cancer in Women Under 40 |journal = Oncology |volume = 23 |issue = 6 |pages = 465–74 |year = 2009 |url = http://www.cancernetwork.com/cme/article/10165/1413886 |url-status = live |archive-url = https://web.archive.org/web/20090616191104/http://www.cancernetwork.com/cme/article/10165/1413886 |archive-date = 16 June 2009 |df = dmy-all |pmid = 19544685 }}</ref>
=== Psychological aspects ===
Not all people with breast cancer experience their illness in the same manner. Factors such as age can have a significant impact on the way a person copes with a breast cancer diagnosis. Premenopausal women with estrogen-receptor positive breast cancer must confront the issues of early [[menopause]] induced by many of the chemotherapy regimens used to treat their breast cancer, especially those that use hormones to counteract ovarian function.<ref>{{cite journal | vauthors = Pritchard KI |title = Ovarian Suppression/Ablation in Premenopausal ER-Positive Breast Cancer Patients |journal = Oncology |volume = 23 |issue = 1 |year = 2009 |url = http://www.cancernetwork.com/display/article/10165/1366719?pageNumber=1 |url-status = live |archive-url = https://web.archive.org/web/20090705230857/http://www.cancernetwork.com/display/article/10165/1366719?pageNumber=1 |archive-date = 5 July 2009 |df = dmy-all }}</ref>
In women with non-metastatic breast cancer, psychological interventions such as [[cognitive behavioral therapy]] can have positive effects on outcomes such as anxiety, depression and mood disturbance.<ref>{{cite journal | vauthors = Jassim GA, Whitford DL, Hickey A, Carter B | title = Psychological interventions for women with non-metastatic breast cancer | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD008729 | date = May 2015 | pmid = 26017383 | doi = 10.1002/14651858.cd008729.pub2 }}</ref> Physical activity interventions may also have beneficial effects on health related quality of life, anxiety, fitness and physical activity in women with breast cancer following adjuvant therapy.<ref>{{cite journal | vauthors = Lahart IM, Metsios GS, Nevill AM, Carmichael AR | title = Physical activity for women with breast cancer after adjuvant therapy | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD011292 | date = January 2018 | pmid = 29376559 | pmc = 6491330 | doi = 10.1002/14651858.cd011292.pub2 }}</ref>
== Epidemiology ==
{{Main|Epidemiology of breast cancer}}
[[File:Breast cancer world map - Death - WHO2004.svg|thumb|upright=1.25|[[Age adjustment|Age-standardized]] death from breast cancer per 100,000 inhabitants in 2004<ref>{{cite web|url=https://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html|title=WHO Disease and injury country estimates|year=2009|work=World Health Organization|access-date=11 November 2009|archive-url= https://web.archive.org/web/20091111101009/http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html|archive-date=11 November 2009|url-status=live}}</ref>
{{Col-begin}}
{{Col-break}}
{{legend|#b3b3b3|no data}}
{{legend|#ffff65|<2}}
{{legend|#fff200|2–4}}
{{legend|#ffdc00|4–6}}
{{legend|#ffc600|6–8}}
{{legend|#ffb000|8–10}}
{{legend|#ff9a00|10–12}}
{{Col-break}}
{{legend|#ff8400|12–14}}
{{legend|#ff6e00|14–16}}
{{legend|#ff5800|16–18}}
{{legend|#ff4200|18–20}}
{{legend|#ff2c00|20–22}}
{{legend|#cb0000|>22}}
{{col-end}} ]]
Worldwide, breast cancer is the most-common invasive cancer in women.<ref name=Malone2015 /> Along with lung cancer, breast cancer is the most commonly diagnosed cancer, with 2.09 million cases each in 2018.<ref>{{cite web|url=https://www.who.int/news-room/fact-sheets/detail/cancer| title=Cancer| website=World Health Organization| date=12 September 2018 | access-date=16 July 2020}}</ref> Breast cancer affects 1 in 7 (14%) of women worldwide.<ref name=genetics2019>{{cite journal |vauthors=Balasubramanian R, Rolph R, Morgan C, Hamed H |title=Genetics of breast cancer: management strategies and risk-reducing surgery. |journal=Br J Hosp Med (Lond) |volume=80 |issue=12 |pages=720–725 |date=2019 |pmid= 31822191 |doi=10.12968/hmed.2019.80.12.720|s2cid=209314404 }}</ref> (The most common form of cancer is non-invasive [[Skin neoplasm|non-melanoma skin cancer]]; non-invasive cancers are generally easily cured, cause very few deaths, and are routinely excluded from cancer statistics.) Breast cancer comprises 22.9% of invasive cancers in women<ref name="IARC GLOBOCAN 2008">{{cite web |publisher = [[International Agency for Research on Cancer]] |year = 2008 |title = World Cancer Report |url = http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/ |access-date = 26 February 2011 |url-status = dead |archive-url = https://web.archive.org/web/20111231111259/http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/ |archive-date = 31 December 2011 |df = dmy-all }} (cancer statistics often exclude non-melanoma skin cancers such as [[basal-cell carcinoma]], which are common but rarely fatal)</ref> and 16% of all female cancers.<ref>{{cite web |url =https://www.who.int/cancer/detection/breastcancer/en/index1.html |title = Breast cancer: prevention and control |work = World Health Organization |url-status = dead |archive-url = https://web.archive.org/web/20150906121739/http://www.who.int/cancer/detection/breastcancer/en/index1.html |archive-date = 6 September 2015 }}</ref> In 2012, it comprised 25.2% of cancers diagnosed in women, making it the most-common female cancer.<ref>{{cite book |title = World Cancer Report 2014 |publisher = International Agency for Research on Cancer, World Health Organization |date = 2014 |isbn = 978-92-832-0432-9 }}</ref>
In 2008, breast cancer caused 458,503 deaths worldwide (13.7% of cancer deaths in women and 6.0% of all cancer deaths for men and women together).<ref name="IARC GLOBOCAN 2008" /> Lung cancer, the second most-common cause of cancer-related deaths in women, caused 12.8% of cancer deaths in women (18.2% of all cancer deaths for men and women together).<ref name="IARC GLOBOCAN 2008" />
The incidence of breast cancer varies greatly around the world: it is lowest in less-developed countries and greatest in the more-developed countries. In the twelve world regions, the annual age-standardized [[incidence rate]]s per 100,000 women are as follows: 18 in Eastern Asia, 22 in South Central Asia and sub-Saharan Africa, 26 in South-Eastern Asia, 26, 28 in North Africa and Western Asia, 42 in South and Central America, 42, 49 in Eastern Europe, 56 in Southern Europe, 73 in Northern Europe, 74 in Oceania, 78 in Western Europe, and 90 in North America.<ref>{{Cite web|url=https://www.scribd.com/doc/2350813/World-Cancer-Report-2003-Stuart-e-Kleihues-WHO-e-IARC|archiveurl=https://web.archive.org/web/20081020000016/http://www.scribd.com/doc/2350813/World-Cancer-Report-2003-Stuart-e-Kleihues-WHO-e-IARC|url-status=dead|title=Stewart B. W. and Kleihues P. (Eds): World Cancer Report. IARCPress. Lyon 2003|archivedate=20 October 2008}}</ref> Metastatic breast cancer affects between 19% (United States) and 50% (parts of Africa) of women with breast cancer.<ref>{{cite book | veditors = Wyld L, Markopoulos C, Leidenius M, Senkus-Konefka E |title=Breast cancer management for surgeons : a European multidisciplinary textbook |date=2018 |publisher=Springer |isbn=978-3-319-56671-9 |page=580}}</ref>
The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly attributed to the modern lifestyles.<ref name=indy>{{Cite news | vauthors = Laurance J |title = Breast cancer cases rise 80% since Seventies |work = [[The Independent]] |date = 29 September 2006 |url = https://www.independent.co.uk/life-style/health-and-wellbeing/health-news/breast-cancer-cases-rise-80-since-seventies-417990.html |location = London |access-date = 9 October 2006 |url-status = dead |archive-url = https://web.archive.org/web/20080425022457/http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/breast-cancer-cases-rise-80-since-seventies-417990.html |archive-date = 25 April 2008 }}</ref><ref>{{cite web |title = Breast Cancer: Statistics on Incidence, Survival, and Screening |publisher = Imaginis Corporation |year = 2006 |url = http://imaginis.com/breasthealth/statistics.asp |access-date = 9 October 2006 |url-status = live |archive-url = https://web.archive.org/web/20061024120910/http://www.imaginis.com/breasthealth/statistics.asp |archive-date = 24 October 2006 |df = dmy-all }}</ref> Breast cancer is strongly related to age with only 5% of all breast cancers occurring in women under 40 years old.<ref>[http://www.webmd.com/breast-cancer/guide/breast-cancer-young-women Breast Cancer: Breast Cancer in Young Women] {{webarchive|url=https://web.archive.org/web/20090910015335/http://www.webmd.com/breast-cancer/guide/breast-cancer-young-women |date=10 September 2009 }} WebMD. Retrieved 9 September 2009</ref> There were more than 41,000 newly diagnosed cases of breast cancer registered in England in 2011, around 80% of these cases were in women age 50 or older.<ref>[http://www.ons.gov.uk/ons/rel/vsob1/cancer-statistics-registrations--england--series-mb1-/no--42--2011/sty-breast-cancer-survival.html Nearly 85% of women diagnosed with breast cancer now survive for 5 year or more] {{webarchive|url=https://web.archive.org/web/20131105085823/http://www.ons.gov.uk/ons/rel/vsob1/cancer-statistics-registrations--england--series-mb1-/no--42--2011/sty-breast-cancer-survival.html |date=5 November 2013 }} Office for National Statistics, 2013</ref> Based on U.S. statistics in 2015 there were 2.8 million women affected by breast cancer.<ref name="Malone2015">{{cite journal | vauthors = McGuire A, Brown JA, Malone C, McLaughlin R, Kerin MJ | title = Effects of age on the detection and management of breast cancer | journal = Cancers | volume = 7 | issue = 2 | pages = 908–29 | date = May 2015 | pmid = 26010605 | pmc = 4491690 | doi = 10.3390/cancers7020815 | doi-access = free }}</ref> In the United States, the [[age adjustment|age-adjusted incidence]] of breast cancer per 100,000 women rose from around 102 cases per year in the 1970s to around 141 in the late-1990s, and has since fallen, holding steady around 125 since 2003. However, age-adjusted deaths from breast cancer per 100,000 women only rose slightly from 31.4 in 1975 to 33.2 in 1989 and have since declined steadily to 20.5 in 2014.<ref>[https://seer.cancer.gov/statfacts/html/breast.html Cancer Stat Facts: Female Breast Cancer], U.S. National Cancer Institute, accessed 16 February 2018</ref>
== Multiple primary tumours ==
<!--- Please note that the page Multi-centric breast cancer redirects to this section --->
[[File:Breast_quadrants_ABC.svg|thumb|Quadrants of breast.]]
Multiple primary tumours can arise in different sites (as opposed to a single tumour spreading). These tumours can occur in both breasts (bilateral tumours), in different quadrants of a single breast (multi-centric cancer), or separate tumours within a single breast quadrant (multi-focal cancer).<ref name =Coombs>{{cite journal | vauthors = Coombs NJ, Boyages J | title = Multifocal and multicentric breast cancer: does each focus matter? | journal = Journal of Clinical Oncology | volume = 23 | issue = 30 | pages = 7497–7502 | date = October 2005 | pmid = 16234516 | doi = 10.1200/JCO.2005.02.1147 }}</ref><ref name="Neri">{{cite journal | vauthors = Neri A, Marrelli D, Megha T, Bettarini F, Tacchini D, De Franco L, Roviello F | title = "Clinical significance of multifocal and multicentric breast cancers and choice of surgical treatment: a retrospective study on a series of 1158 cases" | journal = BMC Surgery | volume = 15 | pages = 1 | date = January 2015 | pmid = 25586679 | pmc = 4324662 | doi = 10.1186/1471-2482-15-1 }}</ref>
Incidence of multi-centric and multi-focal breast cancers (MMBC) is increasing, partly due to improving mammography technology.<ref name="Lang">{{cite journal | vauthors = Lang Z, Wu Y, Li C, Li X, Wang X, Qu G | title = Multifocal and Multicentric Breast Carcinoma: A Significantly More Aggressive Tumor than Unifocal Breast Cancer | journal = Anticancer Research | volume = 37 | issue = 8 | pages = 4593–4598 | date = August 2017 | pmid = 28739757 | doi = 10.21873/anticanres.11858 }}</ref> Incidence of MMBC is reported between 9 and 75% in high income countries, depending on criteria used.<ref name="Lang" /> For instance, China reported that only 2% of patients are defined as MMBC.<ref name="Lang" /> The reason for this difference is due to lack of uniformity in diagnosis.<ref name="Lang" /> Therefore, standardised method and criteria should be made in order to define the incidence of MMBC correctly.<ref name="Lang" />
Mutations in [[tumour suppressor gene]]s such as [[BRCA mutation|BRCA1 and BRCA2]], the [[PI3K/AKT/mTOR pathway]] and [[PTEN (gene)|PTEN]] can be related to formation of multiple primary breast cancers.<ref name="Narod">{{cite journal | vauthors = Narod SA | title = Bilateral breast cancers | journal = Nature Reviews. Clinical Oncology | volume = 11 | issue = 3 | pages = 157–166 | date = March 2014 | pmid = 24492834 | doi = 10.1038/nrclinonc.2014.3 | s2cid = 601112 }}</ref> Diagnosis occurs via the same modalities as other breast cancers.
[[Mastectomy]] is the standard surgical treatment for multi centric breast cancer patients.<ref>{{Cite web |title=Breast-conserving Surgery (Lumpectomy) {{!}} Treating Breast Cancer |url=https://www.cancer.org/cancer/breast-cancer/treatment/surgery-for-breast-cancer/breast-conserving-surgery-lumpectomy.html |access-date=2022-03-24 |website=www.cancer.org |language=en}}</ref> Double [[Lumpectomy|lumpectomies]], also labelled as breast conservative therapy (BCT), is an alternative and preferred surgical treatment to [[mastectomy]] for early stage multi centric breast cancer patients.<ref name="pubmed.ncbi.nlm.nih.gov">{{cite journal | vauthors = Kapoor NS, Chung A, Huynh K, Giuliano AE | title = Preliminary results: double lumpectomies for multicentric breast carcinoma | journal = The American Surgeon | volume = 78 | issue = 12 | pages = 1345–1348 | date = December 2012 | pmid = 23265123 | doi = 10.1177/000313481207801226 | s2cid = 26112023 }}</ref> The procedure of double lumpectomies involves the surgical ablation of the cancerous tumour foci and the surrounding breast tissues in different quadrant of the same breast.<ref name="pubmed.ncbi.nlm.nih.gov"/> The benefits of double lumpectomies are the avoidance of breast reconstruction surgery and minimal breast scarring. However, this surgical treatment is not preferable for patients with over two breast tumours within the same breast due to difficulty in removing all cancer cells.<ref name="ReferenceA"/> Patients with multiple primary breast tumours may receive treatments such as chemotherapy, radiotherapy and [[breast reconstruction surgery]]<ref>{{Cite web |title=Another Study Looks at Quality of Life After Preventive Mastectomy |url=https://www.breastcancer.org/research-news/quality-of-life-after-preventive-mastectomy |access-date=2022-03-24 |website=www.breastcancer.org}}</ref><ref name="ReferenceA">{{cite journal | vauthors = Nguyen QD, Tavana A, Sadruddin S, Chao C | title = Successful Lumpectomy in a Patient With Multicentric Breast Cancer | journal = Cureus | volume = 12 | issue = 8 | pages = e10072 | date = August 2020 | pmid = 32999790 | pmc = 7522052 | doi = 10.7759/cureus.10072 }}</ref> for the same indications as other breast cancer patients.
== History ==
[[File:Louis-Jacques Goussier Enzyklopädie Diderot Pl XXIX.jpg|thumb|Breast cancer surgery in 18th century]]
Because of its visibility, breast cancer was the form of cancer most often described in ancient documents.<ref name="Olson_2002">{{cite book | vauthors = Olson JS |title = Bathsheba's breast: women, cancer & history |publisher = The Johns Hopkins University Press |year = 2002 |isbn = 978-0-8018-6936-5}}</ref>{{rp|9–13}} Because autopsies were rare, cancers of the internal organs were essentially invisible to ancient medicine. Breast cancer, however, could be felt through the skin, and in its advanced state often developed into [[fungating lesion]]s: the tumor would become [[necrotic]] (die from the inside, causing the tumor to appear to break up) and [[Ulcer (dermatology)|ulcerate]] through the skin, weeping fetid, dark fluid.<ref name="Olson_2002" />{{rp|9–13}}
The oldest discovered evidence of breast cancer is from Egypt and dates back 4200 years, to the [[Sixth Dynasty]].<ref name="reuters">{{Cite news |url = http://in.reuters.com/article/egypt-antiquities-cancer-idINKBN0MK1ZW20150324 |title = Oldest evidence of breast cancer found in Egyptian skeleton |date = 24 March 2015 |access-date = 25 March 2015 |url-status = live |archive-url = https://web.archive.org/web/20150327023314/http://in.reuters.com/article/2015/03/24/egypt-antiquities-cancer-idINKBN0MK1ZW20150324 |archive-date = 27 March 2015 |df = dmy-all |newspaper = Reuters }}</ref> The study of a woman's remains from the necropolis of [[Qubbet el-Hawa]] showed the typical destructive damage due to [[metastatic]] spread.<ref name="reuters" /> The [[Edwin Smith Papyrus]] describes eight cases of tumors or ulcers of the breast that were treated by [[cauterization]]. The writing says about the disease, "There is no treatment."<ref>{{cite web |title = The History of Cancer |work = American Cancer Society |date = 25 March 2002 |url = http://www.cancer.org/docroot/CRI/content/CRI_2_6x_the_history_of_cancer_72.asp?sitearea=CRI |access-date = 9 October 2006 |url-status = dead |archive-url = https://web.archive.org/web/20061009011530/http://www.cancer.org/docroot/CRI/content/CRI_2_6x_the_history_of_cancer_72.asp?sitearea=CRI |archive-date = 9 October 2006 |df = dmy-all }}</ref> For centuries, physicians described similar cases in their practices, with the same conclusion. Ancient medicine, from the time of the Greeks through the 17th century, was based on [[humoralism]], and thus believed that breast cancer was generally caused by imbalances in the fundamental fluids that controlled the body, especially an excess of [[black bile]].<ref name="Olson_2002" />{{rp|32}} Alternatively it was seen as [[divine punishment]].<ref name="Yalom">{{cite book | vauthors = Yalom M |title = A history of the breast |publisher = Alfred A. Knopf |location = New York |year = 1997 |page = [https://archive.org/details/historyofbreast00yalo/page/234 234] |isbn = 978-0-679-43459-7 |url = https://archive.org/details/historyofbreast00yalo/page/234 }}</ref>
Mastectomy for breast cancer was performed at least as early as AD 548, when it was proposed by the court physician [[Aetios of Amida]] to [[Theodora (wife of Justinian I)|Theodora]].<ref name="Olson_2002" />{{rp|9–13}} It was not until doctors achieved greater understanding of the circulatory system in the 17th century that they could link breast cancer's spread to the [[lymph nodes]] in the armpit. In the early 18th century the French surgeon [[Jean Louis Petit]] performed total mastectomies that included removing the [[axillary lymph nodes]], as he recognized that this reduced recurrence.<ref name="Faguet 2015">{{cite book| vauthors = Faguet G |title=The Conquest of Cancer: A Distant Goal|date=2015|isbn=9789401791656|page=24|chapter=Chapter 2: An Historical Overview: From Prehistory to WWII. From Medieval Europe to World War II}}</ref> Petit's work built on the methods of the surgeon [[Bernard Peyrilhe]], who in the 17th century additionally removed the [[pectoralis major muscle|pectoral muscle]] underlying the breast, as he judged that this greatly improved the prognosis.<ref>{{cite book| vauthors = Kaartinen M |title=Breast cancer in the eighteenth century|date=2013|publisher=Pickering & Chatto|location=London|isbn=978-1-84893-364-4|page=53|chapter=Chapter 2: "But Sad Resources": Treating Cancer in the Eighteenth Century}}</ref> But poor results and the considerable risk to the patient meant that physicians did not share the opinion of surgeons such as [[Nicolaes Tulp]], who in the 17th century proclaimed "the sole remedy is a timely operation". The eminent surgeon [[Richard Wiseman (surgeon)|Richard Wiseman]] documented in the mid 17th century that following 12 mastectomies, two patients died during the operation, eight patients died shortly after the operation from progressive cancer and only two of the 12 patients were cured.<ref name="Winchester_2006">{{Cite book|title=Breast Cancer | vauthors = Winchester DJ, Winchester DP, Hudis CA, Norton L |publisher=PMPH-USA|year=2006|isbn= 9781550092721 }}</ref>{{rp|6}} Physicians were conservative in the treatment they prescribed in the early stages of breast cancer. Patients were treated with a mixture of [[Detoxification (alternative medicine)|detox purges]], [[blood letting]] and traditional remedies that were supposed to lower acidity, such as the alkaline [[arsenic]].<ref name = "de_Moulin_2013">{{Cite book|title=A short history of breast cancer | vauthors = de Moulin D |publisher=Springer Science & Business Media|year=2013|isbn= 9789401706018 }}</ref>{{rp|24}}
When in 1664 [[Anne of Austria]] was diagnosed with breast cancer, the initial treatment involved compresses saturated with [[Conium|hemlock]] juice. When the lumps increased the King's physician commenced a treatment with arsenic [[ointment]]s.<ref name = "de_Moulin_2013" />{{rp|25}} The royal patient died 1666 in atrocious pain.<ref name = "de_Moulin_2013" />{{rp|26}} Each failing treatment for breast cancer led to the search for new treatments, spurring a market in remedies that were advertised and sold by [[quackery|quacks]], [[herbalist]]s, [[chemist]]s and [[apothecaries]].<ref>{{Cite book|title=Pain and Emotion in Modern History | vauthors = Boddice RG |publisher=Springer|year=2014|isbn= 9781137372437|pages=24}}</ref> The lack of [[anesthesia]] and [[antiseptics]] made [[mastectomy]] a painful and dangerous ordeal.<ref name="Winchester_2006"/> In the 18th century, a wide variety of anatomical discoveries were accompanied by new theories about the cause and growth of breast cancer. The investigative surgeon [[John Hunter (surgeon)|John Hunter]] claimed that neural fluid generated breast cancer. Other surgeons proposed that milk within the [[mammary duct]]s led to cancerous growths. Theories about trauma to the breast as cause for [[malignant]] changes in breast tissue were advanced. The discovery of [[breast lump]]s and swellings fueled controversies about hard [[tumor]]s and whether lumps were benign stages of cancer. Medical opinion about necessary immediate treatment varied.<ref name="Winchester_2006" />{{rp|5}} The surgeon [[Benjamin Bell]] advocated removal of the entire breast, even when only a portion was affected.<ref>{{cite journal | vauthors = Macintyre IM | title = Scientific surgeon of the Enlightenment or 'plagiarist in everything': a reappraisal of Benjamin Bell (1749–1806) | journal = The Journal of the Royal College of Physicians of Edinburgh | volume = 41 | issue = 2 | pages = 174–81 | date = June 2011 | pmid = 21677925 | doi = 10.4997/JRCPE.2011.211 | doi-access = free }}{{open access}}</ref>
[[File:William Stewart Halsted, Surgical papers Wellcome L0004968.jpg|thumb|Radical mastectomy, Halsted's surgical papers]]
Breast cancer was uncommon until the 19th century, when improvements in sanitation and control of deadly [[infectious disease]]s resulted in dramatic increases in lifespan. Previously, most women had died too young to have developed breast cancer.<ref name="Aronowitz">{{cite book | vauthors = Aronowitz RA |title = Unnatural history: breast cancer and American society |publisher = Cambridge University Press |location = Cambridge, UK |year = 2007 |pages = [https://archive.org/details/unnaturalhistory00aron/page/22 22–24] |isbn = 978-0-521-82249-7 |url = https://archive.org/details/unnaturalhistory00aron/page/22 }}</ref> In 1878, an article in ''[[Scientific American]]'' described historical treatment by pressure intended to induce local ischemia in cases when surgical removal were not possible.<ref>{{Cite book|url=https://books.google.com/books?id=p4o9AQAAIAAJ|title=Scientific American, "The Treatment of Cancer by Pressure"|date=10 August 1878|publisher=Munn & Company|pages=86|language=en}}</ref> [[William Stewart Halsted]] started performing [[radical mastectomies]] in 1882, helped greatly by advances in general surgical technology, such as [[aseptic technique]] and anesthesia. The Halsted radical mastectomy often involved removing both breasts, associated lymph nodes, and the underlying chest muscles. This often led to long-term pain and disability, but was seen as necessary to prevent the cancer from recurring..<ref name="Olson_2002" />{{rp|102–106}} Before the advent of the Halsted radical mastectomy, 20-year survival rates were only 10%; Halsted's surgery raised that rate to 50%.<ref name="Olson_2002" />{{rp|1}}
[[Cancer staging|Breast cancer staging system]]s were developed in the 1920s and 1930s to determining the extent to which a cancer has developed by growing and spreading..<ref name="Olson_2002" />{{rp|102–106}} The first [[case-control]]led study on breast cancer epidemiology was done by [[Janet Lane-Claypon]], who published a comparative study in 1926 of 500 breast cancer cases and 500 controls of the same background and lifestyle for the British Ministry of Health.<ref name="isbn3-7643-6818-7">{{Cite book | vauthors = Morabia A |title = A History of Epidemiologic Methods and Concepts |publisher = Birkhauser |location = Boston |year = 2004 |pages = 301–302 |isbn = 978-3-7643-6818-0 |url = https://books.google.com/books?id=E-OZbEmPSTkC&pg=PA301 |access-date = 31 December 2007 }}</ref> Radical mastectomies remained the standard of care in the USA until the 1970s, but in Europe, breast-sparing procedures, often followed by [[radiation therapy]], were generally adopted in the 1950s..<ref name="Olson_2002" />{{rp|102–106}} In 1955 [[George Crile Jr.]] published ''Cancer and Common Sense'' arguing that cancer patients needed to understand available treatment options. Crile became a close friend of the environmentalist [[Rachel Carson]], who had undergone a Halsted radical mastectomy in 1960 to treat her malign breast cancer.<ref name = "Knopf-Newman_2004">{{Cite book|title=Beyond Slash, Burn, and Poison: Transforming Breast Cancer Stories Into Action | vauthors = Knopf-Newman MJ |publisher= Rutgers University Press|year=2004|isbn=9780813534718 }}</ref>{{rp|39–40}} The US oncologist [[Jerome Urban]] promoted superradical mastectomies, taking even more tissue, until 1963, when the ten-year survival rates proved equal to the less-damaging radical mastectomy.<ref name="Olson_2002" />{{rp|102–106}} Carson died in 1964 and Crile went on to published a wide variety of articles, both in the popular press and in medical journals, challenging the widespread used of the Halsted radical mastectomy. In 1973 Crile published ''What Women Should Know About the Breast Cancer Controversy''. When in 1974 [[Betty Ford]] was diagnosed with breast cancer, the options for treating breast cancer were openly discussed in the press.<ref name = "Knopf-Newman_2004" />{{rp|58}} During the 1970s, a new understanding of [[metastasis]] led to perceiving cancer as a systemic illness as well as a localized one, and more sparing procedures were developed that proved equally effective.<ref name="Lax">{{cite book | vauthors = Lacroix M |title = A Concise History of Breast Cancer |publisher = Nova Science Publishers |location = USA |year = 2011 |pages = 59–68 |isbn = 978-1-61122-305-7 }}</ref>
In the 1980s and 1990s, thousands of women who had successfully completed standard treatment then demanded and received high-dose [[bone marrow transplant]]s, thinking this would lead to better long-term survival. However, it proved completely ineffective, and 15–20% of women died because of the brutal treatment.<ref name="Sulik_2010">{{cite book | vauthors = Sulik GA |title = Pink Ribbon Blues: How Breast Cancer Culture Undermines Women's Health |url = https://archive.org/details/pinkribbonbluesh0000suli |url-access = registration |publisher = Oxford University Press |location = USA |year = 2010 |isbn = 978-0-19-974045-1 |oclc = 535493589 }}</ref>{{rp|200–203}} The 1995 reports from the [[Nurses' Health Study]] and the 2002 conclusions of the [[Women's Health Initiative]] trial conclusively proved that [[Hormone replacement therapy (menopause)|hormone replacement therapy]] significantly increased the incidence of breast cancer.<ref name="Sulik_2010" />
== Society and culture ==
{{See also|Breast cancer awareness|List of people with breast cancer}}
Before the 20th century, breast cancer was feared and discussed in hushed tones, as if it were shameful. As little could be safely done with primitive surgical techniques, women tended to suffer silently rather than seeking care.{{citation needed|date=June 2022}} When surgery advanced, and long-term survival rates improved, women began [[raising awareness]] of the disease and the possibility of successful treatment. The "Women's Field Army", run by the American Society for the Control of Cancer (later the [[American Cancer Society]]) during the 1930s and 1940s was one of the first organized campaigns. In 1952, the first peer-to-peer [[support group]], called "Reach to Recovery", began providing post-mastectomy, in-hospital visits from women who had survived breast cancer.<ref name="Sulik_2010" />{{rp|37–38}}
The [[breast cancer movement]] of the 1980s and 1990s developed out of the larger [[feminist movement]]s and [[Women's health movement in the United States|women's health movement]] of the 20th century.<ref name="Sulik_2010" />{{rp|4}} This series of political and educational campaigns, partly inspired by the politically and socially effective AIDS awareness campaigns, resulted in the widespread acceptance of second opinions before surgery, less invasive surgical procedures, support groups, and other advances in care.<ref>{{cite web |url = http://www.crcfl.net/content/view/history-of-breast-cancer-advocacy.html |title = History of Breast Cancer Advocacy | vauthors = Riter B |publisher = Cancer Resource Center of the Finger Lakes |access-date = 29 June 2013 |url-status = dead |archive-url = https://web.archive.org/web/20130623074930/http://www.crcfl.net/content/view/history-of-breast-cancer-advocacy.html |archive-date = 23 June 2013 |df = dmy-all }}</ref>
=== Pink ribbon ===
[[File:Pink ribbon.svg|upright|thumb|The [[pink ribbon]] is a symbol to show support for breast cancer awareness.]]
{{Main|Pink ribbon}}
A [[pink ribbon]] is the most prominent symbol of breast cancer awareness. Pink ribbons, which can be made inexpensively, are sometimes sold as fundraisers, much like [[Poppy day#Poppies|poppies on Remembrance Day]]. They may be worn to honor those who have been diagnosed with breast cancer, or to identify products that the manufacturer would like to sell to consumers that are interested in breast cancer.<ref name="Sulik_2010" />{{rp|27–72}} In the 1990s breast cancer awareness campaigns were launched by US based corporations. As part of these [[cause related marketing]] campaigns corporations donated to a variety of breast cancer initiatives for every pink ribbon product that was purchased.<ref name = "Klawiter_2008">{{cite book | vauthors = Klawiter M |title = The Biopolitics of Breast Cancer: Changing Cultures of Disease and Activism |publisher = University of Minnesota Press |year = 2008 |isbn = 9780816651078 }}</ref>>{{rp|132–133}} ''[[The Wall Street Journal]]'' noted "that the strong emotions provoked by breast cancer translate to a company's [[bottom line]]". While many US corporations donated to existing breast cancer initiatives others such as [[Avon Products|Avon]] established their own breast cancer foundations on the back of pink ribbon products.<ref name = "Klawiter_2008" />{{rp|135–136}}
Wearing or displaying a pink ribbon has been criticized by the opponents of this practice as a kind of [[slacktivism]], because it has no practical positive effect. It has also been criticized as [[hypocrisy]], because some people wear the pink ribbon to show good will towards women with breast cancer, but then oppose these women's practical goals, like [[patient rights]] and [[anti-pollution legislation]].<ref name="Sulik_2010" />{{rp|366–368}}<ref>{{cite web | vauthors = Landeman A |date = 11 June 2008 |url = http://www.prwatch.org/node/7436 |title = Pinkwashing: Can Shopping Cure Breast Cancer? |publisher = [[Center for Media and Democracy]] |url-status = live |archive-url = https://web.archive.org/web/20110605122507/http://www.prwatch.org/node/7436 |archive-date = 5 June 2011 |df = dmy-all }}</ref> Critics say that the feel-good nature of pink ribbons and pink consumption distracts society from the lack of progress on preventing and curing breast cancer.<ref name="Sulik_2010" />{{rp|365–366}} It is also criticized for reinforcing gender stereotypes and [[objectifying]] women and their breasts.<<ref name="Sulik_2010" />{{rp|372–374}} In 2002 [[Breast Cancer Action]] launched the "Think Before You Pink" campaign against [[Pinkwashing (breast cancer)|pinkwashing]] to target businesses that have co-opted the pink campaign to promote products that cause breast cancer, such as alcoholic beverages.<ref>[https://www.ctvnews.ca/breast-cancer-month-overshadowed-by-pinkwashing-1.561275 Breast cancer month overshadowed by 'pinkwashing'] {{webarchive|url=https://web.archive.org/web/20101012151918/http://ottawa.ctv.ca/servlet/an/local/CTVNews/20101008/pinkwashing-pink-ribbon-101009/20101009/?hub=OttawaHome |date=12 October 2010 }} 9 October 2010, Angela Mulholland, CTV.ca News</ref>
=== Breast cancer culture ===
In her 2006 book ''Pink Ribbons, Inc.: Breast Cancer and the Politics of Philanthropy'' Samantha King claimed that breast cancer has been transformed from a serious disease and individual tragedy to a market-driven industry of survivorship and corporate sales pitch.<ref name= "King_2006">{{cite book | vauthors = King S |title=Pink ribbons, inc.: breast cancer and the politics of philanthropy |publisher=University of Minnesota Press |location=Minneapolis |year=2006 |isbn=0-8166-4898-0}}</ref> In 2010 Gayle Sulik argued that the primary purposes or goals of breast cancer culture are to maintain breast cancer's dominance as the pre-eminent women's health issue, to promote the appearance that society is doing something effective about breast cancer, and to sustain and expand the social, political, and financial power of breast cancer activists.<ref name="Sulik_2010" />{{rp|57}} In the same year [[Barbara Ehrenreich]] published an opinion piece in ''[[Harper's Magazine]]'', lamenting that in breast cancer culture, breast cancer therapy is viewed as a [[rite of passage]] rather than a disease. To fit into this mold, the woman with breast cancer needs to normalize and feminize her appearance, and minimize the disruption that her health issues cause anyone else. Anger, sadness, and negativity must be silenced. As with most cultural models, people who conform to the model are given social status, in this case as [[cancer survivor]]s. Women who reject the model are shunned, punished and shamed. The culture is criticized for treating adult women like little girls, as evidenced by "baby" toys such as pink [[teddy bear]]s given to adult women.<ref name=Ehrenreich>{{Cite news | vauthors = Ehrenreich B |title = Welcome to Cancerland |newspaper = Harper's Magazine |date = November 2001 |url = http://www.barbaraehrenreich.com/cancerland.htm |url-status = dead |archive-url = https://web.archive.org/web/20101120135605/http://barbaraehrenreich.com/cancerland.htm |archive-date = 20 November 2010 }}</ref>
=== Emphasis ===
In 2009 the US science journalist [[Christie Aschwanden]] criticized that the emphasis on breast cancer screening may be harming women by subjecting them to unnecessary radiation, biopsies, and surgery. One-third of diagnosed breast cancers might recede on their own.<ref name=Ave>{{cite news |title = The Trouble with Mammograms |date = 17 August 2009 | vauthors = Aschwanden C |newspaper =[[Los Angeles Times]] |url = https://articles.latimes.com/2009/aug/17/health/he-breast-overdiagnosis17 |url-status = live |archive-url = https://web.archive.org/web/20101204073704/http://articles.latimes.com/2009/aug/17/health/he-breast-overdiagnosis17 |archive-date = 4 December 2010 |df = dmy-all }}</ref> Screening mammography efficiently finds non-life-threatening, asymptomatic breast cancers and precancers, even while overlooking serious cancers. According to the cancer researcher [[H. Gilbert Welch]] screening mammography has taken the "brain-dead approach that says the best test is the one that finds the most cancers" rather than the one that finds dangerous cancers.<ref name=Ave />
In 2002 it was noted that as a result of breast cancer's high visibility, the statistical results can be misinterpreted, such as the claim that one in eight women will be diagnosed with breast cancer during their lives – a claim that depends on the unrealistic assumption that no woman will die of any other disease before the age of 95.<ref name="Olson_2002" />{{rp|199–200}} By 2010 the breast cancer survival rate in Europe was 91% at one years and 65% at five years. In the USA the five-year survival rate for localized breast cancer was 96.8%, while in cases of [[metastases]] it was only 20.6%. Because the prognosis for breast cancer was at this stage relatively favorable, compared to the prognosis for other cancers, breast cancer as cause of death among women was 13.9% of all cancer deaths. The second most common cause of death from cancer in women was lung cancer, the most common cancer worldwide for men and women. The improved survival rate made breast cancer the most prevalent cancer in the world. In 2010 an estimated 3.6 million women worldwide have had a breast cancer diagnosis in the past five years, while only 1.4 million male or female survivors from lung cancer were alive.<ref>{{cite book | vauthors = Olopade OI, Falkson CI |title = Breast Cancer in Women of African Descent |publisher = Springer Science & Business Media|year = 2010 |pages = 5 |isbn = 9781402036644}}</ref>
== Health disparities in breast cancer ==
There are ethnic disparities in the mortality rates for breast cancer as well as in breast cancer treatment. Breast cancer is the most prevalent cancer affecting women of every ethnic group in the United States. Breast cancer incidence among black women aged 45 and older is higher than that of white women in the same age group. White women aged 60–84 have higher incidence rates of breast cancer than Black women. Despite this, Black women at every age are more likely to succumb to breast cancer.<ref name="Health and Racial Disparity in Brea">{{cite journal | vauthors = Yedjou CG, Sims JN, Miele L, Noubissi F, Lowe L, Fonseca DD, Alo RA, Payton M, Tchounwou PB | display-authors = 6 | title = Health and Racial Disparity in Breast Cancer | journal = Advances in Experimental Medicine and Biology | volume = 1152 | pages = 31–49 | date = 3 January 2020 | pmid = 31456178 | pmc = 6941147 | doi = 10.1007/978-3-030-20301-6_3 | isbn = 978-3-030-20300-9 }}</ref>
Breast cancer treatment has improved greatly in recent years, but black women are still less likely to obtain treatment compared to white women.<ref name="Health and Racial Disparity in Brea"/> Risk factors such as socioeconomic status, late-stage, or breast cancer at diagnosis, genetic differences in tumor subtypes, differences in health care access all contribute to these disparities. Socioeconomic determinants affecting the disparity in breast cancer illness include poverty, culture, as well as social injustice. In Hispanic women, the incidence of breast cancer is lower than in non-Hispanic women but is often diagnosed at a later stage than white women with larger tumors.
Black women are usually diagnosed with breast cancer at a younger age than white women. The median age of diagnosis for Black women is 59, in comparison to 62 in White women. The incidence of breast cancer in Black women has increased by 0.4% per year since 1975 and 1.5% per year among Asian/Pacific Islander women since 1992. Incidence rates were stable for non-Hispanic White, Hispanics, and Native women. The five-year survival rate is noted to be 81% in Black women and 92% in White women. Chinese and Japanese women have the highest survival rates.<ref name="Health and Racial Disparity in Brea"/>
Poverty is a major driver for disparities related to breast cancer. Low-income women are less likely to undergo breast cancer screening and thus are more likely to have a late-stage diagnosis.<ref name="Health and Racial Disparity in Brea"/> Ensuring women of all ethnic groups receive equitable health care{{Clarify|date=January 2022}} can positively affect these disparities.{{Citation needed|date=January 2022}}
== Pregnancy ==
Pregnancy at an early age decreases the risk of developing breast cancer later in life.<ref name=Preg2019/> The risk of breast cancer also declines with the number of children a woman has.<ref name=Preg2019>{{cite web | url =https://www.cancer.gov/about-cancer/causes-prevention/risk/hormones/reproductive-history-fact-sheet#are-any-pregnancy-related-factors-associated-with-a-lower-risk-of-breast-cancer |title=Reproductive History and Cancer Risk |publisher=[[National Cancer Institute]] |date=30 November 2016 | access-date =22 August 2019}}</ref> Breast cancer then becomes more common in the 5 or 10 years following pregnancy but then becomes less common than among the general population.<ref>{{cite journal | vauthors = Azim HA, Santoro L, Russell-Edu W, Pentheroudakis G, Pavlidis N, Peccatori FA | title = Prognosis of pregnancy-associated breast cancer: a meta-analysis of 30 studies | journal = Cancer Treatment Reviews | volume = 38 | issue = 7 | pages = 834–42 | date = November 2012 | pmid = 22785217 | doi = 10.1016/j.ctrv.2012.06.004 }}</ref> These cancers are known as postpartum breast cancer and have worse outcomes including an increased risk of distant spread of disease and mortality.<ref>{{cite journal | vauthors = Schedin P | title = Pregnancy-associated breast cancer and metastasis | journal = Nature Reviews. Cancer | volume = 6 | issue = 4 | pages = 281–91 | date = April 2006 | pmid = 16557280 | doi = 10.1038/nrc1839 | s2cid = 9085879 }}</ref> Other cancers found during or shortly after pregnancy appear at approximately the same rate as other cancers in women of a similar age.<ref name=yarbro />
Diagnosing new cancer in a pregnant woman is difficult, in part because any symptoms are commonly assumed to be a normal discomfort associated with pregnancy.<ref name=yarbro /> As a result, cancer is typically discovered at a somewhat later stage than average in many pregnant or recently pregnant women. Some imaging procedures, such as [[MRI]]s (magnetic resonance imaging), [[CT scan]]s, ultrasounds, and [[mammogram]]s with fetal shielding are considered safe during pregnancy; some others, such as [[PET scan]]s are not.<ref name=yarbro />
Treatment is generally the same as for non-pregnant women.<ref name=yarbro /> However, radiation is normally avoided during pregnancy, especially if the fetal dose might exceed 100 cGy. In some cases, some or all treatments are postponed until after birth if the cancer is diagnosed late in the pregnancy. Early deliveries to speed the start of treatment are not uncommon. Surgery is generally considered safe during pregnancy, but some other treatments, especially certain chemotherapy drugs given during the [[first trimester]], increase the risk of [[birth defect]]s and pregnancy loss (spontaneous abortions and stillbirths).<ref name=yarbro /> Elective abortions are not required and do not improve the likelihood of the mother surviving or being cured.<ref name=yarbro />
Radiation treatments may interfere with the mother's ability to breastfeed her baby because it reduces the ability of that breast to produce milk and increases the risk of [[mastitis]]. Also, when chemotherapy is being given after birth, many of the drugs pass through breast milk to the baby, which could harm the baby.<ref name="yarbro">{{cite book |title = Cancer nursing: principles and practice | veditors = Yarbro CH, Wujcik D, Gobel BH |edition = 7th |publisher = Jones & Bartlett Publishers |year = 2011 |isbn = 978-1-4496-1829-2 |pages = 901–905 }}</ref>
Regarding future pregnancy among breast [[cancer survivor]]s, there is often fear of cancer recurrence.<ref name="Goncalves2013">{{cite journal | vauthors = Gonçalves V, Sehovic I, Quinn G | title = Childbearing attitudes and decisions of young breast cancer survivors: a systematic review | journal = Human Reproduction Update | volume = 20 | issue = 2 | pages = 279–92 | year = 2013 | pmid = 24077938 | pmc = 3922144 | doi = 10.1093/humupd/dmt039 }}</ref> On the other hand, many still regard pregnancy and parenthood to represent normality, happiness and life fulfillment.<ref name=Goncalves2013 />
== Hormones ==
=== Birth control ===
In breast cancer survivors, non-hormonal [[birth control]] methods such as the [[Copper IUDs|copper intrauterine device (IUD)]] should be used as first-line options.<ref>{{cite journal | vauthors = Patel A, Schwarz EB | title = Cancer and contraception. Release date May 2012. SFP Guideline #20121 | language = en | journal = Contraception | volume = 86 | issue = 3 | pages = 191–8 | date = September 2012 | pmid = 22682881 | doi = 10.1016/j.contraception.2012.05.008 }}</ref> [[Progestogen]]-based methods such as [[depot medroxyprogesterone acetate]], [[IUD with progestogen]] or [[progestogen only pill]]s have a poorly investigated but possible increased risk of cancer recurrence, but may be used if positive effects outweigh this possible risk.<ref>{{cite journal | vauthors = McNaught J, Reid RL | title = Progesterone-only and non-hormonal contraception in the breast cancer survivor: Joint Review and Committee Opinion of the Society of Obstetricians and Gynaecologists of Canada and the Society of Gynecologic Oncologists of Canada | journal = Journal of Obstetrics and Gynaecology Canada | volume = 28 | issue = 7 | pages = 616–626 | date = July 2006 | pmid = 16924781 | doi = 10.1016/S1701-2163(16)32195-8 }}</ref>
=== Menopausal hormone replacement ===
In breast cancer survivors, it is recommended to first consider non-hormonal options for [[menopausal]] effects, such as [[bisphosphonate]]s or [[selective estrogen receptor modulator]]s (SERMs) for osteoporosis, and [[vaginal estrogen]] for local symptoms. Observational studies of systemic [[Hormone replacement therapy (menopause)|hormone replacement therapy]] after breast cancer are generally reassuring. If hormone replacement is necessary after breast cancer, estrogen-only therapy or estrogen therapy with an [[intrauterine device with progestogen]] may be safer options than combined systemic therapy.<ref>[https://archive.today/20160407214503/https://www.ranzcog.edu.au/doc/management-of-the-menopause-after-breast-cancer.html Management of the menopause after breast cancer], from the [[Royal Australian and New Zealand College of Obstetricians and Gynaecologists]]. College Statement C-Gyn 15. 1st Endorsed: February 2003. Current: November 2011. Review: November 2014</ref>
== Research ==
Treatments are being evaluated in clinical trials. This includes individual drugs, combinations of drugs, and surgical and radiation techniques Investigations include new types of [[targeted therapy]],<ref>{{cite journal | vauthors = Venur VA, Leone JP | title = Targeted Therapies for Brain Metastases from Breast Cancer | journal = International Journal of Molecular Sciences | volume = 17 | issue = 9 | pages = 1543 | date = September 2016 | pmid = 27649142 | pmc = 5037817 | doi = 10.3390/ijms17091543 | df = dmy-all | doi-access = free }}</ref> [[cancer vaccine]]s, [[oncolytic virotherapy]],<ref>{{cite journal | vauthors = Suryawanshi YR, Zhang T, Essani K | title = Oncolytic viruses: emerging options for the treatment of breast cancer | journal = Medical Oncology | volume = 34 | issue = 3 | pages = 43 | date = March 2017 | pmid = 28185165 | doi = 10.1007/s12032-017-0899-0 | s2cid = 44562857 }}</ref> [[gene therapy]]<ref>{{cite journal | vauthors = Obermiller PS, Tait DL, Holt JT | title = Gene therapy for carcinoma of the breast: Therapeutic genetic correction strategies | journal = Breast Cancer Research | volume = 2 | issue = 1 | pages = 28–31 | year = 1999 | pmid = 11250690 | pmc = 521211 | doi = 10.1186/bcr26 }}</ref><ref>{{cite journal | vauthors = Roth JA, Swisher SG, Meyn RE | title = p53 tumor suppressor gene therapy for cancer | journal = Oncology | volume = 13 | issue = 10 Suppl 5 | pages = 148–54 | date = October 1999 | pmid = 10550840 }}</ref> and [[immunotherapy]].<ref>{{cite journal | vauthors = Yu LY, Tang J, Zhang CM, Zeng WJ, Yan H, Li MP, Chen XP | title = New Immunotherapy Strategies in Breast Cancer | journal = International Journal of Environmental Research and Public Health | volume = 14 | issue = 1 | pages = 68 | date = January 2017 | pmid = 28085094 | pmc = 5295319 | doi = 10.3390/ijerph14010068 | df = dmy-all | doi-access = free }}</ref>
The latest research is reported annually at scientific meetings such as that of the [[American Society of Clinical Oncology]], San Antonio Breast Cancer Symposium,<ref>[http://www.sabcs.org/EnduringMaterials/Index.asp San Antonio Breast Cancer Symposium] {{webarchive|url=https://web.archive.org/web/20100516171511/http://www.sabcs.org/EnduringMaterials/Index.asp |date=16 May 2010 }} Abstracts, newsletters, and other reports of the meeting.</ref> and the St. Gallen Oncology Conference in St. Gallen, Switzerland.<ref>{{cite journal | vauthors = Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thürlimann B, Senn HJ | title = Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009 | journal = Annals of Oncology | volume = 20 | issue = 8 | pages = 1319–29 | date = August 2009 | pmid = 19535820 | pmc = 2720818 | doi = 10.1093/annonc/mdp322 }}</ref> These studies are reviewed by professional societies and other organizations, and formulated into guidelines for specific treatment groups and risk category.
[[Fenretinide]], a [[retinoid]], is also being studied as a way to reduce the risk of breast cancer.<ref>{{Cite news |url = http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-new-research |title = What's new in breast cancer research and treatment? |work = Cancer |access-date = 17 November 2015 |url-status = live |archive-url = https://web.archive.org/web/20151112202807/http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-new-research |archive-date = 12 November 2015 |df = dmy-all }}</ref><ref>{{cite news |url = http://www.hindawi.com/journals/bmri/2012/172897/ |title = Fenretinide (4-HPR): A Preventive Chance for Women at Genetic and Familial Risk? |work = hindawi |access-date = 17 November 2015 |url-status = live |archive-url = https://web.archive.org/web/20151117181548/http://www.hindawi.com/journals/bmri/2012/172897/ |archive-date = 17 November 2015 |df = dmy-all}}</ref> In particular, combinations of [[ribociclib]] plus endocrine therapy have been the subject of clinical trials.<ref name="pmid29457921">{{cite journal | vauthors = Burris HA | title = Ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer | journal = Expert Review of Anticancer Therapy | volume = 18 | issue = 3 | pages = 201–213 | date = March 2018 | pmid = 29457921 | doi = 10.1080/14737140.2018.1435275| s2cid = 3425945 }}</ref>
A 2019 review found moderate certainty evidence that giving people [[antibiotic]]s before breast cancer surgery helped to prevent [[Perioperative mortality|surgical site infection (SSI)]]. Further study is required to determine the most effective antibiotic protocol and use in women undergoing immediate breast reconstruction.<ref>{{cite journal | vauthors = Gallagher M, Jones DJ, Bell-Syer SV | title = Prophylactic antibiotics to prevent surgical site infection after breast cancer surgery | journal = The Cochrane Database of Systematic Reviews | volume = 9 | pages = CD005360 | date = September 2019 | pmid = 31557310 | pmc = 6953223 | doi = 10.1002/14651858.CD005360.pub5 | collaboration = Cochrane Wounds Group}}</ref>
=== Cryoablation ===
As of 2014 [[cryoablation]] is being studied to see if it could be a substitute for a lumpectomy in small cancers.<ref>{{cite journal | vauthors = Sabel MS | title = Nonsurgical ablation of breast cancer: future options for small breast tumors | journal = Surgical Oncology Clinics of North America | volume = 23 | issue = 3 | pages = 593–608 | date = July 2014 | pmid = 24882353 | doi = 10.1016/j.soc.2014.03.009}}</ref> There is tentative evidence in those with tumors less than 2 centimeters.<ref name=Rou2014 /> It may also be used in those in who surgery is not possible.<ref name="Rou2014">{{cite journal | vauthors = Roubidoux MA, Yang W, Stafford RJ | title = Image-guided ablation in breast cancer treatment | journal = Techniques in Vascular and Interventional Radiology | volume = 17 | issue = 1 | pages = 49–54 | date = March 2014 | pmid = 24636331 | doi = 10.1053/j.tvir.2013.12.008}}</ref> Another review states that cryoablation looks promising for early breast cancer of small size.<ref>{{cite journal | vauthors = Fornage BD, Hwang RF | title = Current status of imaging-guided percutaneous ablation of breast cancer | journal = AJR. American Journal of Roentgenology | volume = 203 | issue = 2 | pages = 442–8 | date = August 2014 | pmid = 25055283 | doi = 10.2214/AJR.13.11600}}</ref>
=== Breast cancer cell lines ===
{{See also|List of breast cancer cell lines}}
Part of the current knowledge on breast carcinomas is based on [[in vivo]] and [[in vitro]] studies performed with [[cell lines]] derived from breast cancers. These provide an unlimited source of homogenous self-replicating material, free of contaminating [[stroma (animal tissue)|stromal]] cells, and often easily cultured in simple standard [[growth medium|media]]. The first breast cancer cell line described, [[BT-20 (cell line)|BT-20]], was established in 1958. Since then, and despite sustained work in this area, the number of permanent lines obtained has been strikingly low (about 100). Indeed, attempts to culture breast cancer cell lines from primary tumors have been largely unsuccessful. This poor efficiency was often due to technical difficulties associated with the extraction of viable tumor cells from their surrounding stroma. Most of the available breast cancer cell lines issued from metastatic tumors, mainly from [[pleural effusion]]s. Effusions provided generally large numbers of dissociated, viable tumor cells with little or no contamination by [[fibroblasts]] and other tumor stroma cells.
Many of the currently used BCC lines were established in the late 1970s. A very few of them, namely [[MCF-7]], [[T-47D]], [[MDA-MB-231]] and [[SK-BR-3]], account for more than two-thirds of all abstracts reporting studies on mentioned breast cancer cell lines, as concluded from a [[Medline]]-based survey.
=== Molecular markers ===
==== Metabolic markers ====
Clinically, the most useful metabolic markers in breast cancer are the estrogen and progesterone receptors that are used to predict response to hormone therapy. New or potentially new markers for breast cancer include BRCA1 and BRCA2<ref name="pmid11522269">{{cite journal | vauthors = Duffy MJ | title = Biochemical markers in breast cancer: which ones are clinically useful? | journal = Clinical Biochemistry | volume = 34 | issue = 5 | pages = 347–52 | date = July 2001 | pmid = 11522269 | doi = 10.1016/s0009-9120(00)00201-0}}</ref> to identify people at high risk of developing breast cancer, [[HER-2]],{{medcn|date=May 2018}} and [[Stearoyl-CoA desaturase-1|SCD1]], for predicting response to therapeutic regimens, and [[urokinase plasminogen activator]], PA1-1 and [[Stearoyl-CoA desaturase-1|SCD1]] for assessing prognosis.{{medcn|date=May 2018}}
== Other animals ==
* [[Mammary tumor]] for breast cancer in other animals
* [[Mouse models of breast cancer metastasis]]
== See also ==
*[[Male breast cancer]]
*[[Breast Cancer Research and Treatment]], a scientific journal
== References ==
{{Reflist}}
== External links ==
{{Medical resources
| eMedicine_mult = {{eMedicine2|med|3287}} {{eMedicine2|radio|115}} {{eMedicine2|plastic|521}}
| DiseasesDB = 1598
| ICD10 = {{ICD10|C|50||c|50}}
| ICD9 = {{ICD9|174}}-{{ICD9|175}},{{ICD9|V10.3}}
| ICDO={{ICDO|8502|3}}
| OMIM = 114480
| MedlinePlus = 000913
| eMedicineSubj = med
| eMedicineTopic = 2808
| MeshID = D001943
}}
{{Library resources box |by=no |onlinebooks=no |others=yes lcheading=Breast cancer}}
* {{curlie|Health/Conditions_and_Diseases/Cancer/Breast/}}
{{Subject bar |portal1= Biology |portal2= Medicine |commons= y |commons-search= Breast cancer |n= y |wikt= y|b= y |q= y |s= y |v= n |voy= n }}
{{Breast cancer types}}
{{Authority control}}
[[Category:Breast cancer| ]]
[[Category:Hereditary cancers]]
[[Category:Human female endocrine system]]
[[Category:Wikipedia medicine articles ready to translate]]' |
All external links in the new text (all_links) | [
0 => 'http://www.ons.gov.uk/ons/dcp171778_333318.pdf',
1 => 'https://web.archive.org/web/20141129124915/http://www.ons.gov.uk/ons/dcp171778_333318.pdf',
2 => '//doi.org/10.3322%2Fcaac.21492',
3 => '//pubmed.ncbi.nlm.nih.gov/30207593',
4 => 'https://api.semanticscholar.org/CorpusID:52188256',
5 => 'http://www.cancer.gov/cancertopics/pdq/treatment/malebreast/HealthProfessional',
6 => 'https://web.archive.org/web/20140704182515/http://www.cancer.gov/cancertopics/pdq/treatment/malebreast/HealthProfessional',
7 => 'http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/breast_cancer.html',
8 => 'https://web.archive.org/web/20111002141649/http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/breast_cancer.html',
9 => 'https://web.archive.org/web/20070410025934/http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf',
10 => 'http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf',
11 => '//doi.org/10.1056%2FNEJMoa062790',
12 => '//pubmed.ncbi.nlm.nih.gov/17229950',
13 => 'https://api.semanticscholar.org/CorpusID:13831558',
14 => '//doi.org/10.1093%2Finnovait%2Finn001',
15 => 'https://api.semanticscholar.org/CorpusID:71908359',
16 => 'https://web.archive.org/web/20080212070431/http://www.emedicine.com/med/TOPIC3287.HTM',
17 => 'http://www.emedicine.com/med/TOPIC3287.HTM',
18 => '//doi.org/10.1002%2F1097-0142(197009)26:3%3C680::aid-cncr2820260329%3E3.0.co;2-p',
19 => '//pubmed.ncbi.nlm.nih.gov/4318756',
20 => '//doi.org/10.1016%2FS1072-7515(98)00143-4',
21 => '//pubmed.ncbi.nlm.nih.gov/9704964',
22 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC138665',
23 => '//doi.org/10.1186%2Fbcr89',
24 => '//pubmed.ncbi.nlm.nih.gov/11250736',
25 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8289843',
26 => 'https://ui.adsabs.harvard.edu/abs/2021NatSR..1114738G',
27 => '//doi.org/10.1038%2Fs41598-021-94351-w',
28 => '//pubmed.ncbi.nlm.nih.gov/34282256',
29 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC9303577',
30 => '//doi.org/10.1002%2Fdc.24945',
31 => '//pubmed.ncbi.nlm.nih.gov/35156343',
32 => 'https://api.semanticscholar.org/CorpusID:246813006',
33 => '//doi.org/10.1016%2Fj.yapd.2021.05.006',
34 => '//pubmed.ncbi.nlm.nih.gov/34243852',
35 => 'https://api.semanticscholar.org/CorpusID:235786044',
36 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8930468',
37 => '//doi.org/10.1002%2Fgcc.23029',
38 => '//pubmed.ncbi.nlm.nih.gov/35106856',
39 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8101654',
40 => '//doi.org/10.4322%2Facr.2020.227',
41 => '//pubmed.ncbi.nlm.nih.gov/34277491',
42 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6528460',
43 => '//doi.org/10.20892%2Fj.issn.2095-3941.2018.0035',
44 => '//pubmed.ncbi.nlm.nih.gov/31119054',
45 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8488779',
46 => '//doi.org/10.1002%2Fonco.13880',
47 => '//pubmed.ncbi.nlm.nih.gov/34176200',
48 => 'http://www.answers.com/topic/phyllodes-tumor',
49 => 'https://web.archive.org/web/20100908032727/http://www.answers.com/topic/phyllodes-tumor',
50 => '//doi.org/10.1677%2FERC-06-0001',
51 => '//pubmed.ncbi.nlm.nih.gov/17158753',
52 => 'https://www.nationalbreastcancer.org/breast-cancer-stage-4',
53 => 'http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic',
54 => 'https://web.archive.org/web/20080827093333/http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic',
55 => '//doi.org/10.1111%2Ftbj.13531',
56 => '//pubmed.ncbi.nlm.nih.gov/31538691',
57 => 'https://books.google.com/books?id=PcARTQwHLpIC&pg=PA99',
58 => 'http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/overview_of_breast_disorders.html',
59 => 'https://web.archive.org/web/20111003004918/http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/overview_of_breast_disorders.html',
60 => '//doi.org/10.1111%2Fimj.12256',
61 => '//pubmed.ncbi.nlm.nih.gov/23910051',
62 => 'https://api.semanticscholar.org/CorpusID:23237732',
63 => '//doi.org/10.1007%2F978-0-387-73161-2_10',
64 => '//pubmed.ncbi.nlm.nih.gov/18274088',
65 => 'http://www.breastcancercare.org.uk/breast-cancer-information/breast-awareness/am-i-risk/risk',
66 => 'https://web.archive.org/web/20131025074635/http://www.breastcancercare.org.uk/breast-cancer-information/breast-awareness/am-i-risk/risk',
67 => '//doi.org/10.1016%2FS0140-6736(02)09454-0',
68 => '//pubmed.ncbi.nlm.nih.gov/12133652',
69 => 'https://api.semanticscholar.org/CorpusID:25250519',
70 => '//doi.org/10.1056%2FNEJMra050776',
71 => '//pubmed.ncbi.nlm.nih.gov/16421368',
72 => 'http://www.center4research.org/hormone-therapy-menopause/',
73 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7109112',
74 => '//doi.org/10.1038%2Fs41416-020-0741-x',
75 => '//pubmed.ncbi.nlm.nih.gov/32037402',
76 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5912140',
77 => '//doi.org/10.4143%2Fcrt.2017.094',
78 => '//pubmed.ncbi.nlm.nih.gov/28546524',
79 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4453639',
80 => '//doi.org/10.1038%2Fbjc.2014.579',
81 => '//pubmed.ncbi.nlm.nih.gov/25422909',
82 => '//doi.org/10.1111%2Facer.13071',
83 => '//pubmed.ncbi.nlm.nih.gov/27130687',
84 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3832299',
85 => '//doi.org/10.1007%2Fs12609-013-0114-z',
86 => '//pubmed.ncbi.nlm.nih.gov/24265860',
87 => 'https://www.cancer.org/cancer/breast-cancer/risk-and-prevention/lifestyle-related-breast-cancer-risk-factors.html',
88 => '//doi.org/10.1093%2Fajcn%2F86.3.878S',
89 => '//pubmed.ncbi.nlm.nih.gov/18265482',
90 => 'http://news.bbc.co.uk/1/hi/health/5171838.stm',
91 => 'https://web.archive.org/web/20070313141518/http://news.bbc.co.uk/1/hi/health/5171838.stm',
92 => '//doi.org/10.1126%2Fscience.342.6162.1028',
93 => '//pubmed.ncbi.nlm.nih.gov/24288308',
94 => '//doi.org/10.1007%2Fs10911-005-5401-5',
95 => '//pubmed.ncbi.nlm.nih.gov/16025225',
96 => 'https://api.semanticscholar.org/CorpusID:16838840',
97 => '//doi.org/10.3109%2F09637486.2014.950207',
98 => '//pubmed.ncbi.nlm.nih.gov/25198160',
99 => 'https://api.semanticscholar.org/CorpusID:207498132',
100 => 'https://www.npr.org/sections/thesalt/2016/02/01/464854395/a-diet-high-in-fiber-may-help-protect-against-breast-cancer',
101 => 'https://web.archive.org/web/20160201114307/http://www.npr.org/sections/thesalt/2016/02/01/464854395/a-diet-high-in-fiber-may-help-protect-against-breast-cancer',
102 => '//doi.org/10.1136%2Ftc.2010.035931',
103 => '//pubmed.ncbi.nlm.nih.gov/21148114',
104 => 'https://api.semanticscholar.org/CorpusID:448229',
105 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3645500',
106 => '//doi.org/10.1016%2FS0140-6736(12)61031-9',
107 => '//pubmed.ncbi.nlm.nih.gov/22818936',
108 => '//doi.org/10.7326%2FM14-1651',
109 => '//pubmed.ncbi.nlm.nih.gov/25599350',
110 => 'https://api.semanticscholar.org/CorpusID:7256176',
111 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6891893',
112 => '//doi.org/10.1016%2FS0140-6736(19)31709-X',
113 => '//pubmed.ncbi.nlm.nih.gov/31474332',
114 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8123798',
115 => '//doi.org/10.3390%2Fijerph18094638',
116 => '//pubmed.ncbi.nlm.nih.gov/33925599',
117 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7253192',
118 => '//doi.org/10.1097%2FAOG.0000000000003889',
119 => '//pubmed.ncbi.nlm.nih.gov/32459439',
120 => '//doi.org/10.1016%2Fj.contraception.2009.04.010',
121 => '//pubmed.ncbi.nlm.nih.gov/19751860',
122 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8494665',
123 => '//doi.org/10.1007%2Fs00404-020-05458-w',
124 => '//pubmed.ncbi.nlm.nih.gov/32140806',
125 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4670483',
126 => '//doi.org/10.1111%2Fapa.13102',
127 => '//pubmed.ncbi.nlm.nih.gov/26172878',
128 => 'https://www.who.int/health-topics/breastfeeding#tab=tab_1',
129 => 'https://www.cdc.gov/breastfeeding/faq/index.htm#benefits',
130 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC1903536',
131 => '//pubmed.ncbi.nlm.nih.gov/6773421',
132 => '//doi.org/10.1016%2FS0140-6736(04)15835-2',
133 => '//pubmed.ncbi.nlm.nih.gov/15051280',
134 => 'https://api.semanticscholar.org/CorpusID:20751083',
135 => 'https://web.archive.org/web/20070613192148/http://www.cancer.org/downloads/STT/CAFF2005BrFacspdf2005.pdf',
136 => 'http://www.cancer.org/downloads/STT/CAFF2005BrFacspdf2005.pdf',
137 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3045028',
138 => '//doi.org/10.1093%2Foccmed%2Fkqr001',
139 => '//pubmed.ncbi.nlm.nih.gov/21355031',
140 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4982776',
141 => '//doi.org/10.1001%2Fjamaoncol.2016.0164',
142 => '//pubmed.ncbi.nlm.nih.gov/27032109',
143 => '//doi.org/10.1002%2Fcncr.22656',
144 => '//pubmed.ncbi.nlm.nih.gov/17503444',
145 => 'https://api.semanticscholar.org/CorpusID:34880415',
146 => '//doi.org/10.1148%2Fradiol.10100570',
147 => '//pubmed.ncbi.nlm.nih.gov/20736332',
148 => '//doi.org/10.1002%2Fjso.21856',
149 => '//pubmed.ncbi.nlm.nih.gov/22441895',
150 => 'https://api.semanticscholar.org/CorpusID:3406636',
151 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3387322',
152 => '//doi.org/10.1007%2Fs10549-012-1985-9',
153 => '//pubmed.ncbi.nlm.nih.gov/22350789',
154 => '//doi.org/10.1016%2FS0140-6736(01)06524-2',
155 => '//pubmed.ncbi.nlm.nih.gov/11705483',
156 => 'https://api.semanticscholar.org/CorpusID:24278814',
157 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3561467',
158 => '//doi.org/10.7326%2F0003-4819-156-9-201205010-00006',
159 => '//pubmed.ncbi.nlm.nih.gov/22547473',
160 => 'https://www.nytimes.com/2012/09/24/health/study-finds-variations-of-breast-cancer.html',
161 => 'https://web.archive.org/web/20120924091105/http://www.nytimes.com/2012/09/24/health/study-finds-variations-of-breast-cancer.html',
162 => 'https://www.cdc.gov/cancer/breast/basic_info/risk_factors.htm',
163 => 'https://web.archive.org/web/20170514183905/http://www.popline.org/node/328955',
164 => '//doi.org/10.1590%2F1414-431X20175612',
165 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5912097',
166 => '//pubmed.ncbi.nlm.nih.gov/29513878',
167 => 'https://www.popline.org/node/328955',
168 => 'https://web.archive.org/web/20100527185336/http://www.cancer.gov/cancertopics/understanding-breast-changes/page6',
169 => 'http://www.cancer.gov/cancertopics/understanding-breast-changes/page6#F8',
170 => 'http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/page6',
171 => 'https://web.archive.org/web/20150425224841/http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page6',
172 => '//doi.org/10.1097%2FCEJ.0b013e3282f75e5d',
173 => '//pubmed.ncbi.nlm.nih.gov/18562954',
174 => 'https://api.semanticscholar.org/CorpusID:388045',
175 => '//doi.org/10.1177%2F1010539513488795',
176 => '//pubmed.ncbi.nlm.nih.gov/23709491',
177 => 'https://api.semanticscholar.org/CorpusID:206616972',
178 => '//doi.org/10.1016%2Fj.breast.2010.12.005',
179 => '//pubmed.ncbi.nlm.nih.gov/21237645',
180 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3816846',
181 => '//doi.org/10.3332%2Fecancer.2013.370',
182 => '//pubmed.ncbi.nlm.nih.gov/24222786',
183 => '//doi.org/10.1007%2Fs10549-007-9618-4',
184 => '//pubmed.ncbi.nlm.nih.gov/17592774',
185 => 'https://api.semanticscholar.org/CorpusID:11394158',
186 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4869065',
187 => 'https://ui.adsabs.harvard.edu/abs/2016NatSR...625998W',
188 => '//doi.org/10.1038%2Fsrep25998',
189 => '//pubmed.ncbi.nlm.nih.gov/27184120',
190 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC9483823',
191 => '//doi.org/10.1017%2FS2045796022000476',
192 => '//pubmed.ncbi.nlm.nih.gov/36059215',
193 => 'https://web.archive.org/web/20130813021816/http://www.sabcs.org/Newsletter/Docs/SABCS_2009_Issue5.pdf',
194 => 'http://www.sabcs.org/Newsletter/Docs/SABCS_2009_Issue5.pdf',
195 => '//doi.org/10.1016%2Fj.bbcan.2006.03.001',
196 => '//pubmed.ncbi.nlm.nih.gov/16675129',
197 => '//doi.org/10.1016%2Fj.jsbmb.2017.05.005',
198 => '//pubmed.ncbi.nlm.nih.gov/28595943',
199 => 'https://api.semanticscholar.org/CorpusID:19644829',
200 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC165024',
201 => '//doi.org/10.1186%2Fbcr615',
202 => '//pubmed.ncbi.nlm.nih.gov/12817994',
203 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2788989',
204 => 'https://ui.adsabs.harvard.edu/abs/2002Sci...296.1046W',
205 => '//doi.org/10.1126%2Fscience.1067431',
206 => '//pubmed.ncbi.nlm.nih.gov/12004111',
207 => '//doi.org/10.1016%2Fj.ejca.2010.09.005',
208 => '//pubmed.ncbi.nlm.nih.gov/20889333',
209 => 'http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10548311',
210 => '//pubmed.ncbi.nlm.nih.gov/10548311',
211 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2714486',
212 => '//doi.org/10.1001%2Fjama.2007.55-a',
213 => '//pubmed.ncbi.nlm.nih.gov/18182601',
214 => '//doi.org/10.1016%2FS1097-2765(00)80035-0',
215 => '//pubmed.ncbi.nlm.nih.gov/9660919',
216 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2807731',
217 => '//doi.org/10.1016%2Fj.mrfmmm.2009.03.011',
218 => '//pubmed.ncbi.nlm.nih.gov/19428384',
219 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC1156964',
220 => '//doi.org/10.1093%2Fnar%2Fgki661',
221 => '//pubmed.ncbi.nlm.nih.gov/15972793',
222 => '//doi.org/10.1056%2FNEJMra012284',
223 => '//pubmed.ncbi.nlm.nih.gov/12788999',
224 => 'https://api.semanticscholar.org/CorpusID:26602401',
225 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3521784',
226 => '//doi.org/10.2119%2Fmolmed.2012.00280',
227 => '//pubmed.ncbi.nlm.nih.gov/22972572',
228 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6716096',
229 => '//doi.org/10.17305%2Fbjbms.2018.3950',
230 => '//pubmed.ncbi.nlm.nih.gov/30579323',
231 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2397451',
232 => '//doi.org/10.1016%2Fj.ceb.2008.02.003',
233 => '//pubmed.ncbi.nlm.nih.gov/18358709',
234 => '//doi.org/10.3322%2Fcanjclin.54.6.327',
235 => '//pubmed.ncbi.nlm.nih.gov/15537576',
236 => '//doi.org/10.1007%2Fs10549-010-0750-1',
237 => '//pubmed.ncbi.nlm.nih.gov/20130983',
238 => 'https://api.semanticscholar.org/CorpusID:22685290',
239 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7276192',
240 => '//doi.org/10.1002%2Fjmrs.379',
241 => '//pubmed.ncbi.nlm.nih.gov/31975569',
242 => 'http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html',
243 => 'https://web.archive.org/web/20111110075702/http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html',
244 => 'https://web.archive.org/web/20120731073425/http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf',
245 => 'http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf',
246 => '//doi.org/10.6004%2Fjnccn.2009.0012',
247 => '//pubmed.ncbi.nlm.nih.gov/19200416',
248 => '//doi.org/10.1056%2FNEJMra0801289',
249 => '//pubmed.ncbi.nlm.nih.gov/19228622',
250 => '//doi.org/10.1056%2FNEJMoa052122',
251 => '//pubmed.ncbi.nlm.nih.gov/16236738',
252 => 'https://api.semanticscholar.org/CorpusID:9534884',
253 => 'https://www.cdc.gov/cancer/breast/basic_info/screening.htm',
254 => 'https://web.archive.org/web/20151118012201/http://www.cdc.gov/cancer/breast/basic_info/screening.htm',
255 => 'https://web.archive.org/web/20130102015424/http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm',
256 => 'http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm',
257 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7387360',
258 => '//doi.org/10.1002%2F14651858.CD003373',
259 => '//pubmed.ncbi.nlm.nih.gov/12804462',
260 => 'http://www.webmd.com/breast-cancer/guide/mammograms',
261 => 'https://web.archive.org/web/20121228104148/http://www.webmd.com/breast-cancer/guide/mammograms',
262 => '//doi.org/10.7326%2FM18-2147',
263 => '//pubmed.ncbi.nlm.nih.gov/30959525',
264 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3104900',
265 => '//doi.org/10.1159%2F000327493',
266 => '//pubmed.ncbi.nlm.nih.gov/21673820',
267 => '//doi.org/10.7326%2FM19-2125',
268 => '//pubmed.ncbi.nlm.nih.gov/31766052',
269 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3225421',
270 => '//doi.org/10.1503%2Fcmaj.110334',
271 => '//pubmed.ncbi.nlm.nih.gov/22106103',
272 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2409834',
273 => '//doi.org/10.1038%2Fsj.bjc.6601966',
274 => '//pubmed.ncbi.nlm.nih.gov/15213718',
275 => 'https://web.archive.org/web/20130616040709/http://www.ahrq.gov/clinic/3rduspstf/breastcancer/brcanrr.htm',
276 => 'http://www.ahrq.gov/clinic/3rduspstf/breastCancer/brcanrr.htm#ref31',
277 => '//doi.org/10.1001%2Fjamainternmed.2013.13635',
278 => '//pubmed.ncbi.nlm.nih.gov/24380095',
279 => 'http://nordic.cochrane.org/screening-breast-cancer-mammography',
280 => 'https://web.archive.org/web/20151029161343/http://nordic.cochrane.org/screening-breast-cancer-mammography',
281 => '//doi.org/10.7326%2F0003-4819-151-10-200911170-00008',
282 => '//pubmed.ncbi.nlm.nih.gov/19920272',
283 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5156844',
284 => '//pubmed.ncbi.nlm.nih.gov/27990198',
285 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3142573',
286 => '//doi.org/10.1001%2Farchinternmed.2010.363',
287 => '//pubmed.ncbi.nlm.nih.gov/20975025',
288 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4979358',
289 => '//doi.org/10.1136%2Fbmj.i3857',
290 => '//pubmed.ncbi.nlm.nih.gov/27510511',
291 => 'https://www.belfasttelegraph.co.uk/news/uk/new-study-finds-strong-evidence-that-exercise-cuts-breast-cancer-risk-41967524.html',
292 => '//www.worldcat.org/issn/0307-1235',
293 => '//doi.org/10.3322%2Fcaac.21319',
294 => '//pubmed.ncbi.nlm.nih.gov/26641959',
295 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3625773',
296 => '//doi.org/10.4048%2Fjbc.2013.16.1.72',
297 => '//pubmed.ncbi.nlm.nih.gov/23593085',
298 => '//doi.org/10.1136%2Fbmj.f3706',
299 => '//pubmed.ncbi.nlm.nih.gov/23814120',
300 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2359677',
301 => '//doi.org/10.1038%2Fsj.bjc.6604145',
302 => '//pubmed.ncbi.nlm.nih.gov/18182974',
303 => '//doi.org/10.1056%2FNEJM199901143400201',
304 => '//pubmed.ncbi.nlm.nih.gov/9887158',
305 => 'https://pure.eur.nl/ws/files/46620151/11463009.pdf',
306 => '//doi.org/10.1056%2FNEJM200107193450301',
307 => '//pubmed.ncbi.nlm.nih.gov/11463009',
308 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6494635',
309 => '//doi.org/10.1002%2F14651858.cd002748.pub4',
310 => '//pubmed.ncbi.nlm.nih.gov/29620792',
311 => '//doi.org/10.7326%2FM13-2747',
312 => '//pubmed.ncbi.nlm.nih.gov/24366376',
313 => '//doi.org/10.7326%2F0003-4819-158-8-201304160-00005',
314 => '//pubmed.ncbi.nlm.nih.gov/23588749',
315 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3671272',
316 => '//doi.org/10.1016%2FS0140-6736(13)60140-3',
317 => '//pubmed.ncbi.nlm.nih.gov/23639488',
318 => '//doi.org/10.1001%2Fjama.2019.11885',
319 => '//pubmed.ncbi.nlm.nih.gov/31479144',
320 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6487387',
321 => '//doi.org/10.1002%2F14651858.cd012191.pub2',
322 => '//pubmed.ncbi.nlm.nih.gov/31032883',
323 => '//doi.org/10.1093%2Fannonc%2Fmdr352',
324 => '//pubmed.ncbi.nlm.nih.gov/21821551',
325 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5551685',
326 => '//doi.org/10.1038%2Fnrclinonc.2016.25',
327 => '//pubmed.ncbi.nlm.nih.gov/26977780',
328 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6122903',
329 => '//doi.org/10.5935%2Fabc.20180138',
330 => '//pubmed.ncbi.nlm.nih.gov/30183988',
331 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2849768',
332 => '//doi.org/10.1200%2FJCO.2009.22.7918',
333 => '//pubmed.ncbi.nlm.nih.gov/20159825',
334 => '//doi.org/10.17925%2FEOH.2011.07.02.106',
335 => 'https://api.semanticscholar.org/CorpusID:1802863',
336 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4876310',
337 => '//doi.org/10.1200%2FJCO.2013.54.2258',
338 => '//pubmed.ncbi.nlm.nih.gov/24868023',
339 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8092675',
340 => '//doi.org/10.1002%2F14651858.CD007245.pub4',
341 => '//pubmed.ncbi.nlm.nih.gov/33348436',
342 => '//doi.org/10.1016%2FS0140-6736(15)61074-1',
343 => '//pubmed.ncbi.nlm.nih.gov/26211827',
344 => '//doi.org/10.1530%2FERC-10-0162',
345 => '//pubmed.ncbi.nlm.nih.gov/21502311',
346 => 'http://www.uptodate.com/contents/treatment-of-metastatic-breast-cancer-beyond-the-basics',
347 => 'https://web.archive.org/web/20170904202736/http://www.uptodate.com/contents/treatment-of-metastatic-breast-cancer-beyond-the-basics?source=search_result&search=letrozole&selectedTitle=4~6',
348 => 'http://ascopost.com/issues/october-25-2016/combination-of-ribociclib-and-letrozole-is-a-home-run-in-advanced-breast-cancer/',
349 => '//doi.org/10.3816%2FCBC.2008.n.037',
350 => '//pubmed.ncbi.nlm.nih.gov/18757259',
351 => 'https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2064',
352 => 'https://web.archive.org/web/20091026055528/http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2064',
353 => 'https://web.archive.org/web/20100406014305/http://www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp',
354 => 'http://www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp',
355 => 'https://www.breastcancer.org/research-news/new-guidelines-to-treat-advanced-her2-pos',
356 => '//doi.org/10.1056%2FNEJM200103153441101',
357 => '//pubmed.ncbi.nlm.nih.gov/11248153',
358 => 'https://web.archive.org/web/20120112122626/http://www.asco.org/ASCOv2/Meetings/Abstracts?vmview=abst_detail_view&confID=40&abstractID=34291',
359 => '//doi.org/10.1200%2Fjco.2006.24.18_suppl.10611',
360 => 'http://www.asco.org/ASCOv2/Meetings/Abstracts?vmview=abst_detail_view&confID=40&abstractID=34291',
361 => '//doi.org/10.1158%2F1078-0432.CCR-07-4453',
362 => '//pubmed.ncbi.nlm.nih.gov/18316551',
363 => 'http://www.breastcancer.org/treatment/radiation',
364 => 'https://web.archive.org/web/20151117193610/http://www.breastcancer.org/treatment/radiation',
365 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8406917',
366 => '//doi.org/10.1002%2F14651858.CD007077.pub4',
367 => '//pubmed.ncbi.nlm.nih.gov/34459500',
368 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7073405',
369 => '//doi.org/10.1002%2F14651858.cd001768.pub3',
370 => '//pubmed.ncbi.nlm.nih.gov/27230946',
371 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8078577',
372 => '//doi.org/10.1002%2F14651858.cd009553.pub2',
373 => '//pubmed.ncbi.nlm.nih.gov/23235677',
374 => '//doi.org/10.1007%2Fs10549-007-9710-9',
375 => '//pubmed.ncbi.nlm.nih.gov/17899373',
376 => 'https://api.semanticscholar.org/CorpusID:24976113',
377 => 'https://evidence.nihr.ac.uk/alert/exercise-programme-improves-arm-function-pain-after-breast-cancer-surgery/',
378 => '//doi.org/10.3310%2Fnihrevidence_53632',
379 => 'https://api.semanticscholar.org/CorpusID:252562000',
380 => '//doi.org/10.3310%2FJKNZ2003',
381 => '//pubmed.ncbi.nlm.nih.gov/35220995',
382 => 'https://api.semanticscholar.org/CorpusID:247157545',
383 => 'https://web.archive.org/web/20130813054115/http://www.stopcancerfund.org/wp/wp-content/uploads/2009/12/booklet04bc.pdf',
384 => 'http://www.stopcancerfund.org/wp/wp-content/uploads/2009/12/booklet04bc.pdf',
385 => '//doi.org/10.1111%2Fj.1365-2559.1991.tb00229.x',
386 => '//pubmed.ncbi.nlm.nih.gov/1757079',
387 => 'https://api.semanticscholar.org/CorpusID:17622089',
388 => 'http://www.cancernetwork.com/cme/article/10165/1413886',
389 => '//pubmed.ncbi.nlm.nih.gov/19544685',
390 => 'https://web.archive.org/web/20090616191104/http://www.cancernetwork.com/cme/article/10165/1413886',
391 => 'http://www.cancernetwork.com/display/article/10165/1366719?pageNumber=1',
392 => 'https://web.archive.org/web/20090705230857/http://www.cancernetwork.com/display/article/10165/1366719?pageNumber=1',
393 => '//doi.org/10.1002%2F14651858.cd008729.pub2',
394 => '//pubmed.ncbi.nlm.nih.gov/26017383',
395 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6491330',
396 => '//doi.org/10.1002%2F14651858.cd011292.pub2',
397 => '//pubmed.ncbi.nlm.nih.gov/29376559',
398 => 'https://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html',
399 => 'https://web.archive.org/web/20091111101009/http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html',
400 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4491690',
401 => '//doi.org/10.3390%2Fcancers7020815',
402 => '//pubmed.ncbi.nlm.nih.gov/26010605',
403 => 'https://www.who.int/news-room/fact-sheets/detail/cancer',
404 => '//doi.org/10.12968%2Fhmed.2019.80.12.720',
405 => '//pubmed.ncbi.nlm.nih.gov/31822191',
406 => 'https://api.semanticscholar.org/CorpusID:209314404',
407 => 'https://web.archive.org/web/20111231111259/http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/',
408 => 'http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/',
409 => 'https://web.archive.org/web/20150906121739/http://www.who.int/cancer/detection/breastcancer/en/index1.html',
410 => 'https://www.who.int/cancer/detection/breastcancer/en/index1.html',
411 => 'https://web.archive.org/web/20081020000016/http://www.scribd.com/doc/2350813/World-Cancer-Report-2003-Stuart-e-Kleihues-WHO-e-IARC',
412 => 'https://www.scribd.com/doc/2350813/World-Cancer-Report-2003-Stuart-e-Kleihues-WHO-e-IARC',
413 => 'https://web.archive.org/web/20080425022457/http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/breast-cancer-cases-rise-80-since-seventies-417990.html',
414 => 'https://www.independent.co.uk/life-style/health-and-wellbeing/health-news/breast-cancer-cases-rise-80-since-seventies-417990.html',
415 => 'http://imaginis.com/breasthealth/statistics.asp',
416 => 'https://web.archive.org/web/20061024120910/http://www.imaginis.com/breasthealth/statistics.asp',
417 => 'http://www.webmd.com/breast-cancer/guide/breast-cancer-young-women',
418 => 'https://web.archive.org/web/20090910015335/http://www.webmd.com/breast-cancer/guide/breast-cancer-young-women',
419 => 'http://www.ons.gov.uk/ons/rel/vsob1/cancer-statistics-registrations--england--series-mb1-/no--42--2011/sty-breast-cancer-survival.html',
420 => 'https://web.archive.org/web/20131105085823/http://www.ons.gov.uk/ons/rel/vsob1/cancer-statistics-registrations--england--series-mb1-/no--42--2011/sty-breast-cancer-survival.html',
421 => 'https://seer.cancer.gov/statfacts/html/breast.html',
422 => '//doi.org/10.1200%2FJCO.2005.02.1147',
423 => '//pubmed.ncbi.nlm.nih.gov/16234516',
424 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4324662',
425 => '//doi.org/10.1186%2F1471-2482-15-1',
426 => '//pubmed.ncbi.nlm.nih.gov/25586679',
427 => '//doi.org/10.21873%2Fanticanres.11858',
428 => '//pubmed.ncbi.nlm.nih.gov/28739757',
429 => '//doi.org/10.1038%2Fnrclinonc.2014.3',
430 => '//pubmed.ncbi.nlm.nih.gov/24492834',
431 => 'https://api.semanticscholar.org/CorpusID:601112',
432 => 'https://www.cancer.org/cancer/breast-cancer/treatment/surgery-for-breast-cancer/breast-conserving-surgery-lumpectomy.html',
433 => '//doi.org/10.1177%2F000313481207801226',
434 => '//pubmed.ncbi.nlm.nih.gov/23265123',
435 => 'https://api.semanticscholar.org/CorpusID:26112023',
436 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7522052',
437 => '//doi.org/10.7759%2Fcureus.10072',
438 => '//pubmed.ncbi.nlm.nih.gov/32999790',
439 => 'https://www.breastcancer.org/research-news/quality-of-life-after-preventive-mastectomy',
440 => 'http://in.reuters.com/article/egypt-antiquities-cancer-idINKBN0MK1ZW20150324',
441 => 'https://web.archive.org/web/20150327023314/http://in.reuters.com/article/2015/03/24/egypt-antiquities-cancer-idINKBN0MK1ZW20150324',
442 => 'https://web.archive.org/web/20061009011530/http://www.cancer.org/docroot/CRI/content/CRI_2_6x_the_history_of_cancer_72.asp?sitearea=CRI',
443 => 'http://www.cancer.org/docroot/CRI/content/CRI_2_6x_the_history_of_cancer_72.asp?sitearea=CRI',
444 => 'https://archive.org/details/historyofbreast00yalo/page/234',
445 => '//doi.org/10.4997%2FJRCPE.2011.211',
446 => '//pubmed.ncbi.nlm.nih.gov/21677925',
447 => 'https://archive.org/details/unnaturalhistory00aron/page/22',
448 => 'https://books.google.com/books?id=p4o9AQAAIAAJ',
449 => 'https://books.google.com/books?id=E-OZbEmPSTkC&pg=PA301',
450 => 'https://archive.org/details/pinkribbonbluesh0000suli',
451 => '//www.worldcat.org/oclc/535493589',
452 => 'https://web.archive.org/web/20130623074930/http://www.crcfl.net/content/view/history-of-breast-cancer-advocacy.html',
453 => 'http://www.crcfl.net/content/view/history-of-breast-cancer-advocacy.html',
454 => 'http://www.prwatch.org/node/7436',
455 => 'https://web.archive.org/web/20110605122507/http://www.prwatch.org/node/7436',
456 => 'https://www.ctvnews.ca/breast-cancer-month-overshadowed-by-pinkwashing-1.561275',
457 => 'https://web.archive.org/web/20101012151918/http://ottawa.ctv.ca/servlet/an/local/CTVNews/20101008/pinkwashing-pink-ribbon-101009/20101009/?hub=OttawaHome',
458 => 'https://web.archive.org/web/20101120135605/http://barbaraehrenreich.com/cancerland.htm',
459 => 'http://www.barbaraehrenreich.com/cancerland.htm',
460 => 'https://articles.latimes.com/2009/aug/17/health/he-breast-overdiagnosis17',
461 => 'https://web.archive.org/web/20101204073704/http://articles.latimes.com/2009/aug/17/health/he-breast-overdiagnosis17',
462 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6941147',
463 => '//doi.org/10.1007%2F978-3-030-20301-6_3',
464 => '//pubmed.ncbi.nlm.nih.gov/31456178',
465 => 'https://www.cancer.gov/about-cancer/causes-prevention/risk/hormones/reproductive-history-fact-sheet#are-any-pregnancy-related-factors-associated-with-a-lower-risk-of-breast-cancer',
466 => '//doi.org/10.1016%2Fj.ctrv.2012.06.004',
467 => '//pubmed.ncbi.nlm.nih.gov/22785217',
468 => '//doi.org/10.1038%2Fnrc1839',
469 => '//pubmed.ncbi.nlm.nih.gov/16557280',
470 => 'https://api.semanticscholar.org/CorpusID:9085879',
471 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3922144',
472 => '//doi.org/10.1093%2Fhumupd%2Fdmt039',
473 => '//pubmed.ncbi.nlm.nih.gov/24077938',
474 => '//doi.org/10.1016%2Fj.contraception.2012.05.008',
475 => '//pubmed.ncbi.nlm.nih.gov/22682881',
476 => '//doi.org/10.1016%2FS1701-2163(16)32195-8',
477 => '//pubmed.ncbi.nlm.nih.gov/16924781',
478 => 'https://archive.today/20160407214503/https://www.ranzcog.edu.au/doc/management-of-the-menopause-after-breast-cancer.html',
479 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5037817',
480 => '//doi.org/10.3390%2Fijms17091543',
481 => '//pubmed.ncbi.nlm.nih.gov/27649142',
482 => '//doi.org/10.1007%2Fs12032-017-0899-0',
483 => '//pubmed.ncbi.nlm.nih.gov/28185165',
484 => 'https://api.semanticscholar.org/CorpusID:44562857',
485 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC521211',
486 => '//doi.org/10.1186%2Fbcr26',
487 => '//pubmed.ncbi.nlm.nih.gov/11250690',
488 => '//pubmed.ncbi.nlm.nih.gov/10550840',
489 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5295319',
490 => '//doi.org/10.3390%2Fijerph14010068',
491 => '//pubmed.ncbi.nlm.nih.gov/28085094',
492 => 'http://www.sabcs.org/EnduringMaterials/Index.asp',
493 => 'https://web.archive.org/web/20100516171511/http://www.sabcs.org/EnduringMaterials/Index.asp',
494 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2720818',
495 => '//doi.org/10.1093%2Fannonc%2Fmdp322',
496 => '//pubmed.ncbi.nlm.nih.gov/19535820',
497 => 'http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-new-research',
498 => 'https://web.archive.org/web/20151112202807/http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-new-research',
499 => 'http://www.hindawi.com/journals/bmri/2012/172897/',
500 => 'https://web.archive.org/web/20151117181548/http://www.hindawi.com/journals/bmri/2012/172897/',
501 => '//doi.org/10.1080%2F14737140.2018.1435275',
502 => '//pubmed.ncbi.nlm.nih.gov/29457921',
503 => 'https://api.semanticscholar.org/CorpusID:3425945',
504 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6953223',
505 => '//doi.org/10.1002%2F14651858.CD005360.pub5',
506 => '//pubmed.ncbi.nlm.nih.gov/31557310',
507 => '//doi.org/10.1016%2Fj.soc.2014.03.009',
508 => '//pubmed.ncbi.nlm.nih.gov/24882353',
509 => '//doi.org/10.1053%2Fj.tvir.2013.12.008',
510 => '//pubmed.ncbi.nlm.nih.gov/24636331',
511 => '//doi.org/10.2214%2FAJR.13.11600',
512 => '//pubmed.ncbi.nlm.nih.gov/25055283',
513 => '//doi.org/10.1016%2Fs0009-9120(00)00201-0',
514 => '//pubmed.ncbi.nlm.nih.gov/11522269',
515 => 'https://www.wikidata.org/wiki/Q128581#identifiers',
516 => 'https://icd.who.int/browse10/2019/en#/C50',
517 => 'http://www.icd9data.com/getICD9Code.ashx?icd9=174',
518 => 'http://www.icd9data.com/getICD9Code.ashx?icd9=175',
519 => 'http://www.icd9data.com/getICD9Code.ashx?icd9=V10.3',
520 => 'https://progenetix.org/subsets/?term_id=icdom:8502_3',
521 => 'https://omim.org/entry/114480',
522 => 'https://meshb.nlm.nih.gov/record/ui?ui=D001943',
523 => 'http://www.diseasesdatabase.com/ddb1598.htm',
524 => 'https://www.nlm.nih.gov/medlineplus/ency/article/000913.htm',
525 => 'https://emedicine.medscape.com/med/2808-overview',
526 => 'http://www.emedicine.com/med/topic3287.htm#',
527 => 'http://www.emedicine.com/radio/topic115.htm#',
528 => 'http://www.emedicine.com/plastic/topic521.htm#',
529 => 'https://patient.info/doctor/breast-cancer-pro',
530 => 'https://www.cancer.gov/breast',
531 => 'https://ftl.toolforge.org/cgi-bin/ftl?st=wp&su=Breast+cancer',
532 => 'https://ftl.toolforge.org/cgi-bin/ftl?st=wp&su=Breast+cancer&library=0CHOOSE0',
533 => 'https://curlie.org/Health/Conditions_and_Diseases/Cancer/Breast/',
534 => 'https://d-nb.info/gnd/4008528-4',
535 => 'http://uli.nli.org.il/F/?func=find-b&local_base=NLX10&find_code=UID&request=987007583504205171',
536 => 'http://uli.nli.org.il/F/?func=find-b&local_base=NLX10&find_code=UID&request=987007282518605171',
537 => 'https://id.loc.gov/authorities/subjects/sh85016679',
538 => 'https://id.loc.gov/authorities/subjects/sh2010009734',
539 => 'https://id.ndl.go.jp/auth/ndlna/00568758',
540 => 'https://aleph.nkp.cz/F/?func=find-c&local_base=aut&ccl_term=ica=ph135010&CON_LNG=ENG'
] |
Links in the page, before the edit (old_links) | [
0 => '//doi.org/10.1001%2Farchinternmed.2010.363',
1 => '//doi.org/10.1001%2Fjama.2007.55-a',
2 => '//doi.org/10.1001%2Fjama.2019.11885',
3 => '//doi.org/10.1001%2Fjamainternmed.2013.13635',
4 => '//doi.org/10.1001%2Fjamaoncol.2016.0164',
5 => '//doi.org/10.1002%2F1097-0142(197009)26:3%3C680::aid-cncr2820260329%3E3.0.co;2-p',
6 => '//doi.org/10.1002%2F14651858.CD001877.pub5',
7 => '//doi.org/10.1002%2F14651858.CD003373',
8 => '//doi.org/10.1002%2F14651858.CD005360.pub5',
9 => '//doi.org/10.1002%2F14651858.CD007077.pub4',
10 => '//doi.org/10.1002%2F14651858.CD007245.pub4',
11 => '//doi.org/10.1002%2F14651858.cd001768.pub3',
12 => '//doi.org/10.1002%2F14651858.cd002748.pub4',
13 => '//doi.org/10.1002%2F14651858.cd008729.pub2',
14 => '//doi.org/10.1002%2F14651858.cd009553.pub2',
15 => '//doi.org/10.1002%2F14651858.cd011292.pub2',
16 => '//doi.org/10.1002%2F14651858.cd012191.pub2',
17 => '//doi.org/10.1002%2Fcncr.22656',
18 => '//doi.org/10.1002%2Fdc.24945',
19 => '//doi.org/10.1002%2Fgcc.23029',
20 => '//doi.org/10.1002%2Fjmrs.379',
21 => '//doi.org/10.1002%2Fjso.21856',
22 => '//doi.org/10.1002%2Fonco.13880',
23 => '//doi.org/10.1007%2F978-0-387-73161-2_10',
24 => '//doi.org/10.1007%2F978-3-030-20301-6_3',
25 => '//doi.org/10.1007%2Fs00404-020-05458-w',
26 => '//doi.org/10.1007%2Fs10549-007-9618-4',
27 => '//doi.org/10.1007%2Fs10549-007-9710-9',
28 => '//doi.org/10.1007%2Fs10549-010-0750-1',
29 => '//doi.org/10.1007%2Fs10549-012-1985-9',
30 => '//doi.org/10.1007%2Fs10911-005-5401-5',
31 => '//doi.org/10.1007%2Fs12032-017-0899-0',
32 => '//doi.org/10.1007%2Fs12609-013-0114-z',
33 => '//doi.org/10.1016%2FS0140-6736(01)06524-2',
34 => '//doi.org/10.1016%2FS0140-6736(02)09454-0',
35 => '//doi.org/10.1016%2FS0140-6736(04)15835-2',
36 => '//doi.org/10.1016%2FS0140-6736(12)61031-9',
37 => '//doi.org/10.1016%2FS0140-6736(13)60140-3',
38 => '//doi.org/10.1016%2FS0140-6736(15)61074-1',
39 => '//doi.org/10.1016%2FS0140-6736(19)31709-X',
40 => '//doi.org/10.1016%2FS1072-7515(98)00143-4',
41 => '//doi.org/10.1016%2FS1097-2765(00)80035-0',
42 => '//doi.org/10.1016%2FS1701-2163(16)32195-8',
43 => '//doi.org/10.1016%2Fj.bbcan.2006.03.001',
44 => '//doi.org/10.1016%2Fj.breast.2010.12.005',
45 => '//doi.org/10.1016%2Fj.ceb.2008.02.003',
46 => '//doi.org/10.1016%2Fj.contraception.2009.04.010',
47 => '//doi.org/10.1016%2Fj.contraception.2012.05.008',
48 => '//doi.org/10.1016%2Fj.ctrv.2012.06.004',
49 => '//doi.org/10.1016%2Fj.ejca.2010.09.005',
50 => '//doi.org/10.1016%2Fj.jsbmb.2017.05.005',
51 => '//doi.org/10.1016%2Fj.mrfmmm.2009.03.011',
52 => '//doi.org/10.1016%2Fj.soc.2014.03.009',
53 => '//doi.org/10.1016%2Fj.yapd.2021.05.006',
54 => '//doi.org/10.1016%2Fs0009-9120(00)00201-0',
55 => '//doi.org/10.1017%2FS2045796022000476',
56 => '//doi.org/10.1038%2Fbjc.2014.579',
57 => '//doi.org/10.1038%2Fnrc1839',
58 => '//doi.org/10.1038%2Fnrclinonc.2014.3',
59 => '//doi.org/10.1038%2Fnrclinonc.2016.25',
60 => '//doi.org/10.1038%2Fs41416-020-0741-x',
61 => '//doi.org/10.1038%2Fs41598-021-94351-w',
62 => '//doi.org/10.1038%2Fsj.bjc.6601966',
63 => '//doi.org/10.1038%2Fsj.bjc.6604145',
64 => '//doi.org/10.1038%2Fsrep25998',
65 => '//doi.org/10.1053%2Fj.tvir.2013.12.008',
66 => '//doi.org/10.1056%2FNEJM199901143400201',
67 => '//doi.org/10.1056%2FNEJM200103153441101',
68 => '//doi.org/10.1056%2FNEJM200107193450301',
69 => '//doi.org/10.1056%2FNEJMoa052122',
70 => '//doi.org/10.1056%2FNEJMoa062790',
71 => '//doi.org/10.1056%2FNEJMra012284',
72 => '//doi.org/10.1056%2FNEJMra050776',
73 => '//doi.org/10.1056%2FNEJMra0801289',
74 => '//doi.org/10.1080%2F14737140.2018.1435275',
75 => '//doi.org/10.1093%2Fajcn%2F86.3.878S',
76 => '//doi.org/10.1093%2Fannonc%2Fmdp322',
77 => '//doi.org/10.1093%2Fannonc%2Fmdr352',
78 => '//doi.org/10.1093%2Fhumupd%2Fdmt039',
79 => '//doi.org/10.1093%2Finnovait%2Finn001',
80 => '//doi.org/10.1093%2Fnar%2Fgki661',
81 => '//doi.org/10.1093%2Foccmed%2Fkqr001',
82 => '//doi.org/10.1097%2FAOG.0000000000003889',
83 => '//doi.org/10.1097%2FCEJ.0b013e3282f75e5d',
84 => '//doi.org/10.1111%2Facer.13071',
85 => '//doi.org/10.1111%2Fapa.13102',
86 => '//doi.org/10.1111%2Fimj.12256',
87 => '//doi.org/10.1111%2Fj.1365-2559.1991.tb00229.x',
88 => '//doi.org/10.1111%2Ftbj.13531',
89 => '//doi.org/10.1126%2Fscience.1067431',
90 => '//doi.org/10.1126%2Fscience.342.6162.1028',
91 => '//doi.org/10.1136%2Fbmj.f3706',
92 => '//doi.org/10.1136%2Fbmj.i3857',
93 => '//doi.org/10.1136%2Ftc.2010.035931',
94 => '//doi.org/10.1148%2Fradiol.10100570',
95 => '//doi.org/10.1158%2F1078-0432.CCR-07-4453',
96 => '//doi.org/10.1159%2F000327493',
97 => '//doi.org/10.1177%2F000313481207801226',
98 => '//doi.org/10.1177%2F1010539513488795',
99 => '//doi.org/10.1186%2F1471-2482-15-1',
100 => '//doi.org/10.1186%2Fbcr26',
101 => '//doi.org/10.1186%2Fbcr615',
102 => '//doi.org/10.1186%2Fbcr89',
103 => '//doi.org/10.1200%2FJCO.2005.02.1147',
104 => '//doi.org/10.1200%2FJCO.2009.22.7918',
105 => '//doi.org/10.1200%2FJCO.2013.54.2258',
106 => '//doi.org/10.1200%2Fjco.2006.24.18_suppl.10611',
107 => '//doi.org/10.12968%2Fhmed.2019.80.12.720',
108 => '//doi.org/10.1503%2Fcmaj.110334',
109 => '//doi.org/10.1530%2FERC-10-0162',
110 => '//doi.org/10.1590%2F1414-431X20175612',
111 => '//doi.org/10.1677%2FERC-06-0001',
112 => '//doi.org/10.17305%2Fbjbms.2018.3950',
113 => '//doi.org/10.17925%2FEOH.2011.07.02.106',
114 => '//doi.org/10.20892%2Fj.issn.2095-3941.2018.0035',
115 => '//doi.org/10.2119%2Fmolmed.2012.00280',
116 => '//doi.org/10.21873%2Fanticanres.11858',
117 => '//doi.org/10.2214%2FAJR.13.11600',
118 => '//doi.org/10.3109%2F09637486.2014.950207',
119 => '//doi.org/10.3310%2FJKNZ2003',
120 => '//doi.org/10.3310%2Fnihrevidence_53632',
121 => '//doi.org/10.3322%2Fcaac.21319',
122 => '//doi.org/10.3322%2Fcaac.21492',
123 => '//doi.org/10.3322%2Fcaac.21660',
124 => '//doi.org/10.3322%2Fcanjclin.54.6.327',
125 => '//doi.org/10.3332%2Fecancer.2013.370',
126 => '//doi.org/10.3390%2Fcancers7020815',
127 => '//doi.org/10.3390%2Fijerph14010068',
128 => '//doi.org/10.3390%2Fijerph18094638',
129 => '//doi.org/10.3390%2Fijms17091543',
130 => '//doi.org/10.3816%2FCBC.2008.n.037',
131 => '//doi.org/10.4048%2Fjbc.2013.16.1.72',
132 => '//doi.org/10.4143%2Fcrt.2017.094',
133 => '//doi.org/10.4322%2Facr.2020.227',
134 => '//doi.org/10.4997%2FJRCPE.2011.211',
135 => '//doi.org/10.5935%2Fabc.20180138',
136 => '//doi.org/10.6004%2Fjnccn.2009.0012',
137 => '//doi.org/10.7326%2F0003-4819-151-10-200911170-00008',
138 => '//doi.org/10.7326%2F0003-4819-156-9-201205010-00006',
139 => '//doi.org/10.7326%2F0003-4819-158-8-201304160-00005',
140 => '//doi.org/10.7326%2FM13-2747',
141 => '//doi.org/10.7326%2FM14-1651',
142 => '//doi.org/10.7326%2FM15-2886',
143 => '//doi.org/10.7326%2FM18-2147',
144 => '//doi.org/10.7326%2FM19-2125',
145 => '//doi.org/10.7759%2Fcureus.10072',
146 => '//pubmed.ncbi.nlm.nih.gov/10548311',
147 => '//pubmed.ncbi.nlm.nih.gov/10550840',
148 => '//pubmed.ncbi.nlm.nih.gov/11248153',
149 => '//pubmed.ncbi.nlm.nih.gov/11250690',
150 => '//pubmed.ncbi.nlm.nih.gov/11250736',
151 => '//pubmed.ncbi.nlm.nih.gov/11463009',
152 => '//pubmed.ncbi.nlm.nih.gov/11522269',
153 => '//pubmed.ncbi.nlm.nih.gov/11705483',
154 => '//pubmed.ncbi.nlm.nih.gov/12004111',
155 => '//pubmed.ncbi.nlm.nih.gov/12133652',
156 => '//pubmed.ncbi.nlm.nih.gov/12788999',
157 => '//pubmed.ncbi.nlm.nih.gov/12804462',
158 => '//pubmed.ncbi.nlm.nih.gov/12817994',
159 => '//pubmed.ncbi.nlm.nih.gov/15051280',
160 => '//pubmed.ncbi.nlm.nih.gov/15213718',
161 => '//pubmed.ncbi.nlm.nih.gov/15537576',
162 => '//pubmed.ncbi.nlm.nih.gov/15972793',
163 => '//pubmed.ncbi.nlm.nih.gov/16025225',
164 => '//pubmed.ncbi.nlm.nih.gov/16234516',
165 => '//pubmed.ncbi.nlm.nih.gov/16236738',
166 => '//pubmed.ncbi.nlm.nih.gov/16421368',
167 => '//pubmed.ncbi.nlm.nih.gov/16557280',
168 => '//pubmed.ncbi.nlm.nih.gov/16675129',
169 => '//pubmed.ncbi.nlm.nih.gov/16924781',
170 => '//pubmed.ncbi.nlm.nih.gov/17158753',
171 => '//pubmed.ncbi.nlm.nih.gov/17229950',
172 => '//pubmed.ncbi.nlm.nih.gov/17503444',
173 => '//pubmed.ncbi.nlm.nih.gov/1757079',
174 => '//pubmed.ncbi.nlm.nih.gov/17592774',
175 => '//pubmed.ncbi.nlm.nih.gov/17899373',
176 => '//pubmed.ncbi.nlm.nih.gov/18182601',
177 => '//pubmed.ncbi.nlm.nih.gov/18182974',
178 => '//pubmed.ncbi.nlm.nih.gov/18265482',
179 => '//pubmed.ncbi.nlm.nih.gov/18274088',
180 => '//pubmed.ncbi.nlm.nih.gov/18316551',
181 => '//pubmed.ncbi.nlm.nih.gov/18358709',
182 => '//pubmed.ncbi.nlm.nih.gov/18562954',
183 => '//pubmed.ncbi.nlm.nih.gov/18757259',
184 => '//pubmed.ncbi.nlm.nih.gov/19200416',
185 => '//pubmed.ncbi.nlm.nih.gov/19228622',
186 => '//pubmed.ncbi.nlm.nih.gov/19428384',
187 => '//pubmed.ncbi.nlm.nih.gov/19535820',
188 => '//pubmed.ncbi.nlm.nih.gov/19544685',
189 => '//pubmed.ncbi.nlm.nih.gov/19751860',
190 => '//pubmed.ncbi.nlm.nih.gov/19920272',
191 => '//pubmed.ncbi.nlm.nih.gov/20130983',
192 => '//pubmed.ncbi.nlm.nih.gov/20159825',
193 => '//pubmed.ncbi.nlm.nih.gov/20722173',
194 => '//pubmed.ncbi.nlm.nih.gov/20736332',
195 => '//pubmed.ncbi.nlm.nih.gov/20889333',
196 => '//pubmed.ncbi.nlm.nih.gov/20975025',
197 => '//pubmed.ncbi.nlm.nih.gov/21148114',
198 => '//pubmed.ncbi.nlm.nih.gov/21237645',
199 => '//pubmed.ncbi.nlm.nih.gov/21355031',
200 => '//pubmed.ncbi.nlm.nih.gov/21502311',
201 => '//pubmed.ncbi.nlm.nih.gov/21673820',
202 => '//pubmed.ncbi.nlm.nih.gov/21677925',
203 => '//pubmed.ncbi.nlm.nih.gov/21821551',
204 => '//pubmed.ncbi.nlm.nih.gov/22106103',
205 => '//pubmed.ncbi.nlm.nih.gov/22350789',
206 => '//pubmed.ncbi.nlm.nih.gov/22441895',
207 => '//pubmed.ncbi.nlm.nih.gov/22547473',
208 => '//pubmed.ncbi.nlm.nih.gov/22682881',
209 => '//pubmed.ncbi.nlm.nih.gov/22785217',
210 => '//pubmed.ncbi.nlm.nih.gov/22818936',
211 => '//pubmed.ncbi.nlm.nih.gov/22972572',
212 => '//pubmed.ncbi.nlm.nih.gov/23235677',
213 => '//pubmed.ncbi.nlm.nih.gov/23265123',
214 => '//pubmed.ncbi.nlm.nih.gov/23588749',
215 => '//pubmed.ncbi.nlm.nih.gov/23593085',
216 => '//pubmed.ncbi.nlm.nih.gov/23639488',
217 => '//pubmed.ncbi.nlm.nih.gov/23709491',
218 => '//pubmed.ncbi.nlm.nih.gov/23737396',
219 => '//pubmed.ncbi.nlm.nih.gov/23814120',
220 => '//pubmed.ncbi.nlm.nih.gov/23910051',
221 => '//pubmed.ncbi.nlm.nih.gov/24077938',
222 => '//pubmed.ncbi.nlm.nih.gov/24222786',
223 => '//pubmed.ncbi.nlm.nih.gov/24265860',
224 => '//pubmed.ncbi.nlm.nih.gov/24288308',
225 => '//pubmed.ncbi.nlm.nih.gov/24366376',
226 => '//pubmed.ncbi.nlm.nih.gov/24380095',
227 => '//pubmed.ncbi.nlm.nih.gov/24492834',
228 => '//pubmed.ncbi.nlm.nih.gov/24636331',
229 => '//pubmed.ncbi.nlm.nih.gov/24868023',
230 => '//pubmed.ncbi.nlm.nih.gov/24882353',
231 => '//pubmed.ncbi.nlm.nih.gov/25055283',
232 => '//pubmed.ncbi.nlm.nih.gov/25198160',
233 => '//pubmed.ncbi.nlm.nih.gov/25422909',
234 => '//pubmed.ncbi.nlm.nih.gov/25586679',
235 => '//pubmed.ncbi.nlm.nih.gov/25599350',
236 => '//pubmed.ncbi.nlm.nih.gov/26010605',
237 => '//pubmed.ncbi.nlm.nih.gov/26017383',
238 => '//pubmed.ncbi.nlm.nih.gov/26172878',
239 => '//pubmed.ncbi.nlm.nih.gov/26211827',
240 => '//pubmed.ncbi.nlm.nih.gov/26641959',
241 => '//pubmed.ncbi.nlm.nih.gov/26757170',
242 => '//pubmed.ncbi.nlm.nih.gov/26977780',
243 => '//pubmed.ncbi.nlm.nih.gov/27032109',
244 => '//pubmed.ncbi.nlm.nih.gov/27130687',
245 => '//pubmed.ncbi.nlm.nih.gov/27184120',
246 => '//pubmed.ncbi.nlm.nih.gov/27230946',
247 => '//pubmed.ncbi.nlm.nih.gov/27510511',
248 => '//pubmed.ncbi.nlm.nih.gov/27649142',
249 => '//pubmed.ncbi.nlm.nih.gov/27990198',
250 => '//pubmed.ncbi.nlm.nih.gov/28085094',
251 => '//pubmed.ncbi.nlm.nih.gov/28185165',
252 => '//pubmed.ncbi.nlm.nih.gov/28546524',
253 => '//pubmed.ncbi.nlm.nih.gov/28595943',
254 => '//pubmed.ncbi.nlm.nih.gov/28739757',
255 => '//pubmed.ncbi.nlm.nih.gov/29376559',
256 => '//pubmed.ncbi.nlm.nih.gov/29457921',
257 => '//pubmed.ncbi.nlm.nih.gov/29513878',
258 => '//pubmed.ncbi.nlm.nih.gov/29620792',
259 => '//pubmed.ncbi.nlm.nih.gov/30183988',
260 => '//pubmed.ncbi.nlm.nih.gov/30207593',
261 => '//pubmed.ncbi.nlm.nih.gov/30579323',
262 => '//pubmed.ncbi.nlm.nih.gov/30959525',
263 => '//pubmed.ncbi.nlm.nih.gov/31032883',
264 => '//pubmed.ncbi.nlm.nih.gov/31119054',
265 => '//pubmed.ncbi.nlm.nih.gov/31456178',
266 => '//pubmed.ncbi.nlm.nih.gov/31474332',
267 => '//pubmed.ncbi.nlm.nih.gov/31479144',
268 => '//pubmed.ncbi.nlm.nih.gov/31538691',
269 => '//pubmed.ncbi.nlm.nih.gov/31557310',
270 => '//pubmed.ncbi.nlm.nih.gov/31766052',
271 => '//pubmed.ncbi.nlm.nih.gov/31822191',
272 => '//pubmed.ncbi.nlm.nih.gov/31975569',
273 => '//pubmed.ncbi.nlm.nih.gov/32037402',
274 => '//pubmed.ncbi.nlm.nih.gov/32140806',
275 => '//pubmed.ncbi.nlm.nih.gov/32459439',
276 => '//pubmed.ncbi.nlm.nih.gov/32999790',
277 => '//pubmed.ncbi.nlm.nih.gov/33348436',
278 => '//pubmed.ncbi.nlm.nih.gov/33538338',
279 => '//pubmed.ncbi.nlm.nih.gov/33925599',
280 => '//pubmed.ncbi.nlm.nih.gov/34176200',
281 => '//pubmed.ncbi.nlm.nih.gov/34243852',
282 => '//pubmed.ncbi.nlm.nih.gov/34277491',
283 => '//pubmed.ncbi.nlm.nih.gov/34282256',
284 => '//pubmed.ncbi.nlm.nih.gov/34459500',
285 => '//pubmed.ncbi.nlm.nih.gov/35106856',
286 => '//pubmed.ncbi.nlm.nih.gov/35156343',
287 => '//pubmed.ncbi.nlm.nih.gov/35220995',
288 => '//pubmed.ncbi.nlm.nih.gov/36059215',
289 => '//pubmed.ncbi.nlm.nih.gov/4318756',
290 => '//pubmed.ncbi.nlm.nih.gov/6773421',
291 => '//pubmed.ncbi.nlm.nih.gov/9660919',
292 => '//pubmed.ncbi.nlm.nih.gov/9704964',
293 => '//pubmed.ncbi.nlm.nih.gov/9887158',
294 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC1903536',
295 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC165024',
296 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC1156964',
297 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC138665',
298 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2788989',
299 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2714486',
300 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2807731',
301 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2397451',
302 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2849768',
303 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2720818',
304 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2359677',
305 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC2409834',
306 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3045028',
307 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3387322',
308 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3561467',
309 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3521784',
310 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3922144',
311 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3645500',
312 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3104900',
313 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3225421',
314 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3142573',
315 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3625773',
316 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3671272',
317 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3832299',
318 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC3816846',
319 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4491690',
320 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4876310',
321 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4979358',
322 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4982776',
323 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4670483',
324 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4869065',
325 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4453639',
326 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC4324662',
327 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5037817',
328 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5295319',
329 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC521211',
330 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5912097',
331 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5551685',
332 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5156844',
333 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC5912140',
334 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6464778',
335 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6122903',
336 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6494635',
337 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6491330',
338 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6891893',
339 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6716096',
340 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6953223',
341 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6487387',
342 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6941147',
343 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC6528460',
344 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7073405',
345 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7276192',
346 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7387360',
347 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7109112',
348 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7253192',
349 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC7522052',
350 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8078577',
351 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8092675',
352 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8123798',
353 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8494665',
354 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8289843',
355 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8930468',
356 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8101654',
357 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8488779',
358 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC8406917',
359 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC9303577',
360 => '//www.ncbi.nlm.nih.gov/pmc/articles/PMC9483823',
361 => '//www.worldcat.org/issn/0307-1235',
362 => '//www.worldcat.org/oclc/535493589',
363 => 'http://ascopost.com/issues/october-25-2016/combination-of-ribociclib-and-letrozole-is-a-home-run-in-advanced-breast-cancer/',
364 => 'http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10548311',
365 => 'http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf',
366 => 'http://imaginis.com/breasthealth/statistics.asp',
367 => 'http://in.reuters.com/article/egypt-antiquities-cancer-idINKBN0MK1ZW20150324',
368 => 'http://news.bbc.co.uk/1/hi/health/5171838.stm',
369 => 'http://nordic.cochrane.org/screening-breast-cancer-mammography',
370 => 'http://seer.cancer.gov/statfacts/html/breast.html',
371 => 'http://uli.nli.org.il/F/?func=find-b&local_base=NLX10&find_code=UID&request=987007583504205171',
372 => 'http://uli.nli.org.il/F/?func=find-b&local_base=NLX10&find_code=UID&request=987007282518605171',
373 => 'http://www.ahrq.gov/clinic/3rduspstf/breastCancer/brcanrr.htm#ref31',
374 => 'http://www.answers.com/topic/phyllodes-tumor',
375 => 'http://www.asco.org/ASCOv2/Meetings/Abstracts?vmview=abst_detail_view&confID=40&abstractID=34291',
376 => 'http://www.barbaraehrenreich.com/cancerland.htm',
377 => 'http://www.breastcancer.org/treatment/radiation',
378 => 'http://www.breastcancercare.org.uk/breast-cancer-information/breast-awareness/am-i-risk/risk',
379 => 'http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic',
380 => 'http://www.cancer.gov/cancertopics/pdq/treatment/breast/HealthProfessional/page6',
381 => 'http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page1/AllPages',
382 => 'http://www.cancer.gov/cancertopics/pdq/treatment/malebreast/HealthProfessional',
383 => 'http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page1/AllPages',
384 => 'http://www.cancer.gov/cancertopics/types/breast',
385 => 'http://www.cancer.gov/cancertopics/understanding-breast-changes/page6#F8',
386 => 'http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-new-research',
387 => 'http://www.cancer.org/docroot/CRI/content/CRI_2_6x_the_history_of_cancer_72.asp?sitearea=CRI',
388 => 'http://www.cancer.org/downloads/STT/CAFF2005BrFacspdf2005.pdf',
389 => 'http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf',
390 => 'http://www.cancernetwork.com/cme/article/10165/1413886',
391 => 'http://www.cancernetwork.com/display/article/10165/1366719?pageNumber=1',
392 => 'http://www.center4research.org/hormone-therapy-menopause/',
393 => 'http://www.choosingwisely.org/doctor-patient-lists/american-college-of-surgeons/',
394 => 'http://www.crcfl.net/content/view/history-of-breast-cancer-advocacy.html',
395 => 'http://www.diseasesdatabase.com/ddb1598.htm',
396 => 'http://www.emedicine.com/med/TOPIC3287.HTM',
397 => 'http://www.emedicine.com/med/topic3287.htm#',
398 => 'http://www.emedicine.com/plastic/topic521.htm#',
399 => 'http://www.emedicine.com/radio/topic115.htm#',
400 => 'http://www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp',
401 => 'http://www.hindawi.com/journals/bmri/2012/172897/',
402 => 'http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/',
403 => 'http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/wcr_2008.pdf',
404 => 'http://www.icd9data.com/getICD9Code.ashx?icd9=174',
405 => 'http://www.icd9data.com/getICD9Code.ashx?icd9=175',
406 => 'http://www.icd9data.com/getICD9Code.ashx?icd9=V10.3',
407 => 'http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/overview_of_breast_disorders.html',
408 => 'http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/breast_cancer.html',
409 => 'http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html',
410 => 'http://www.nichd.nih.gov/health/topics/klinefelter_syndrome.cfm',
411 => 'http://www.ons.gov.uk/ons/dcp171778_333318.pdf',
412 => 'http://www.ons.gov.uk/ons/rel/vsob1/cancer-statistics-registrations--england--series-mb1-/no--42--2011/sty-breast-cancer-survival.html',
413 => 'http://www.prwatch.org/node/7436',
414 => 'http://www.sabcs.org/EnduringMaterials/Index.asp',
415 => 'http://www.sabcs.org/Newsletter/Docs/SABCS_2009_Issue5.pdf',
416 => 'http://www.stopcancerfund.org/wp/wp-content/uploads/2009/12/booklet04bc.pdf',
417 => 'http://www.uptodate.com/contents/treatment-of-metastatic-breast-cancer-beyond-the-basics',
418 => 'http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm',
419 => 'http://www.webmd.com/breast-cancer/guide/breast-cancer-young-women',
420 => 'http://www.webmd.com/breast-cancer/guide/mammograms',
421 => 'https://aleph.nkp.cz/F/?func=find-c&local_base=aut&ccl_term=ica=ph135010&CON_LNG=ENG',
422 => 'https://api.semanticscholar.org/CorpusID:26602401',
423 => 'https://api.semanticscholar.org/CorpusID:1802863',
424 => 'https://api.semanticscholar.org/CorpusID:25250519',
425 => 'https://api.semanticscholar.org/CorpusID:16838840',
426 => 'https://api.semanticscholar.org/CorpusID:207498132',
427 => 'https://api.semanticscholar.org/CorpusID:448229',
428 => 'https://api.semanticscholar.org/CorpusID:7256176',
429 => 'https://api.semanticscholar.org/CorpusID:24278814',
430 => 'https://api.semanticscholar.org/CorpusID:388045',
431 => 'https://api.semanticscholar.org/CorpusID:206616972',
432 => 'https://api.semanticscholar.org/CorpusID:19644829',
433 => 'https://api.semanticscholar.org/CorpusID:22685290',
434 => 'https://api.semanticscholar.org/CorpusID:9085879',
435 => 'https://api.semanticscholar.org/CorpusID:44562857',
436 => 'https://api.semanticscholar.org/CorpusID:3425945',
437 => 'https://api.semanticscholar.org/CorpusID:23237732',
438 => 'https://api.semanticscholar.org/CorpusID:34880415',
439 => 'https://api.semanticscholar.org/CorpusID:3406636',
440 => 'https://api.semanticscholar.org/CorpusID:17622089',
441 => 'https://api.semanticscholar.org/CorpusID:20751083',
442 => 'https://api.semanticscholar.org/CorpusID:52188256',
443 => 'https://api.semanticscholar.org/CorpusID:231804598',
444 => 'https://api.semanticscholar.org/CorpusID:209314404',
445 => 'https://api.semanticscholar.org/CorpusID:11394158',
446 => 'https://api.semanticscholar.org/CorpusID:71908359',
447 => 'https://api.semanticscholar.org/CorpusID:246813006',
448 => 'https://api.semanticscholar.org/CorpusID:235786044',
449 => 'https://api.semanticscholar.org/CorpusID:13831558',
450 => 'https://api.semanticscholar.org/CorpusID:26112023',
451 => 'https://api.semanticscholar.org/CorpusID:9534884',
452 => 'https://api.semanticscholar.org/CorpusID:24976113',
453 => 'https://api.semanticscholar.org/CorpusID:252562000',
454 => 'https://api.semanticscholar.org/CorpusID:247157545',
455 => 'https://api.semanticscholar.org/CorpusID:601112',
456 => 'https://archive.org/details/historyofbreast00yalo/page/234',
457 => 'https://archive.org/details/pinkribbonbluesh0000suli',
458 => 'https://archive.org/details/unnaturalhistory00aron/page/22',
459 => 'https://archive.today/20160407214503/https://www.ranzcog.edu.au/doc/management-of-the-menopause-after-breast-cancer.html',
460 => 'https://articles.latimes.com/2009/aug/17/health/he-breast-overdiagnosis17',
461 => 'https://books.google.com/books?id=E-OZbEmPSTkC&pg=PA301',
462 => 'https://books.google.com/books?id=PcARTQwHLpIC&pg=PA99',
463 => 'https://books.google.com/books?id=as46WowY_usC&pg=PT123',
464 => 'https://books.google.com/books?id=p4o9AQAAIAAJ',
465 => 'https://curlie.org/Health/Conditions_and_Diseases/Cancer/Breast/',
466 => 'https://d-nb.info/gnd/4008528-4',
467 => 'https://emedicine.medscape.com/med/2808-overview',
468 => 'https://evidence.nihr.ac.uk/alert/exercise-programme-improves-arm-function-pain-after-breast-cancer-surgery/',
469 => 'https://ftl.toolforge.org/cgi-bin/ftl?st=wp&su=Breast+cancer',
470 => 'https://ftl.toolforge.org/cgi-bin/ftl?st=wp&su=Breast+cancer&library=0CHOOSE0',
471 => 'https://icd.who.int/browse10/2019/en#/C50',
472 => 'https://id.loc.gov/authorities/subjects/sh85016679',
473 => 'https://id.loc.gov/authorities/subjects/sh2010009734',
474 => 'https://id.ndl.go.jp/auth/ndlna/00568758',
475 => 'https://meshb.nlm.nih.gov/record/ui?ui=D001943',
476 => 'https://omim.org/entry/114480',
477 => 'https://patient.info/doctor/breast-cancer-pro',
478 => 'https://progenetix.org/subsets/?term_id=icdom:8502_3',
479 => 'https://pure.eur.nl/ws/files/46620151/11463009.pdf',
480 => 'https://seer.cancer.gov/statfacts/html/breast.html',
481 => 'https://ui.adsabs.harvard.edu/abs/2002Sci...296.1046W',
482 => 'https://ui.adsabs.harvard.edu/abs/2016NatSR...625998W',
483 => 'https://ui.adsabs.harvard.edu/abs/2021NatSR..1114738G',
484 => 'https://web.archive.org/web/20061009011530/http://www.cancer.org/docroot/CRI/content/CRI_2_6x_the_history_of_cancer_72.asp?sitearea=CRI',
485 => 'https://web.archive.org/web/20061024120910/http://www.imaginis.com/breasthealth/statistics.asp',
486 => 'https://web.archive.org/web/20070313141518/http://news.bbc.co.uk/1/hi/health/5171838.stm',
487 => 'https://web.archive.org/web/20070410025934/http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf',
488 => 'https://web.archive.org/web/20070613192148/http://www.cancer.org/downloads/STT/CAFF2005BrFacspdf2005.pdf',
489 => 'https://web.archive.org/web/20080212070431/http://www.emedicine.com/med/TOPIC3287.HTM',
490 => 'https://web.archive.org/web/20080425022457/http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/breast-cancer-cases-rise-80-since-seventies-417990.html',
491 => 'https://web.archive.org/web/20080827093333/http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic',
492 => 'https://web.archive.org/web/20081020000016/http://www.scribd.com/doc/2350813/World-Cancer-Report-2003-Stuart-e-Kleihues-WHO-e-IARC',
493 => 'https://web.archive.org/web/20090616191104/http://www.cancernetwork.com/cme/article/10165/1413886',
494 => 'https://web.archive.org/web/20090705230857/http://www.cancernetwork.com/display/article/10165/1366719?pageNumber=1',
495 => 'https://web.archive.org/web/20090910015335/http://www.webmd.com/breast-cancer/guide/breast-cancer-young-women',
496 => 'https://web.archive.org/web/20091026055528/http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2064',
497 => 'https://web.archive.org/web/20091111101009/http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html',
498 => 'https://web.archive.org/web/20100406014305/http://www.herceptin.com/hcp/adjuvant-treatment/studies-efficacy/joint-analysis.jsp',
499 => 'https://web.archive.org/web/20100516171511/http://www.sabcs.org/EnduringMaterials/Index.asp',
500 => 'https://web.archive.org/web/20100527185336/http://www.cancer.gov/cancertopics/understanding-breast-changes/page6',
501 => 'https://web.archive.org/web/20100908032727/http://www.answers.com/topic/phyllodes-tumor',
502 => 'https://web.archive.org/web/20101012151918/http://ottawa.ctv.ca/servlet/an/local/CTVNews/20101008/pinkwashing-pink-ribbon-101009/20101009/?hub=OttawaHome',
503 => 'https://web.archive.org/web/20101120135605/http://barbaraehrenreich.com/cancerland.htm',
504 => 'https://web.archive.org/web/20101204073704/http://articles.latimes.com/2009/aug/17/health/he-breast-overdiagnosis17',
505 => 'https://web.archive.org/web/20110605122507/http://www.prwatch.org/node/7436',
506 => 'https://web.archive.org/web/20110720232417/http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/wcr_2008.pdf',
507 => 'https://web.archive.org/web/20111002141649/http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/breast_cancer.html',
508 => 'https://web.archive.org/web/20111003004918/http://www.merckmanuals.com/home/womens_health_issues/breast_disorders/overview_of_breast_disorders.html',
509 => 'https://web.archive.org/web/20111110075702/http://www.merckmanuals.com/professional/gynecology_and_obstetrics/breast_disorders/breast_cancer.html',
510 => 'https://web.archive.org/web/20111231111259/http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/',
511 => 'https://web.archive.org/web/20120112122626/http://www.asco.org/ASCOv2/Meetings/Abstracts?vmview=abst_detail_view&confID=40&abstractID=34291',
512 => 'https://web.archive.org/web/20120731073425/http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf',
513 => 'https://web.archive.org/web/20120924091105/http://www.nytimes.com/2012/09/24/health/study-finds-variations-of-breast-cancer.html',
514 => 'https://web.archive.org/web/20121127030744/http://www.nichd.nih.gov/health/topics/klinefelter_syndrome.cfm',
515 => 'https://web.archive.org/web/20121228104148/http://www.webmd.com/breast-cancer/guide/mammograms',
516 => 'https://web.archive.org/web/20130102015424/http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm',
517 => 'https://web.archive.org/web/20130616040709/http://www.ahrq.gov/clinic/3rduspstf/breastcancer/brcanrr.htm',
518 => 'https://web.archive.org/web/20130623074930/http://www.crcfl.net/content/view/history-of-breast-cancer-advocacy.html',
519 => 'https://web.archive.org/web/20130813021816/http://www.sabcs.org/Newsletter/Docs/SABCS_2009_Issue5.pdf',
520 => 'https://web.archive.org/web/20130813054115/http://www.stopcancerfund.org/wp/wp-content/uploads/2009/12/booklet04bc.pdf',
521 => 'https://web.archive.org/web/20131025074635/http://www.breastcancercare.org.uk/breast-cancer-information/breast-awareness/am-i-risk/risk',
522 => 'https://web.archive.org/web/20131027085747/http://www.choosingwisely.org/doctor-patient-lists/american-college-of-surgeons/',
523 => 'https://web.archive.org/web/20131105085823/http://www.ons.gov.uk/ons/rel/vsob1/cancer-statistics-registrations--england--series-mb1-/no--42--2011/sty-breast-cancer-survival.html',
524 => 'https://web.archive.org/web/20140625232947/http://www.cancer.gov/cancertopics/types/breast',
525 => 'https://web.archive.org/web/20140703030149/http://seer.cancer.gov/statfacts/html/breast.html',
526 => 'https://web.archive.org/web/20140704182515/http://www.cancer.gov/cancertopics/pdq/treatment/malebreast/HealthProfessional',
527 => 'https://web.archive.org/web/20140705110404/http://www.cancer.gov/cancertopics/pdq/treatment/breast/Patient/page1/AllPages',
528 => 'https://web.archive.org/web/20140705110521/http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page1/AllPages',
529 => 'https://web.archive.org/web/20141129124915/http://www.ons.gov.uk/ons/dcp171778_333318.pdf',
530 => 'https://web.archive.org/web/20150327023314/http://in.reuters.com/article/2015/03/24/egypt-antiquities-cancer-idINKBN0MK1ZW20150324',
531 => 'https://web.archive.org/web/20150425224841/http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional/page6',
532 => 'https://web.archive.org/web/20150906121739/http://www.who.int/cancer/detection/breastcancer/en/index1.html',
533 => 'https://web.archive.org/web/20151025013217/https://books.google.com/books?id=as46WowY_usC&pg=PT123',
534 => 'https://web.archive.org/web/20151029161343/http://nordic.cochrane.org/screening-breast-cancer-mammography',
535 => 'https://web.archive.org/web/20151112202807/http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-new-research',
536 => 'https://web.archive.org/web/20151117181548/http://www.hindawi.com/journals/bmri/2012/172897/',
537 => 'https://web.archive.org/web/20151117193610/http://www.breastcancer.org/treatment/radiation',
538 => 'https://web.archive.org/web/20151118012201/http://www.cdc.gov/cancer/breast/basic_info/screening.htm',
539 => 'https://web.archive.org/web/20160201114307/http://www.npr.org/sections/thesalt/2016/02/01/464854395/a-diet-high-in-fiber-may-help-protect-against-breast-cancer',
540 => 'https://web.archive.org/web/20170514183905/http://www.popline.org/node/328955',
541 => 'https://web.archive.org/web/20170904202736/http://www.uptodate.com/contents/treatment-of-metastatic-breast-cancer-beyond-the-basics?source=search_result&search=letrozole&selectedTitle=4~6',
542 => 'https://www.belfasttelegraph.co.uk/news/uk/new-study-finds-strong-evidence-that-exercise-cuts-breast-cancer-risk-41967524.html',
543 => 'https://www.breastcancer.org/research-news/new-guidelines-to-treat-advanced-her2-pos',
544 => 'https://www.breastcancer.org/research-news/quality-of-life-after-preventive-mastectomy',
545 => 'https://www.cancer.gov/about-cancer/causes-prevention/risk/hormones/reproductive-history-fact-sheet#are-any-pregnancy-related-factors-associated-with-a-lower-risk-of-breast-cancer',
546 => 'https://www.cancer.gov/breast',
547 => 'https://www.cancer.org/cancer/breast-cancer/risk-and-prevention/lifestyle-related-breast-cancer-risk-factors.html',
548 => 'https://www.cancer.org/cancer/breast-cancer/treatment/surgery-for-breast-cancer/breast-conserving-surgery-lumpectomy.html',
549 => 'https://www.cdc.gov/breastfeeding/faq/index.htm#benefits',
550 => 'https://www.cdc.gov/cancer/breast/basic_info/risk_factors.htm',
551 => 'https://www.cdc.gov/cancer/breast/basic_info/screening.htm',
552 => 'https://www.ctvnews.ca/breast-cancer-month-overshadowed-by-pinkwashing-1.561275',
553 => 'https://www.independent.co.uk/life-style/health-and-wellbeing/health-news/breast-cancer-cases-rise-80-since-seventies-417990.html',
554 => 'https://www.nationalbreastcancer.org/breast-cancer-stage-4',
555 => 'https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2064',
556 => 'https://www.nlm.nih.gov/medlineplus/ency/article/000913.htm',
557 => 'https://www.npr.org/sections/thesalt/2016/02/01/464854395/a-diet-high-in-fiber-may-help-protect-against-breast-cancer',
558 => 'https://www.nytimes.com/2012/09/24/health/study-finds-variations-of-breast-cancer.html',
559 => 'https://www.popline.org/node/328955',
560 => 'https://www.scribd.com/doc/2350813/World-Cancer-Report-2003-Stuart-e-Kleihues-WHO-e-IARC',
561 => 'https://www.who.int/cancer/detection/breastcancer/en/index1.html',
562 => 'https://www.who.int/health-topics/breastfeeding#tab=tab_1',
563 => 'https://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html',
564 => 'https://www.who.int/news-room/fact-sheets/detail/cancer',
565 => 'https://www.wikidata.org/wiki/Q128581#identifiers'
] |
