Impact of genetic variability and treatment-related factors on outcome in early breast cancer patients receiving (neo-) adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide, and docetaxel

Breast Cancer Res Treat. 2014 Oct;147(3):557-70. doi: 10.1007/s10549-014-3105-5. Epub 2014 Aug 29.

Abstract

To assess the impact of patient-related factors, including genetic variability in genes involved in the metabolism of chemotherapeutic agents, on breast cancer-specific survival (BCSS) and recurrence-free interval (RFI). We selected early breast cancer patients treated between 2000 and 2010 with 4-6 cycles of (neo-)adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) or 3 cycles FEC followed by 3 cycles docetaxel. Tumor stage/subtype; febrile neutropenia and patient-related factors such as selected single nucleotide polymorphisms and baseline laboratory parameters were evaluated. Multivariable Cox regression was performed. Of 991 patients with a mean follow-up of 5.2 years, 152 (15.3 %) patients relapsed and 63 (6.4 %) patients died. Advanced stage and more aggressive subtype were associated with poorer BCSS and RFI in multivariable analysis (p < 0.0001). Associations with worse BCSS in multivariable analysis were: homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (hazard ratio [HR] 30.4; 95 % confidence interval [CI] 6.1-151.5; p < 0.001) and higher white blood cell count (WBC) (HR 1.2; 95 % CI 1.0-1.3; p = 0.014). The GT genotype of the ABCB1 variant rs2032582 was associated with better BCSS (HR 0.5; 95 % CI 0.3-0.9, p = 0.021). Following associations with worse RFI were observed: higher WBC (HR 1.1; 95 % CI 1.0-1.2; p = 0.026), homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (HR 10.9; 95 % CI 2.5-47.9; p = 0.002), CT genotype of the CYBA variant rs4673 (HR 1.8; 95 % CI 1.2-2.7; p = 0.006), and G-allele homozygosity for the UGT2B7 variant rs3924194 (HR 3.4; 95 % CI 1.2-9.7, p = 0.023). Patient-related factors including genetic variability and baseline white blood cell count, impacted on outcome in early breast cancer.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cyclophosphamide / administration & dosage
  • Cytochrome P-450 CYP2C9 / genetics
  • Disease-Free Survival
  • Docetaxel
  • Epirubicin / administration & dosage
  • Female
  • Fluorouracil / administration & dosage
  • Glucuronosyltransferase / genetics
  • Humans
  • Leukocyte Count
  • Middle Aged
  • Neoadjuvant Therapy
  • Polymorphism, Single Nucleotide
  • Taxoids / administration & dosage
  • Treatment Outcome

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Taxoids
  • Docetaxel
  • Epirubicin
  • Cyclophosphamide
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • UGT2B7 protein, human
  • Glucuronosyltransferase
  • Fluorouracil