Prognostic association of PTGS2 (COX-2) over-expression according to BRAF mutation status in colorectal cancer: Results from two prospective cohorts and CALGB 89803 (Alliance) trial

Keisuke Kosumi; Tsuyoshi Hamada; Sui Zhang; Li Liu; Annacarolina da Silva; Hideo Koh; Tyler S Twombly; Kosuke Mima; Teppei Morikawa; Mingyang Song; Jonathan A Nowak; Reiko Nishihara; Leonard B Saltz; Donna Niedzwiecki; Fang-Shu Ou; Tyler Zemla; Robert J Mayer; Hideo Baba; Kimmie Ng; Marios Giannakis; Xuehong Zhang; Kana Wu; Edward L Giovannucci; Andrew T Chan; Charles S Fuchs; Jeffrey A Meyerhardt; Shuji Ogino

doi:10.1016/j.ejca.2019.01.022

Prognostic association of PTGS2 (COX-2) over-expression according to BRAF mutation status in colorectal cancer: Results from two prospective cohorts and CALGB 89803 (Alliance) trial

Eur J Cancer. 2019 Apr:111:82-93. doi: 10.1016/j.ejca.2019.01.022. Epub 2019 Mar 1.

Authors

Keisuke Kosumi¹, Tsuyoshi Hamada², Sui Zhang³, Li Liu⁴, Annacarolina da Silva², Hideo Koh⁵, Tyler S Twombly², Kosuke Mima¹, Teppei Morikawa⁶, Mingyang Song⁷, Jonathan A Nowak⁸, Reiko Nishihara⁹, Leonard B Saltz¹⁰, Donna Niedzwiecki¹¹, Fang-Shu Ou¹², Tyler Zemla¹², Robert J Mayer³, Hideo Baba¹³, Kimmie Ng³, Marios Giannakis¹⁴, Xuehong Zhang¹⁵, Kana Wu¹⁶, Edward L Giovannucci¹⁶, Andrew T Chan¹⁷, Charles S Fuchs¹⁸, Jeffrey A Meyerhardt³, Shuji Ogino¹⁹

Affiliations

¹ Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.
² Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁴ Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, PR China.
⁵ Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
⁶ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁷ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
⁸ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹¹ Alliance Statistics and Data Center and Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
¹² Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
¹³ Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁷ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁸ Yale Cancer Center, New Haven, CT, USA; Department of Medicine, Yale School of Medicine, New Haven, CT, USA; Smilow Cancer Hospital, New Haven, CT, USA.
¹⁹ Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: [email protected].

Abstract

Background: Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2, COX-2)-prostaglandin E₂ (PGE₂) pathway promotes tumour progression. Considering evidence suggesting increased PGE₂ synthesis by BRAF mutation in tumour cells, we hypothesised that the association of tumour PTGS2 (COX-2) expression with colorectal cancer mortality might be stronger in BRAF-mutated tumours than in BRAF-wild-type tumours.

Methods: Using 1708 patients, including 1200 stage I-IV colorectal carcinoma cases in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) and 508 stage III colon cancer cases in a National Cancer Institute-sponsored randomised controlled trial of adjuvant therapy (CALGB/Alliance 89803), we evaluated tumour PTGS2 (COX-2) expression status using immunohistochemistry. We examined the prognostic association of PTGS2 (COX-2) expression in strata of BRAF mutation status by multivariable Cox proportional hazards regression models to adjust for potential confounders, including disease stage, tumour differentiation, microsatellite instability status and KRAS and PIK3CA mutations.

Results: In NHS and HPFS, the association of PTGS2 (COX-2) expression with colorectal cancer-specific survival differed by BRAF mutation status (P_interaction = 0.0005); compared with PTGS2 (COX-2)-negative/low carcinomas, the multivariable-adjusted hazard ratios for PTGS2 (COX-2)-high carcinomas were 2.44 (95% confidence interval, 1.39-4.28) in BRAF-mutated cases and 0.82 (95% confidence interval, 0.65-1.04) in BRAF-wild-type cases. Differential prognostic associations of PTGS2 (COX-2) expression in strata of BRAF mutation status were similarly observed in CALGB/Alliance 89803 trial (P_interaction = 0.03).

Conclusions: The association of tumour PTGS2 (COX-2) expression with colorectal cancer mortality is stronger in BRAF-mutated tumours than in BRAF-wild-type tumours, supporting interactive roles of PTGS2 (COX-2) expression and BRAF mutation statuses in prognostication of patients with colorectal cancer; ClinicalTrials.gov Identifier, NCT00003835.

Keywords: Adenocarcinoma; Clinical outcome; Colorectal neoplasm; Immunity; Inflammation; Molecular pathological epidemiology; PTGS; Precision medicine; Prostaglandin; RAF.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / metabolism*
Adenocarcinoma / mortality
Adult
Aged
Biomarkers, Tumor / analysis*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / mortality
Cyclooxygenase 2 / biosynthesis*
Databases, Factual
Female
Humans
Male
Middle Aged
Mutation
Prognosis
Proto-Oncogene Proteins B-raf / genetics
Retrospective Studies
Up-Regulation

Substances

Biomarkers, Tumor
Cyclooxygenase 2
PTGS2 protein, human
BRAF protein, human
Proto-Oncogene Proteins B-raf

Associated data

ClinicalTrials.gov/NCT00003835

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding