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 GiannakisXuehong Zhang, Kana Wu, Edward L. Giovannucci, Andrew T. Chan, Charles S. Fuchs, Jeffrey A. Meyerhardt, Shuji Ogino

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background: Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2, COX-2)-prostaglandin E 2 (PGE 2 ) pathway promotes tumour progression. Considering evidence suggesting increased PGE 2 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.

Original languageEnglish (US)
Pages (from-to)82-93
Number of pages12
JournalEuropean Journal of Cancer
Volume111
DOIs
StatePublished - Apr 2019

Keywords

  • Adenocarcinoma
  • Clinical outcome
  • Colorectal neoplasm
  • Immunity
  • Inflammation
  • Molecular pathological epidemiology
  • PTGS
  • Precision medicine
  • Prostaglandin
  • RAF

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kosumi, K., Hamada, T., Zhang, S., Liu, L., da Silva, A., Koh, H., Twombly, T. S., Mima, K., Morikawa, T., Song, M., Nowak, J. A., Nishihara, R., Saltz, L. B., Niedzwiecki, D., Ou, F. S., Zemla, T., Mayer, R. J., Baba, H., Ng, K., ... Ogino, S. (2019). 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. European Journal of Cancer, 111, 82-93. https://doi.org/10.1016/j.ejca.2019.01.022