@article{c617b7fed72742f59bb9367c80e00e02,
title = "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",
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{\textquoteright} 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",
author = "Keisuke Kosumi and Tsuyoshi Hamada and Sui Zhang and Li Liu and {da Silva}, Annacarolina and Hideo Koh and Twombly, {Tyler S.} and Kosuke Mima and Teppei Morikawa and Mingyang Song and Nowak, {Jonathan A.} and Reiko Nishihara and Saltz, {Leonard B.} and Donna Niedzwiecki and Ou, {Fang Shu} and Tyler Zemla and Mayer, {Robert J.} and Hideo Baba and Kimmie Ng and Marios Giannakis and Xuehong Zhang and Kana Wu and Giovannucci, {Edward L.} and Chan, {Andrew T.} and Fuchs, {Charles S.} and Meyerhardt, {Jeffrey A.} and Shuji Ogino",
note = "Funding Information: Research reported in this publication was supported by U.S. National Cancer Institute of the National Institutes of Health (NIH) under award numbers U10CA180821, U10CA180882 and U24CA196171 (to the Alliance for Clinical Trials in Oncology), U10CA180791, U10CA180867 and P01 CA87969 (to M.J. Stampfer), UM1 CA186107 (to M.J. Stampfer), P01 CA55075 (to W.C. Willett), UM1 CA167552 (to W.C. Willett), U01 CA167552 (to L.A. Mucci and W.C. Willett), P50 CA127003 (to C.S.F.), R01 CA118553 (to C.S.F.), R01 CA169141 (to C.S.F.), R01 CA137178 (to A.T.C.), K24 DK098311 (to A.T.C.), R01 CA205406 (to K.N.), R35 CA197735 (to S.O.), R01 CA151993 (to S.O.), K07 CA190673 (to R.N.) and K07 CA188126 (to X.Z.). This work was also supported by the Nodal Award (2016-02) from the Dana-Farber Harvard Cancer Center (to S.O.); by grants from the Project P Fund, the Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance and by the Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to C.S.F. and M.G.), administered by the American Association for Cancer Research, a scientific partner of SU2C. CALGB/Alliance 89803 was supported in part by Pfizer. K.K. was supported by grants from Overseas Research Fellowship from Japan Society for the Promotion of Science (JP2017-775). T.H. was supported by a fellowship grant from the Mitsukoshi Health and Welfare Foundation. L.L. was supported by a scholarship grant from Chinese Scholarship Council and a fellowship grant from Huazhong University of Science and Technology. A.T.C. is a Stuart and Suzanne Steele MGH research scholar. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review and approval of the manuscript and decision to submit the manuscript for publication. Funding Information: Research reported in this publication was supported by U.S. National Cancer Institute of the National Institutes of Health (NIH) under award numbers U10CA180821 , U10CA180882 and U24CA196171 (to the Alliance for Clinical Trials in Oncology), U10CA180791 , U10CA180867 and P01 CA87969 (to M.J. Stampfer), UM1 CA186107 (to M.J. Stampfer), P01 CA55075 (to W.C. Willett), UM1 CA167552 (to W.C. Willett), U01 CA167552 (to L.A. Mucci and W.C. Willett), P50 CA127003 (to C.S.F.), R01 CA118553 (to C.S.F.), R01 CA169141 (to C.S.F.), R01 CA137178 (to A.T.C.), K24 DK098311 (to A.T.C.), R01 CA205406 (to K.N.), R35 CA197735 (to S.O.), R01 CA151993 (to S.O.), K07 CA190673 (to R.N.) and K07 CA188126 (to X.Z.). This work was also supported by the Nodal Award (2016-02) from the Dana-Farber Harvard Cancer Center (to S.O.); by grants from the Project P Fund, the Friends of the Dana-Farber Cancer Institute , Bennett Family Fund, the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance and by the Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant ( SU2C-AACR-DT22-17 to C.S.F. and M.G.), administered by the American Association for Cancer Research , a scientific partner of SU2C . CALGB /Alliance 89803 was supported in part by Pfizer . K.K. was supported by grants from Overseas Research Fellowship from Japan Society for the Promotion of Science ( JP2017-775 ). T.H. was supported by a fellowship grant from the Mitsukoshi Health and Welfare Foundation . L.L. was supported by a scholarship grant from Chinese Scholarship Council and a fellowship grant from Huazhong University of Science and Technology . A.T.C. is a Stuart and Suzanne Steele MGH research scholar. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review and approval of the manuscript and decision to submit the manuscript for publication. ",
year = "2019",
month = apr,
doi = "10.1016/j.ejca.2019.01.022",
language = "English (US)",
volume = "111",
pages = "82--93",
journal = "European Journal of Cancer",
issn = "0959-8049",
publisher = "Elsevier Limited",
}