TY - JOUR
T1 - Aspirin use and colorectal cancer survival according to tumor CD274 (programmed cell death 1 ligand 1) expression status
AU - Hamada, Tsuyoshi
AU - Cao, Yin
AU - Qian, Zhi Rong
AU - Masugi, Yohei
AU - Nowak, Jonathan A.
AU - Yang, Juhong
AU - Song, Mingyang
AU - Mima, Kosuke
AU - Kosumi, Keisuke
AU - Liu, Li
AU - Shi, Yan
AU - Silva, Annacarolina da
AU - Gu, Mancang
AU - Li, Wanwan
AU - Keum, Na Na
AU - Zhang, Xuehong
AU - Wu, Kana
AU - Meyerhardt, Jeffrey A.
AU - Giovannucci, Edward L.
AU - Giannakis, Marios
AU - Rodig, Scott J.
AU - Freeman, Gordon J.
AU - Nevo, Daniel
AU - Wang, Molin
AU - Chan, Andrew T.
AU - Fuchs, Charles S.
AU - Nishihara, Reiko
AU - Ogino, Shuji
N1 - Funding Information:
We thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-Up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AR, AZ, CA, CO, CT, DE, FL, GA, IA, ID, IL, IN, KY, LA, MA, ME, MI, NC, ND, NE, NH, NJ, NY, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data. Supported by National Institutes of Health Grants No. P01 CA87969 (M.J. Stampfer); UM1 CA186107 (M.J. Stampfer); P01 CA55075 (W.C. Willett); UM1 CA167552 (W.C. Willett); P50 CA127003 (C.S.F.); R01 CA137178 and K24 DK098311 (A.T.C.); K07 CA190673 (R.N.); and K07 CA188126 (X.Z.); R01 CA151993, R35 CA197735, and Nodal Award fromthe Dana-Farber Harvard Cancer Center (S.O.); and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. T.H. was supported by a fellowship grant from the Uehara Memorial Foundation and by a grant from the Mochida Memorial Foundation for Medical and Pharmaceutical Research. K.M. and K.K. were supported by a grant from Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from Japan Society for the Promotion of Science. L.L. was supported by a scholarship grant from Chinese Scholarship Council and a fellowship grant fromHuazhong University of Science and Technology. S.J.R. was supported in part by research funding from Bristol-Myers Squibb, MedImmune, and Merck.
Publisher Copyright:
© 2017 by American Society of Clinical Oncology.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Purpose Blockade of the programmed cell death 1 (PDCD1, PD-1) immune checkpoint pathway can improve clinical outcomes in various malignancies. Evidence suggests that aspirin (a widely used nonsteroidal anti-inflammatory drug) not only prolongs colorectal cancer survival, but can also activate T cell–mediated antitumor immunity and synergize with immunotherapy through inhibition of prostaglandin E2 production. We hypothesized that the survival benefit associated with aspirin might be stronger in colorectal carcinoma with a lower CD274 (PDCD1 ligand 1, PD-L1) expression level that resulted in lower signaling of the immune checkpoint pathway. Patients and Methods Using data from 617 patients with rectal and colon cancer in the Nurses’ Health Study and the Health Professionals Follow-Up Study, we examined the association of postdiagnosis aspirin use with patient survival in strata of tumor CD274 expression status measured by immunohistochemistry. We used multivariable Cox proportional hazards regression models to control for potential con-founders, including disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, cyclooxygenase-2 (PTGS2), and CDX2 expression, and KRAS, BRAF, and PIK3CA mutations. Results The association of postdiagnosis aspirin use with colorectal cancer–specific survival differed by CD274 expression status (Pinteraction , .001); compared with aspirin nonusers; multivariable-adjusted hazard ratios for regular aspirin users were 0.16 (95% CI, 0.06 to 0.41) in patients with low CD274 and 1.01 (95% CI, 0.61 to 1.67) in patients with high CD274. This differential association seemed consistent in patients with microsatellite-stable or PIK3CA wild-type disease and in strata of PTGS2 expression, CDX2 expression, tumor-infiltrating lymphocytes, or prediagnosis aspirin use status. Conclusion The association of aspirin use with colorectal cancer survival is stronger in patients with CD274-low tumors than CD274-high tumors. Our findings suggest a differential antitumor effect of aspirin according to immune checkpoint status.
AB - Purpose Blockade of the programmed cell death 1 (PDCD1, PD-1) immune checkpoint pathway can improve clinical outcomes in various malignancies. Evidence suggests that aspirin (a widely used nonsteroidal anti-inflammatory drug) not only prolongs colorectal cancer survival, but can also activate T cell–mediated antitumor immunity and synergize with immunotherapy through inhibition of prostaglandin E2 production. We hypothesized that the survival benefit associated with aspirin might be stronger in colorectal carcinoma with a lower CD274 (PDCD1 ligand 1, PD-L1) expression level that resulted in lower signaling of the immune checkpoint pathway. Patients and Methods Using data from 617 patients with rectal and colon cancer in the Nurses’ Health Study and the Health Professionals Follow-Up Study, we examined the association of postdiagnosis aspirin use with patient survival in strata of tumor CD274 expression status measured by immunohistochemistry. We used multivariable Cox proportional hazards regression models to control for potential con-founders, including disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, cyclooxygenase-2 (PTGS2), and CDX2 expression, and KRAS, BRAF, and PIK3CA mutations. Results The association of postdiagnosis aspirin use with colorectal cancer–specific survival differed by CD274 expression status (Pinteraction , .001); compared with aspirin nonusers; multivariable-adjusted hazard ratios for regular aspirin users were 0.16 (95% CI, 0.06 to 0.41) in patients with low CD274 and 1.01 (95% CI, 0.61 to 1.67) in patients with high CD274. This differential association seemed consistent in patients with microsatellite-stable or PIK3CA wild-type disease and in strata of PTGS2 expression, CDX2 expression, tumor-infiltrating lymphocytes, or prediagnosis aspirin use status. Conclusion The association of aspirin use with colorectal cancer survival is stronger in patients with CD274-low tumors than CD274-high tumors. Our findings suggest a differential antitumor effect of aspirin according to immune checkpoint status.
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U2 - 10.1200/JCO.2016.70.7547
DO - 10.1200/JCO.2016.70.7547
M3 - Article
C2 - 28406723
AN - SCOPUS:85021935139
SN - 0732-183X
VL - 35
SP - 1836
EP - 1844
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 16
ER -
