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J Clin Oncol. 2017 Jun 1;35(16):1836-1844. doi: 10.1200/JCO.2016.70.7547. Epub 2017 Apr 13.

Aspirin Use and Colorectal Cancer Survival According to Tumor CD274 (Programmed Cell Death 1 Ligand 1) Expression Status.

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Tsuyoshi Hamada, Zhi Rong Qian, Yohei Masugi, Juhong Yang, Kosuke Mima, Keisuke Kosumi, Li Liu, Yan Shi, Annacarolina da Silva, Mancang Gu, Wanwan Li, Jeffrey A. Meyerhardt, Marios Giannakis, Scott J. Rodig, Gordon J. Freeman, Charles S. Fuchs, Reiko Nishihara, and Shuji Ogino, Dana-Farber Cancer Institute and Harvard Medical School; Yin Cao, Mingyang Song, and Andrew T. Chan, Massachusetts General Hospital and Harvard Medical School; Yin Cao, Mingyang Song, Li Liu, NaNa Keum, Kana Wu, Edward L. Giovannucci, Daniel Nevo, Molin Wang, Reiko Nishihara, and Shuji Ogino, Harvard T.H. Chan School of Public Health; Jonathan A. Nowak, Xuehong Zhang, Edward L. Giovannucci, Marios Giannakis, Gordon J. Freeman, Molin Wang, Andrew T. Chan, Charles S. Fuchs, and Shuji Ogino, Brigham and Women's Hospital and Harvard Medical School, Boston; Marios Giannakis and Andrew T. Chan, Broad Institute of MIT and Harvard University, Cambridge, MA; Li Liu, Huazhong University of Science and Technology, Wuhan; Yan Shi, Chinese People's Liberation Army General Hospital, Beijing; and Mancang Gu, Zhejiang Chinese Medical University, Hangzhou, People's Republic of China.


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 confounders, 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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