Aspirin use and colorectal cancer survival according to tumor CD274 (programmed cell death 1 ligand 1) expression status

Tsuyoshi Hamada, Yin Cao, Zhi Rong Qian, Yohei Masugi, Jonathan A. Nowak, Juhong Yang, Mingyang Song, Kosuke Mima, Keisuke Kosumi, Li Liu, Yan Shi, Annacarolina da Silva, Mancang Gu, Wanwan Li, Na Na Keum, Xuehong Zhang, Kana Wu, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Marios GiannakisScott J. Rodig, Gordon J. Freeman, Daniel Nevo, Molin Wang, Andrew T. Chan, Charles S. Fuchs, Reiko Nishihara, Shuji Ogino

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1836-1844
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number16
DOIs
Publication statusPublished - 2017 Jun 1
Externally publishedYes

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CD274 Antigen
Aspirin
Colorectal Neoplasms
Survival
Neoplasms
Cyclooxygenase 2
Long Interspersed Nucleotide Elements
Tumor-Infiltrating Lymphocytes
Microsatellite Instability
CpG Islands
Health
Rectal Neoplasms
Proportional Hazards Models
Dinoprostone
Microsatellite Repeats
Immunotherapy
Colonic Neoplasms
Methylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Aspirin use and colorectal cancer survival according to tumor CD274 (programmed cell death 1 ligand 1) expression status. / Hamada, Tsuyoshi; Cao, Yin; Qian, Zhi Rong; Masugi, Yohei; Nowak, Jonathan A.; Yang, Juhong; Song, Mingyang; Mima, Kosuke; Kosumi, Keisuke; Liu, Li; Shi, Yan; Silva, Annacarolina da; Gu, Mancang; Li, Wanwan; Keum, Na Na; Zhang, Xuehong; Wu, Kana; Meyerhardt, Jeffrey A.; Giovannucci, Edward L.; Giannakis, Marios; Rodig, Scott J.; Freeman, Gordon J.; Nevo, Daniel; Wang, Molin; Chan, Andrew T.; Fuchs, Charles S.; Nishihara, Reiko; Ogino, Shuji.

In: Journal of Clinical Oncology, Vol. 35, No. 16, 01.06.2017, p. 1836-1844.

Research output: Contribution to journalArticle

Hamada, T, Cao, Y, Qian, ZR, Masugi, Y, Nowak, JA, Yang, J, Song, M, Mima, K, Kosumi, K, Liu, L, Shi, Y, Silva, AD, Gu, M, Li, W, Keum, NN, Zhang, X, Wu, K, Meyerhardt, JA, Giovannucci, EL, Giannakis, M, Rodig, SJ, Freeman, GJ, Nevo, D, Wang, M, Chan, AT, Fuchs, CS, Nishihara, R & Ogino, S 2017, 'Aspirin use and colorectal cancer survival according to tumor CD274 (programmed cell death 1 ligand 1) expression status', Journal of Clinical Oncology, vol. 35, no. 16, pp. 1836-1844. https://doi.org/10.1200/JCO.2016.70.7547
Hamada, Tsuyoshi ; Cao, Yin ; Qian, Zhi Rong ; Masugi, Yohei ; Nowak, Jonathan A. ; Yang, Juhong ; Song, Mingyang ; Mima, Kosuke ; Kosumi, Keisuke ; Liu, Li ; Shi, Yan ; Silva, Annacarolina da ; Gu, Mancang ; Li, Wanwan ; Keum, Na Na ; Zhang, Xuehong ; Wu, Kana ; Meyerhardt, Jeffrey A. ; Giovannucci, Edward L. ; Giannakis, Marios ; Rodig, Scott J. ; Freeman, Gordon J. ; Nevo, Daniel ; Wang, Molin ; Chan, Andrew T. ; Fuchs, Charles S. ; Nishihara, Reiko ; Ogino, Shuji. / Aspirin use and colorectal cancer survival according to tumor CD274 (programmed cell death 1 ligand 1) expression status. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 16. pp. 1836-1844.
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abstract = "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.",
author = "Tsuyoshi Hamada and Yin Cao and Qian, {Zhi Rong} and Yohei Masugi and Nowak, {Jonathan A.} and Juhong Yang and Mingyang Song and Kosuke Mima and Keisuke Kosumi and Li Liu and Yan Shi and Silva, {Annacarolina da} and Mancang Gu and Wanwan Li and Keum, {Na Na} and Xuehong Zhang and Kana Wu and Meyerhardt, {Jeffrey A.} and Giovannucci, {Edward L.} and Marios Giannakis and Rodig, {Scott J.} and Freeman, {Gordon J.} and Daniel Nevo and Molin Wang and Chan, {Andrew T.} and Fuchs, {Charles S.} and Reiko Nishihara and Shuji Ogino",
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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

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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