“Aspirin Use and Colorectal Cancer Survival According to Tumor CD274 (Programmed Cell Death 1 Ligand 1) Expression Status”
Journal: Journal of Clinical Oncology
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 post-diagnosis 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 < 0.001); 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 pre-diagnosis 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.
Shuji Ogino, MD, PhD, MS, of Brigham and Women’s Hospital
Q: What did your study reveal about aspirin use as it pertains to colorectal cancer?
Dr. Ogino: Ample evidence supports the antitumor effects of aspirin to prolong patient survival after colorectal cancer diagnosis. Beyond this, our study showed that survival benefits associated with postdiagnosis aspirin use for patients with colorectal cancer may be stronger in CD274 (PD-L1)-low tumors than in CD274-high tumors.
Q: Were these results surprising?
Dr. Ogino: The results were not surprising. Our study was conducted based on experimental evidence for synergistic effects of aspirin and immune checkpoint blockade on stimulating T-cell–mediated immune response to tumors.1 Our study is the first to support the synergism of aspirin-mediated antitumor pathways and immune checkpoint blockade in human populations.
Q: How does your study serve to improve treatment going forward?
Dr. Ogino: Tumor CD274 (PD-L1)-expression status may be used as a biomarker to stratify patients with colorectal cancer according to possible survival benefits from postdiagnosis aspirin use. Worthy of note is that our findings suggest a differential antitumor effect of aspirin according to immune checkpoint status.
Q: Have you seen any significant changes in treatment decisions in the wake of your study?
Dr. Ogino: Our population-based data provide evidence supporting not only use of aspirin for patients with CD274 (PD-L1)-low colorectal cancers, but also future clinical trials that investigate adjuvant aspirin therapy in targeted patients, including patients with CD274-low colorectal cancer, and patients receiving CD274-PDCD1 (PD-1) immune checkpoint inhibitors.