Abstract B036: Non-steroidal anti-inflammatory drugs use and risk of colorectal cancer molecular subtypes: A systematic review and meta-analysis

Background Current evidence suggests that the association between non-steroidal anti-inflammatory drug (NSAID) use and colorectal cancer (CRC) risk remains uncertain, and little is known about potential heterogeneity by molecular subtype. Clarifying these associations may provide insights into CRC carcinogenesis. The aim of this systematic review was to evaluate the association between NSAID use and CRC risk by four clinically relevant molecular subtypes. Methods PubMed, Web of Science and Embase were searched for studies assessing NSAID use in relation CRC risk by microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), somatic mutations in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene or the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) status. Meta-analyses were performed to calculate summary relative risks (sRR). Results Nine studies met the inclusion criteria (n = 4,726 overall study population). NSAID use was associated with a stronger inverse association for BRAF-wildtype CRC (sRR = 0.73; 95% CI: 0.66–0.80) than for BRAF-mutated CRC (sRR = 0.85; 95% CI: 0.71–1.02), although the difference was not statistically significant (P heterogeneity = 0.11). Associations were in a similar direction for CIMP-high (sRR = 0.71; 95% CI: 0.61–0.83) and CIMP-low CRC (sRR = 0.73; 95% CI: 0.66–0.80), with no difference by CIMP status (P heterogeneity = 0.80). Similarly, risk reductions were observed for KRAS-mutated (sRR = 0.78; 95% CI: 0.69–0.88) and KRAS-wildtype (sRR = 0.76; 95% CI: 0.69–0.84), and for both MSI-high (sRR = 0.80; 95% CI: 0.67–0.96) and MSI-low/MSS CRC (sRR = 0.75; 95% CI: 0.69–0.82), with no evidence of heterogeneity by KRAS or MSI status (P heterogeneity = 0.76 and P heterogeneity = 0.51 respectively). Conclusion NSAID use was associated with lower risk of CRC across molecular subtypes, with suggestive differences by BRAF mutation status. These findings highlight the need for further studies to clarify potential subtype-specific associations and their implications for targeted chemoprevention strategies. Citation Format: Mary Jose. Urruchúa-Rodríguez, Toktam Pour, Hermann Brenner, Michael Hoffmeister. Non-steroidal anti-inflammatory drugs use and risk of colorectal cancer molecular subtypes: A systematic review and meta-analysis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr B036.