Association of Aspirin and Nonsteroidal Anti-Inflammatory Drugs With Colorectal Cancer Risk by Molecular Subtypes

Efrat L. Amitay; Prudence R. Carr; Lina Jansen; Viola Walter; Wilfried Roth; Esther Herpel; Matthias Kloor; Hendrik Bläker; Jenny Chang-Claude; Hermann Brenner; Michael Hoffmeister


J Natl Cancer Inst. 2019;111(5):475-483. 

In This Article

Abstract and Introduction


Background: Regular use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) for a longer period has been inversely associated with colorectal cancer (CRC) risk. However, CRC is a heterogenic disease, and little is known regarding the associations with molecular pathological subtypes.

Methods: Analyses included 2444 cases with a first diagnosis of CRC and 3130 healthy controls from a German population-based case control study. Tumor tissue samples were analyzed for major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype, B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation. Information on past and current use of NSAIDs, including aspirin, was obtained by standardized interviews. Multinomial logistic regression models were used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided.

Results: Regular use of NSAIDs was associated with a reduced CRC risk if tumors were MSS (OR = 0.66, 95% CI = 0.57 to 0.77), BRAF wildtype (OR = 0.67, 95% CI = 0.58 to 0.78), or KRAS wildtype (OR = 0.68, 95% CI = 0.58 to 0.80). Regular NSAID use was less clearly and mostly not statistically significantly associated with CRC risk reduction for MSI-high, BRAF-mutated, or KRAS-mutated CRC. In more specific analyses on MSI-high CRC, regular use of NSAIDs was associated with much stronger risk reduction in the absence of BRAF or KRAS mutations (OR = 0.34, 95% CI = 0.18 to 0.65) but not with KRAS- or BRAF-mutated MSI-high CRC (P heterogeneity < .001). Results for just aspirin use were similar.

Conclusion: Our study suggests variation in risk reduction of CRC subtypes following regular use of NSAIDs and aspirin. Regular use of NSAIDs and aspirin may be more strongly associated with risk reduction of MSI-high CRC without KRAS or BRAF mutation.


Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality.[1] Although often considered a single entity, CRC is a heterogeneous disease characterized by different underlying molecular pathways and features, such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene or the Kirsten rat sarcoma viral oncogene homolog gene (KRAS).[2]

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin, has been shown to be inversely associated with CRC risk when taken on a regular basis for a length of time.[3,4] Studies using colon cancer cells and tumor models have demonstrated that aspirin can prevent cancer cell growth and induce apoptosis. Furthermore, various mechanisms and cellular pathways have been recognized as contributors to the anticancer effects of aspirin as several COX-dependent pathways and downstream targets have been identified.[5,6]

Approximately 95% of all CRC cases are considered sporadic, lacking an identified causative inherited genetic alteration.[7] MSI-high is observed in approximately 15% of sporadic CRC cases, CIMP-high cancers account for approximately 20%,[8] BRAF mutations occur in up to 10%,[9,10] and KRAS mutations in 30% to 50% of cases.[11–13] KRAS and BRAF mutations are generally considered mutually exclusive.[14–16]

Thus far, very few studies investigated the association between NSAIDs, including aspirin, intake, and risk of CRC according to molecular subtypes defined by MSI, CIMP, BRAF, and KRAS.[17–22] Increased knowledge of the association between NSAID use and CRC risk by molecular subtypes may contribute to better understanding of the etiologic mechanisms by which NSAIDs lower CRC risk and help shed more light on the various carcinogenic processes.

The aim of this study on primary prevention was to investigate whether the associations between regular intake of NSAIDs and aspirin and CRC risk vary by the molecular pathological tumor subtypes of CRC.