Aspects of aspirin in colorectal cancer development and prognosis

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide and its incidence continues to rise. Despite advancement in treatment, CRC survival remains around 60%. Since the first study in 1988 reported aspirin's potential role in CRC prevention, extensive research has been conducted to explore its impact on both CRC prevention and prognosis. However other areas remain unexplored. Aspirin's widespread availability, low cost, and well-documented safety profile make it an attractive candidate for further investigation, particularly if new therapeutic benefits can be identified. The aim of this thesis was to explore under-investigated aspects of aspirin's impact on CRC. This includes examining its effects on survival outcomes, metastatic risk, interactions with metformin, and mutation profiles. By addressing these areas, this research offers new insights into aspirin's role in CRC development and prognosis.

Study I investigated the association between low-dose aspirin use and CRC outcomes in 32,195 non-metastatic CRC, aged 18-85 years, diagnosed between 2007 and 2016, who underwent curative-intended surgery. Using data from the Colorectal cancer database (CRCBaSe) Sweden, the study found no significant association between aspirin use at the time of surgery and 5-year all-cause mortality (adjusted HR 1.03, 95% CI: 0.97–1.08), CRC-specific mortality (adjusted HR 0.99, 95% CI: 0.91–1.07) or relapse-free survival (adjusted HR 1.01, 95% CI: 0.96- 1.06). This represents the largest observational study to date on aspirin use and CRC outcomes, suggesting no clear survival benefit from aspirin use in non?metastatic CRC patients, while also being one of the few studies to investigate the risk of recurrence.

Study II examined the impact of type 2 diabetes mellitus (T2DM) and metformin use on CRC outcomes, along with the potential synergistic effect of combining metformin and aspirin, in a nationwide cohort of 33,028 non-metastatic CRC patients aged ≥18 years, diagnosed between 2007 and 2016 using CRCBaSe. The study found no significant association between T2DM or metformin use and time to recurrence or CRC-specific mortality (adjusted HR 0.95, 95% CI: 0.87–1.05 for T2DM; adjusted HR 0.98, 95% CI: 0.85–1.13 for metformin users). Additionally, no synergistic effect was observed between metformin and aspirin use in relation to CRC outcomes.

Study III explored the relationship between low-dose aspirin use and the risk of synchronous distant CRC metastasis in 88,960 patients diagnosed between 2007 and 2021 aged ≥18 years, using CRCBaSe. The study revealed that current and past aspirin users had a reduced risk of synchronous distant metastases in right-sided colon cancer (adjusted OR 0.87, 95% CI: 0.80–0.94 for current users; adjusted OR 0.83, 95% CI: 0.73–0.95 for past users), particularly among long-term users (adjusted OR 0.84, 95% CI: 0.76–0.92 for ≥5 years of use and adjusted OR 0.78, 95% CI: 0.68–0.90 for ≥1825 pills of use). No such association was observed for rectal cancer.

Study IV explored the relationship between aspirin use and mutation profiles in 3,030 non-metastatic CRC patients who were screened for the ALASCCA trial. Aspirin users had a lower probability of PIK3CA mutations (0.18, 95% CI 0.14–0.22) compared to non-users (0.25, 95% CI 0.23–0.26). Among MSI-high tumors, aspirin users exhibited higher probabilities of BRAF and PTEN mutations but lower probabilities of KRAS and PIK3CA mutations. No significant differences were observed in microsatellite stable tumors. These findings highlight potential molecular mechanisms through which aspirin may influence CRC development.

This thesis sheds light on several underexplored aspects of aspirin's role in CRC. Aspirin use demonstrates potential in reducing metastatic risk, only in colon cancer, and influences specific molecular profiles associated with tumor development. It is associated with a lower probability of PIK3CA mutations and distinct mutation patterns in MSI-high tumors, such as increased BRAF and PTEN mutations and decreased KRAS mutations. However, aspirin does not confer a clear survival benefit in non-metastatic CRC, and its interaction with metformin has no impact on CRC outcomes. These findings highlight the complex role of aspirin in CRC and underscore the need for further biomarker-driven studies to clarify its therapeutic potential.

List of scientific papers

I. Low-dose aspirin use and colorectal cancer survival in 32,195 patients – A national cohort study. Shahrivar M, Weibull CE, Ekström Smedby K, Glimelius B, Syk I, Matthiessen P, Nordenvall C, Martling A. Cancer Medicine 2023 Jan; 12(1):315-324. https://doi.org/10.1002/cam4.4859

II. Type II diabetes and metformin use does not affect colorectal cancer prognosis. Shahrivar M, Dietrich CE, Glimelius B, Saraste D, Martling A, Buchli C, Nordenvall C. International Journal of Cancer 2024 Nov. 27. Online ahead of print. https://doi.org/10.1002/ijc.35266

III. Low-dose aspirin use and the risk of synchronous metastatic colorectal cancer: results from a population-based cohort study. Shahrivar M, Dietrich CE, Glimelius B, Martling A, Nordenvall C. [Submitted]

IV. Aspirin use and mutation profile in non-metastatic colorectal cancer. Shahrivar M, Nordenvall C, Mayrhofer M, Dietrich CE, Bergström R, Myrberg IH, Lindberg J, Martling A. [Manuscript]