Dataset Information

Evaluation of PTGS2 Expression, PIK3CA Mutation, Aspirin Use and Colon Cancer Survival in a Population-Based Cohort Study.

ABSTRACT: The association between aspirin use and improved survival after colorectal cancer diagnosis may be more pronounced in tumors that have PIK3CA mutations or high PTGS2 expression. However, the evidence of a difference in association by biomarker status lacks consistency. In this population-based colon cancer cohort study the interaction between these biomarkers, aspirin use, and survival was assessed.The cohort consisted of 740 stage II and III colon cancer patients diagnosed between 2004 and 2008. Aspirin use was determined through clinical note review. Tissue blocks were retrieved to determine immunohistochemical assessment of PTGS2 expression and the presence of PIK3CA mutations. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for colorectal cancer-specific and overall survival.In this cohort aspirin use was associated with a 31% improvement in cancer-specific survival compared to non-use (adjusted HR=0.69, 95% CI 0.47-0.98). This effect was more pronounced in tumors with high PTGS2 expression (PTGS2-high adjusted HR=0.55, 95% CI 0.32-0.96) compared to those with low PTGS2 expression (PTGS2-low adjusted HR=1.19, 95% CI 0.68-2.07, P for interaction=0.09). The aspirin by PTGS2 interaction was significant for overall survival (PTGS2-high adjusted HR=0.64, 95% CI 0.42-0.98 vs. PTGS2-low adjusted HR=1.28, 95% CI 0.80-2.03, P for interaction=0.04). However, no interaction was observed between aspirin use and PIK3CA mutation status for colorectal cancer-specific or overall survival.Aspirin use was associated with improved survival outcomes in this population-based cohort of colon cancer patients. This association differed according to PTGS2 expression but not PIK3CA mutation status. Limiting adjuvant aspirin trials to PIK3CA-mutant colorectal cancer may be too restrictive.

SUBMITTER: Gray RT

PROVIDER: S-EPMC5543466 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Evaluation of PTGS2 Expression, PIK3CA Mutation, Aspirin Use and Colon Cancer Survival in a Population-Based Cohort Study.

Gray Ronan T RT Cantwell Marie M MM Coleman Helen G HG Loughrey Maurice B MB Bankhead Peter P McQuaid Stephen S O'Neill Roisin F RF Arthur Kenneth K Bingham Victoria V McGready Claire C Gavin Anna T AT Cardwell Chris R CR Johnston Brian T BT James Jacqueline A JA Hamilton Peter W PW Salto-Tellez Manuel M Murray Liam J LJ

Clinical and translational gastroenterology 20170427 4

<h4>Objectives</h4>The association between aspirin use and improved survival after colorectal cancer diagnosis may be more pronounced in tumors that have PIK3CA mutations or high PTGS2 expression. However, the evidence of a difference in association by biomarker status lacks consistency. In this population-based colon cancer cohort study the interaction between these biomarkers, aspirin use, and survival was assessed.<h4>Methods</h4>The cohort consisted of 740 stage II and III colon cancer patie ...[more]

PMID: 28448072

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Project description:BackgroundRegular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers.MethodsWe obtained data on 964 patients with rectal or colon cancer from the Nurses' Health Study and the Health Professionals Follow-up Study, including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation. We used a Cox proportional-hazards model to compute the multivariate hazard ratio for death. We examined tumor markers, including PTGS2, phosphorylated AKT, KRAS, BRAF, microsatellite instability, CpG island methylator phenotype, and methylation of long interspersed nucleotide element 1.ResultsAmong patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer-specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P=0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer-specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P=0.76 by the log-rank test; P=0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P=0.96 by the log-rank test; P=0.07 for interaction).ConclusionsRegular use of aspirin after diagnosis was associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. The findings from this molecular pathological epidemiology study suggest that the PIK3CA mutation in colorectal cancer may serve as a predictive molecular biomarker for adjuvant aspirin therapy. (Funded by The National Institutes of Health and others.).

Project description:BackgroundThe preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients.MethodsData concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998-2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure.ResultsIn total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63-0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50-0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46-0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79-1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70-2.20; P<0.001).ConclusionAspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients.

Dataset Information

Evaluation of PTGS2 Expression, PIK3CA Mutation, Aspirin Use and Colon Cancer Survival in a Population-Based Cohort Study.

Publications

Evaluation of PTGS2 Expression, PIK3CA Mutation, Aspirin Use and Colon Cancer Survival in a Population-Based Cohort Study.

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