ASPO Abstracts
Post-Diagnostic Aspirin Use and Survival from PIK3CA Mutant Colorectal Cancer: Potential Mechanisms
Category: Early Detection & Risk Prediction, Survivorship & Health Outcomes/Comparative Effectiveness Research
Conference Year: 2018
Abstract Body:
Purpose: Activation of the PI3K (phosphatidyl inositol 3 kinase) signaling pathway is one of the most frequent occurrences in human cancer and 10-20% of colorectal tumors harbor a mutation in the gene encoding the PI3K catalytic subunit (PIK3CA). Prior studies suggest a differential survival benefit from post-diagnostic aspirin use in patients whose tumor harbors a PIK3CA mutation, but the mechanisms underlying this benefit are unclear. We hypothesize that this survival advantage is restricted to PIK3CA mutations that result in novel acetylation sites, which aspirin modifies. The objective of this study is to investigate potential mechanisms of an aspirin survival benefit in patients with PIK3CA mutant colorectal cancer (CRC). Methods: CRC cell lines with and without specific PIK3CA mutations (SW-48 respectively) were treated with a synthesized 2-acetylpheny pent-4-ynoate (AspAlk) aspirin derivative, which was adapted to carry out Copper (I) catalyzed azide-alkyne cycloaddition. Soluble lysates were collected and combined with a click chemistry cocktail, allowing for robust, in-gel fluorescent detection of acetylation and the subsequent enrichment and identification of proteins. As a proof-of-principle, we evaluated survival in a local cohort of CRC patients by PIK3CA mutation and aspirin use. Multivariable Cox proportional hazards regression models were used to test the effects of PIK3CA mutation and aspirin use on survival. Models were adjusted for age, sex, race, ethnicity, stage at diagnosis, and educational level. Results: In this study, we found AspAlk to be a useful tool for identifying modifications in proteins compared to unlabeled aspirin. In the survival analysis, patients with PIK3CA mutant tumors who take aspirin show a modest survival benefit that is trending towards significance. A larger sample size is needed to clarify this observation. Conclusions: Due to the inherent risks of aspirin use, it is vital to distinguish groups of patients who are most likely to benefit from aspirin in order to minimize aspirin toxicity and potentially improve outcomes in patients with particular PIK3CA mutations. Our future work includes identifying the amino acids modified by aspirin using Mass Spectrometry.
Keywords: PIK3CA, Aspirin, Colorectal, Cancer,