Are the Benefits of Aspirin in Colorectal Cancer Limited to PIK3CA Mutated Cancers?

Abstract

Introduction: Evidence has recently emerged to suggest that mutations in the PIK3CA gene in colorectal cancer might identify patients that receive greater benefit from aspirin in the adjuvant setting. Add-Aspirin is a planned and funded, double blind, placebo-controlled, randomised trial assessing the potential benefits of aspirin after primary curative therapy for non-metastatic cancer (colorectal, gastro-oesophageal, breast and prostate cancer). Participants (n = 9920 which includes 2600 with colorectal cancer) will receive aspirin 100mg daily, aspirin 300mg daily or matching placebo for at least 5 years. Each tumour specific cohort is individually powered and has a separate co-primary outcome measure. Methods: We assessed current data on the association between PIK3CA mutation status and benefit from aspirin after a colorectal diagnosis, as well as other genetic mutations associated with benefit from aspirin to assess how this should be addressed within the setting of a planned randomised adjuvant trial. Results: Long-term follow-up of randomised trials designed to assess vascular benefits of aspirin, show that taking daily low-dose aspirin for 5 years reduces the incidence of cancer, particularly those that arise from the gastrointestinal tract (1). Observational data suggest aspirin is associated with a lower risk of developing BRAF-wild type colorectal tumours (2). Recent data on the association between PIK3CA mutation status, aspirin use and survival outcomes involve small numbers of patients with mutations, and include stage I-IV patients where the biological effects may be different and are not consistent (see table1). Conclusion: The potential benefits of aspirin include effects on both the development of primary tumours, as well as the development and spread of metastases which may involve different signaling pathways. To date the data suggest that patients with both mutated and wild type PIK3CA colorectal tumours may benefit from aspirin after a diagnosis of colorectal cancer. Add-Aspirin incorporates an active run-in period which can be utilised to ascertain PIK3CA mutation status in the colorectal cohort prior to randomisation and used as a stratification factor, providing a framework to investigate this important clinical question efficiently and reliably. Subgroup analyses by PIK3CA status are planned and accumulating data will be reviewed by an Independent Data Monitoring Committee ensuring the full potential benefits of aspirin are realised. (Table Presented).