Adjuvant aspirin and Cyclooxygenase-2 inhibitors in resected, PIK3CA-mutated colorectal cancer: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are widely available and inexpensive agents with proposed antitumor activity, particularly in tumors harboring PIK3CA mutations. This meta-analysis of randomized controlled trials (RCTs) evaluated whether adjuvant NSAID therapy improves outcomes in patients with resected PIK3CA-mutated colorectal cancer (CRC). METHODS: PubMed, Embase, and the Cochrane Library were systematically searched for RCTs assessing NSAID use following curative-intent resection of CRC in patients with confirmed PIK3CA mutations. Pooled hazard ratios (HRs) with corresponding 95 % confidence intervals (CIs) were calculated for disease-free survival (DFS) and overall survival (OS) using both fixed and random-effects models. Sensitivity analyses excluded participants with low-dose aspirin exposure concomitant with cyclooxygenase-2 (COX-2) inhibitors. RESULTS: Among 477 records screened, four RCTs met eligibility criteria, comprising 426 patients assigned to NSAIDs (aspirin or COX-2 inhibitors) and 363 receiving placebo. Adjuvant NSAID therapy improves DFS (HR 0.65; 95 % CI, 0.46-0.90). In sensitivity analyses excluding concomitant aspirin exposure, a similar magnitude of effect was observed (HR 0.57; 95 % CI, 0.39-0.83). The pooled OS analysis was not statistically significant (HR 0.78; 95 % CI, 0.39-1.57). Exclusion of low-dose aspirin users was associated with lower mortality risk (HR 0.54; 95 % CI, 0.30-0.99), although these findings should be interpreted cautiously. CONCLUSION: Adjuvant NSAID therapy is associated with improved DFS in patients with PIK3CA-mutated CRC. OS benefit remains uncertain, and findings from sensitivity analyses are exploratory. These findings support consideration of NSAIDs as a biomarker-informed adjuvant strategy in selected patients while underscoring the need for confirmatory evidence from ongoing randomized trials.