Adjuvant aspirin for colorectal cancer with PIK3CA-mutated and COX-2 overexpressed tumours: the ASCOLT translational research study and meta-analysis.
Level 1 - systematic review of randomized trials
Meta-analysis of randomized controlled trials combined with a preplanned biomarker subgroup analysis of an RCT.
PubMed 42475879 · doi:10.1016/j.ebiom.2026.106389
What was done
This study conducted a preplanned translational research subgroup analysis of the ASCOLT trial (adjuvant aspirin vs placebo in 1587 patients with colorectal cancer) and a systematic review/meta-analysis of completed randomized controlled trials (RCTs). Among 778 participants who started study treatment, tumour tissue was evaluated for PIK3CA and PTEN mutations (targeted next-generation sequencing in 289, Sanger sequencing for PIK3CA exon 9/20 in 108) and PTGS2/COX-2 expression by immunohistochemistry in 450. Disease-free survival (DFS) hazard ratios (HR) were estimated using Cox models, followed by a meta-analysis of RCTs in patients with PIK3CA mutations.
What was found
Among 397 patients with tumour assessable for PIK3CA, 86 DFS events occurred over 5 years. In 69 patients (17%) with any PIK3CA mutation, DFS showed 8 events on aspirin vs 8 on placebo (HR 0.93, 95% CI 0.35–2.47). In 45 patients (11%) with exon 9/20 mutations, there were 4 events on aspirin vs 7 on placebo (HR 0.72, 95% CI 0.21–2.46). In 84 patients (21%) with PIK3CA or PTEN mutations, there were 9 events on aspirin vs 8 on placebo (HR 1.23, 95% CI 0.47–3.19). In 307 patients (69%) with COX-2 overexpression, there were 34 events on aspirin vs 28 on placebo (HR 0.99, 95% CI 0.60–1.63). Meta-analysis of three trials in patients with PIK3CA exon 9/20 mutations showed reduced DFS events with aspirin (HR 0.61, 95% CI 0.39–0.96).
Why it matters
While single-trial biomarker cohorts lacked statistical power, pooled evidence from three randomized trials supports a disease-free survival benefit from adjuvant aspirin specifically in colorectal cancer harbouring PIK3CA exon 9 or 20 mutations.
Limits
Only 397 of 1587 trial participants had tissue assessable for PIK3CA, leading to small subgroup sizes and very wide confidence intervals in the ASCOLT analysis. The meta-analysis was restricted to three published trials, and effects across other molecular subgroups (e.g., PTEN or non-exon 9/20 mutations) remain inconclusive.