Adjuvant aspirin for colorectal cancer with PIK3CA-mutated and COX-2 overexpressed tumours: the ASCOLT translational research study and meta-analysis

Background: ASCOLT compared adjuvant aspirin versus (vs) placebo in 1587 patients with colorectal cancer (CRC) and reported no significant improvement in disease-free survival (DFS). Subsequently, two randomised controlled trials (RCTs) reported benefit of adjuvant aspirin in CRC patients with somatic PI3K-related mutations. Methods: The ASCOLT Translational Research (TR) study was a preplanned subgroup analysis by PIK3CA mutation status and COX-2 overexpression, and an exploratory analysis including PTEN mutation status. Among 778 participants who commenced study medication, tissue was evaluable for targeted next generation sequencing of PIK3CA and PTEN in 289 tumours and by Sanger sequencing for PIK3CA exon 9 or 20 (9/20) mutations in a further 108. PTGS2/COX-2 expression was assessed by immunohistochemistry in 450. Hazard ratio (HR) and 95% confidence intervals (CI) for DFS of aspirin vs placebo in subgroups were assessed in Cox models. A systematic review of completed RCTs of adjuvant aspirin in CRC patients with PIK3CA mutations was also undertaken. Registration: NCT00565708 and ACTRN12614000513617. Findings: Among 397 patients with tumour assessable for PIK3CA, there were 80 recurrences, 40 deaths and 86 DFS events after 5 years follow-up. Among 69 (17%) with PIK3CA mutations (any exon), there were 8 vs 8 DFS events on placebo vs aspirin (HR 0.93 (95% CI 0.35–2.47); in 45 (11%) with exon 9/20 mutations, 7 vs 4 events (HR 0.72 (95% CI 0.21–2.46) and in 84 (21%) with PIK3CA or PTEN mutations, 8 vs 9 events (HR 1.23 (95% CI 0.47–3.19). Tumours were positive for COX-2 overexpression in 307 (69%) with 28 vs 34 events (HR 0.99 (95% CI 0.60–1.63). A meta-analysis of trials in patients with PIK3CA exon 9/20 mutations showed reduced DFS events with HR 0.61 (95% CI 0.39–0.96). Interpretation: In ASCOLT TR, adjuvant aspirin was not associated with significantly improved DFS in CRC with PI3K-related mutations or COX-2 overexpression, albeit with wide confidence intervals. Combined results of the three published trials showed improved DFS among patients with PIK3CA exon 9/20 mutations. Moderate, but important, effects of aspirin in other patient groups have not been excluded. Funding: National Health and Medical Research Council, Australia; Cancer Australia; National Cancer Centre Singapore Cancer Fund; Rising Tide Foundation; SingHealth Duke-NUS Academic Clinical Programme; Lee Foundation; Lee Kim Tah Foundation; Silent Foundation; Australasian Gastro-Intestinal Trials Group.