Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer.
Level 2 - randomized trial
Individual randomized, double-blind, placebo-controlled trial
PubMed 40961426 · doi:10.1056/NEJMoa2504650
What was done
A double-blind, randomized, placebo-controlled phase III trial (ALASCCA) evaluated whether 160 mg of aspirin daily for 3 years reduced recurrence compared to placebo in patients with stage I–III rectal cancer or stage II–III colon cancer harboring somatic PI3K pathway alterations. Patients were categorized into Group A (prespecified PIK3CA hotspot mutations in exon 9 or 20) and Group B (other somatic alterations in PIK3CA, PIK3R1, or PTEN) and randomized 1:1 to aspirin or placebo. The primary endpoint was time to colorectal cancer recurrence in Group A; secondary endpoints included recurrence in Group B, disease-free survival, and safety.
What was found
PI3K pathway alterations were identified in 1,103 of 2,980 screened patients (37.0%). Among 515 patients with Group A alterations and 588 with Group B alterations, 314 and 312 were randomized, respectively. - Group A: 3-year cumulative incidence of recurrence was 7.7% with aspirin vs. 14.1% with placebo (HR 0.49; 95% CI, 0.24 to 0.98; P = 0.04). Estimated 3-year disease-free survival was 88.5% with aspirin vs. 81.4% with placebo (HR 0.61; 95% CI, 0.34 to 1.08). - Group B: 3-year cumulative incidence of recurrence was 7.7% with aspirin vs. 16.8% with placebo (HR 0.42; 95% CI, 0.21 to 0.83). Estimated 3-year disease-free survival was 89.1% with aspirin vs. 78.7% with placebo (HR 0.51; 95% CI, 0.29 to 0.88). - Safety: Severe adverse events occurred in 16.8% of aspirin recipients and 11.6% of placebo recipients.
Why it matters
This phase III randomized trial demonstrates that biomarker-directed therapy with low-dose adjuvant aspirin significantly reduces recurrence in localized colorectal cancer with somatic PI3K pathway alterations.
Limits
Only 626 of 1,103 eligible mutation-positive patients underwent randomization. The disease-free survival confidence interval for Group A crossed 1.00 (95% CI, 0.34 to 1.08). Aspirin increased severe adverse events (16.8% vs. 11.6%), and overall survival outcomes were not reported in the abstract. Results cannot be extrapolated to patients without PI3K pathway alterations.