Low-Dose Aspirin Significantly Reduces Recurrence in PI3K-Altered Localized Colorectal Cancer
Key Clinical Takeaways
- Design/Population: The ALASCCA trial was a double-blind, placebo-controlled study enrolling 626 patients with stage I–III CRC harboring somatic PI3K pathway alterations. Patients were randomized 1:1 to receive aspirin 160 mg once daily or matched placebo for 3 years and stratified by molecular subtype into PIK3CA hotspot and broader PI3K pathway variant cohorts.
- Key Outcomes: Among patients with PIK3CA hotspot mutations, aspirin reduced the 3-year cumulative incidence of recurrence to 7.7% compared with 14.1% for placebo (HR, 0.49; P = .04). Similar reductions in recurrence and improvements in 3-year disease-free survival were observed in patients with moderate- or high-impact variants in PIK3CA, PIK3R1, or PTEN.
- Clinical Relevance: Aspirin demonstrated a significant recurrence-prevention benefit in patients with PIK3CA hotspot mutations and showed comparable benefit across additional PI3K pathway alterations. These findings support aspirin as a promising biomarker-guided adjuvant strategy for select patients with early-stage CRC harboring PI3K pathway mutations.
According to results from the ALASCCA trial, aspirin significantly reduced the risk of colorectal cancer (CRC) recurrence among patients with PIK3CA hotspot mutations and appeared to provide a similar benefit in those with other PI3K pathway alterations.
“Aspirin reduces the incidence of colorectal adenoma and colorectal cancer among high-risk persons,” stated Anna Martling, MD, PhD, Karolinska Institutet, Stockholm, Sweden, and coauthors, explaining that, “Observational studies suggest that aspirin may also improve disease-free survival after diagnosis, particularly among patients with tumors harboring somatic PIK3CA mutations.”
In this double-blind, placebo-controlled trial, investigators enrolled 626 patients with stage I to III rectal cancer or stage II to III colon cancer harboring somatic PI3K pathway alterations. Patients were randomized 1:1 to receive either 160 mg of once daily aspirin (n = 314) or matched placebo (n = 312) for 3 years. Participants were stratified by molecular subtype into 2 cohorts:
- Group A: patients with PIK3CA hotspot mutations in exon 9 or 20 (n = 515)
- Group B: patients with moderate- or high-impact variants in PIK3CA, PIK3R1, or PTEN (n = 588)
The primary end point was disease recurrence in patients with PIK3CA exon 9 or 20 alterations. Secondary end points included disease recurrence in patients with PIK3CA, PIK3R1, or PTEN variants, disease-free survival (DFS), and safety.
At analysis, the 3-year cumulative incidence of recurrence was 7.7% in the aspirin arm and 14.1% in the placebo arm (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.24 to 0.98; P = .04) among patients with PIK3CA hotspot mutations in exon 9 or 20. Among patients with moderate- or high-impact variants in PIK3CA, PIK3R1, or PTEN, the 3-year cumulative incidence of recurrence was 7.7% and 16.8%, respectively. The 3-year DFS was 88.5% in the aspirin arm and 81.4% in the placebo arm among patients with PIK3CA hotspot mutations in exon 9 or 20, and 89.1% and 78.7%, respectively, among those with moderate- or high-impact variants in PIK3CA, PIK3R1, or PTEN. Severe adverse events occurred in 16.8% of patients receiving aspirin and 11.6% of those receiving placebo.
“Aspirin led to a significantly lower incidence of colorectal cancer recurrence than placebo among patients with PIK3CA hotspot mutations in exon 9 or 20 and appeared to have a similar benefit among those with other somatic alterations in PI3K pathway genes,” concluded the investigators.
Source:
Martling A, Myrberg IH, Nilbert M, et al. Low-dose aspirin for PI3K-altered localized colorectal cancer. N Engl J Med. Published online: September 17, 2025. doi: 10.1056/NEJMoa2504650
