Low-Dose Aspirin Cuts Recurrence Risk in PI3K-Altered Colorectal Cancer, Trial Shows
Sweden: A new randomized trial has found that daily low-dose aspirin significantly lowers the risk of colorectal cancer recurrence in patients whose tumors harbor specific PI3K pathway alterations.
Published in the New England Journal of Medicine, the study led by Dr. Anna Martling of Karolinska Institutet demonstrates that aspirin not only reduces recurrence among patients with PIK3CA hotspot mutations but also provides similar benefits for those with other high- or moderate-impact variants in PI3K pathway genes.
The double-blind, placebo-controlled trial enrolled patients with stage I–III rectal cancer or stage II–III colon cancer who had somatic alterations in PI3K pathway genes, including PIK3CA, PIK3R1, and PTEN. Eligible participants were randomly assigned in a 1:1 ratio to receive either 160 mg of aspirin or a matched placebo once daily for three years. The primary focus was disease recurrence in patients with PIK3CA hotspot mutations in exon 9 or 20, referred to as group A alterations, while secondary outcomes included recurrence in patients with other PI3K-related mutations (group B), overall disease-free survival, and safety.
Out of 2,980 patients with complete genomic profiling, 1,103 (37%) had detectable PI3K pathway alterations. Among these, 515 had group A mutations and 588 had group B alterations.
The study led to the following findings:
- In the aspirin arm, the 3-year cumulative incidence of colorectal cancer recurrence for group A patients was 7.7%, compared with 14.1% in the placebo group, with a hazard ratio of 0.49.
- For group B patients, aspirin reduced recurrence to 7.7% versus 16.8% with placebo, corresponding to a hazard ratio of 0.42.
- Disease-free survival favored aspirin, with group A patients showing 88.5% survival versus 81.4% with placebo (hazard ratio, 0.61).
- Group B patients experienced 89.1% disease-free survival with aspirin compared to 78.7% with placebo (hazard ratio, 0.51).
- These results indicate that aspirin’s protective effect extends beyond PIK3CA hotspot mutations to other somatic alterations in the PI3K pathway.
- Severe adverse events occurred in 16.8% of aspirin recipients and 11.6% of placebo recipients.
- Most adverse events were consistent with known aspirin-related risks, primarily gastrointestinal complications.
- No unexpected safety issues were reported during the three-year treatment period.
The study provides strong evidence supporting the use of low-dose aspirin as an adjuvant therapy for patients with PI3K-altered colorectal cancer. By targeting tumors with specific molecular profiles, aspirin may serve as a precision therapy to reduce recurrence risk and improve long-term outcomes. While further studies may be needed to optimize dosing and patient selection, these findings highlight aspirin’s potential as a cost-effective and widely accessible intervention in molecularly defined colorectal cancer populations.
"The trial represents a major step toward integrating routine molecular profiling with targeted preventive strategies, offering new hope for patients with PI3K pathway–altered colorectal tumors," the authors concluded.
Reference:
Martling A, Hed Myrberg I, Nilbert M, Grönberg H, Granath F, Eklund M, Öresland T, Iversen LH, Haapamäki C, Janson M, Westberg K, Segelman J, Ersson U, Prytz M, Angenete E, Bergström R, Mayrhofer M, Glimelius B, Lindberg J; ALASCCA Study Group. Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer. N Engl J Med. 2025 Sep 18;393(11):1051-1064. doi: 10.1056/NEJMoa2504650. PMID: 40961426.
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