Low-Dose Aspirin Cuts Recurrence Risk in PI3K-Altered Colorectal Cancer

Low-dose aspirin significantly reduced colorectal cancer (CRC) recurrence among patients with PIK3CA hotspot mutations and other PI3K pathway gene alterations, a study has found.¹ Over 3 years, recurrence rates were nearly halved compared with placebo, highlighting aspirin’s potential as a targeted adjuvant therapy in localized CRC.

This randomized, placebo-controlled trial is published in The New England Journal of Medicine.

“Aspirin is being tested here in a completely new context as a precision medicine treatment,” said Anna Martling, MD, PhD, professor at the Department of Molecular Medicine and Surgery, Karolinska Institute, and senior consultant surgeon at Karolinska University Hospital, in a statement.² “This is a clear example of how we can use genetic information to personalize treatment and at the same time save both resources and suffering.”

In this trial, patients with stage I-III rectal cancer or stage II-III colon cancer harboring somatic alterations in PI3K pathway genes were enrolled.¹ Eligible participants had prespecified PIK3CA hotspot mutations in exon 9 or 20 (group A) or with other moderate- or high-impact variants in PIK3CA, PIK3R1, or PTEN (group B). Patients were randomly assigned in a 1:1 ratio to receive either 160 mg of aspirin or a matched placebo once daily for 3 years.

The primary end point was time-to-event analysis of CRC recurrence in patients with group A alterations, while secondary end points included recurrence in group B, disease-free survival, and safety outcomes.

Among the 1103 patients with PI3K pathway alterations, 314 with group A mutations and 312 with group B mutations were randomized to aspirin or placebo. In group A, the 3-year cumulative incidence of recurrence was 7.7% with aspirin compared with 14.1% with placebo (HR, 0.49; 95% CI, 0.24-0.98; P = .04). In group B, recurrence occurred in 7.7% of aspirin recipients vs 16.8% of placebo recipients (HR, 0.42; 95% CI, 0.21-0.83).

Disease-free survival at 3 years was 88.5% with aspirin and 81.4% with placebo in group A (HR, 0.61; 95% CI, 0.34-1.08) and 89.1% vs 78.7% in group B (HR, 0.51; 95% CI, 0.29-0.88). Additionally, severe adverse events were reported in 16.8% of patients receiving aspirin compared with 11.6% in the placebo group.

The researchers believe their study has significant implications for global guidelines for patients with colon and rectal cancer, in which aspirin may help lower recurrence rates in patients with the PI3K pathway gene.

However, they also acknowledged some limitations. Patients may have been healthier than the general CRC population, although placebo recurrence rates matched national data. Genomic data were missing for 803 patients, mainly those who had rectal cancer, likely due to tumor regression after neoadjuvant therapy. About half of patients with rectal cancer received such therapy and appeared to benefit from aspirin, highlighting the need to test biopsy specimens before treatment. The study was also not powered to assess alternative doses, treatment durations, or detailed subgroup effects.

“Although we do not yet fully understand all the molecular links, the findings strongly support the biological rationale and suggest that the treatment may be particularly effective in genetically defined subgroups of patients,” said Martling in a statement.² “Aspirin is a drug that is readily available globally and extremely inexpensive compared to many modern cancer drugs, which is very positive.”

References

1. Martling A, Hed Myrberg I, Nilbert M, et al. Low-dose aspirin for PI3K-altered localized colorectal cancer. N Engl J Med. 2025;393(11):1051-1064. doi:10.1056/NEJMoa2504650

2. Common and inexpensive medicine halves the risk of recurrence in patients with colorectal cancer. News release. Karolinska Institute. Published September 17, 2025. Accessed September 19, 2025. https://www.eurekalert.org/news-releases/1098145