Authors: Anna Martling, M.D., Ph.D. https://orcid.org/0000-0001-5998-4735, Ida Hed Myrberg, M.Sc., Mef Nilbert, M.D., Ph.D., Henrik Grönberg, M.D., Ph.D., Fredrik Granath, Ph.D., Martin Eklund, Ph.D., Tom Öresland, M.D., Ph.D., +12 , Lene H. Iversen, M.D., Ph.D., Carola Haapamäki, M.D., Ph.D., Martin Janson, M.D., Ph.D., Karin Westberg, M.D., Ph.D., Josefin Segelman, M.D., Ph.D., Urban Ersson, M.D., Mattias Prytz, M.D., Ph.D., Eva Angenete, M.D., Ph.D. https://orcid.org/0000-0001-9966-4904, Rebecka Bergström, M.Sc. https://orcid.org/0000-0001-7609-0733, Markus Mayrhofer, Ph.D., Bengt Glimelius, M.D., Ph.D., and Johan Lindberg, Ph.D., for the ALASCCA Study Group*
Published September 17, 2025
N Engl J Med 2025;393:1051-1064
DOI: 10.1056/NEJMoa2504650
Abstract
Background
Aspirin reduces the incidence of colorectal adenoma and colorectal cancer among high-risk persons. Observational studies suggest that aspirin may also improve disease-free survival after diagnosis, particularly among patients with tumors harboring somatic PIK3CA mutations. However, data from randomized trials are lacking.
Methods
We conducted a double-blind, randomized, placebo-controlled trial involving patients with stage I, II, or III rectal cancer or stage II or III colon cancer with somatic alterations in PI3K pathway genes. The patients were assigned in a 1:1 ratio to receive 160 mg of aspirin or matched placebo once daily for 3 years. Patients with prespecified PIK3CA hotspot mutations in exon 9 or 20 (group A alterations) and those with other moderate- or high-impact somatic variants in PIK3CA, PIK3R1, or PTEN (group B alterations) were eligible for randomization. The primary end point was colorectal cancer recurrence, assessed in a time-to-event analysis, in patients with group A alterations. Secondary end points included colorectal cancer recurrence in patients with group B alterations, disease-free survival, and safety.
Results
Alterations in PI3K pathway genes were detected in 1103 of 2980 patients (37.0%) with complete genomic data. Of 515 patients with group A alterations and 588 patients with group B alterations, 314 and 312, respectively, were assigned to receive aspirin or placebo. The estimated 3-year cumulative incidence of recurrence was 7.7% with aspirin and 14.1% with placebo (hazard ratio, 0.49; 95% confidence interval [CI], 0.24 to 0.98; P=0.04) among patients with group A alterations and 7.7% and 16.8%, respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.83), among those with group B alterations. The estimated 3-year disease-free survival was 88.5% with aspirin and 81.4% with placebo (hazard ratio, 0.61; 95% CI, 0.34 to 1.08) among patients with group A alterations and 89.1% and 78.7%, respectively (hazard ratio, 0.51; 95% CI, 0.29 to 0.88), among those with group B alterations. Severe adverse events occurred in 16.8% of aspirin recipients and 11.6% of placebo recipients.
Conclusions
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. (Funded by the Swedish Research Council and others; ALASCCA ClinicalTrials.gov number, NCT02647099; EudraCT number, 2015-004240-19.)
Notes
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Supported by grants from the Swedish Research Council, Swedish Cancer Society, Cancer Research Funds of Radiumhemmet, ALF (regional agreement grant between Karolinska Institutet and Region Stockholm, 2016–2024), Danish Comprehensive Cancer Center, and private donors (B. Carlson family, B. Lehander family, and B. Savén family).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank all the patients and their families; the participating personnel at the trial sites; the staff at the Karolinska Trial Alliance for independent monitoring of the trial; the Regional Cancer Center Umeå for maintaining the national quality registry for colorectal cancer; Tongplaew Singnomklao for assistance with data management; Ola Steinberg for support with the initiation and launch of the trial, Christina Edberg for research administrative support; Johan Zetterqvist for reviewing the statistical analysis; the staff at the biobank of Karolinska Institutet for weekly processing of the biomaterial for genomic analysis; and the staff at Clinical Genomics, Science for Life Laboratory, for providing timely and cost-efficient DNA sequencing.