Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer

Author(s): Anna Martling, M.D., Ph.D.^1,2; Ida Hed Myrberg, M.Sc.³; Mef Nilbert, M.D., Ph.D.⁴; Henrik Grönberg, M.D., Ph.D.⁵; Fredrik Granath, Ph.D.³; Martin Eklund, Ph.D.⁵; Tom Öresland, M.D., Ph.D.^6,7; Lene H. Iversen, M.D., Ph.D.⁸; Carola Haapamäki, M.D., Ph.D.⁹; Martin Janson, M.D., Ph.D.¹⁰; Karin Westberg, M.D., Ph.D.^1,11; Josefin Segelman, M.D., Ph.D.^1,12; Urban Ersson, M.D.¹³; Mattias Prytz, M.D., Ph.D.^14,15; Eva Angenete, M.D., Ph.D.^15,16; Rebecka Bergström, M.Sc.⁵; Markus Mayrhofer, Ph.D.^5,17; Bengt Glimelius, M.D., Ph.D.¹⁸; Johan Lindberg, Ph.D.¹⁹; the ALASCCA Study Group*;

Source: N Engl J Med 2025;393:1051-1064

Dr. Anjan Patel's Thoughts

The ALASCCA phase III trial randomized patients with resected stage I-III rectal or stage II-III colon cancer and PI3K pathway alterations to adjuvant aspirin (160 mg daily) or placebo for 3 years. In those with PIK3CA mutations, aspirin significantly reduced 3-year recurrence (~7.5% vs ~15%) and improved 3-year DFS (~90% vs 80%). Severe AEs were higher with aspirin (16.8% vs 11.6%), but the number needed to treat (NNT) to prevent one recurrence was as low as 6 in stage III rectal cancer. For our colorectal cancer (CRC) patients with PI3K pathway mutations, adjuvant aspirin looks like a practical, low-cost targeted option worth considering in routine care. This may make more sense than celecoxib as the long-term risk of aspirin use is more defined, and the cardiovascular benefits may also be applicable to some patients.

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. Research Summary Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer

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.)

Author Affiliations

¹Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm; ²Theme Cancer, Department of Pelvic Cancer, Karolinska University Hospital, Stockholm; ³Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm; ⁴Institute of Clinical Sciences, Lund University and Skane University Hospital Cancer Center, Lund, Sweden; ⁵Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; ⁶Department of Gastrointestinal Surgery, Akershus University Hospital, Oslo; ⁷Clinic for Surgical Sciences, University of Oslo, Oslo; ⁸Department of Surgery, Aarhus University Hospital, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; ⁹Department of Gastroenterologic Surgery, Helsinki University Hospital and University of Helsinki, Helsinki; ¹⁰Department of Clinical Science and Education, Stockholm South General Hospital, Stockholm; ¹¹Danderyds Hospital, Department of Surgery, Stockholm; ¹²Ersta Hospital, Department of Surgery, Stockholm; ¹³Skaraborg Hospital, Skövde, Sweden; ¹⁴Department of Surgery, Region Västra Götaland, NU Hospital group, Trollhättan, Sweden; ¹⁵Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; ¹⁶Department of Surgery, Sahlgrenska University Hospital–Östra, Region Västra Götaland, Gothenburg, Sweden; ¹⁷National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden; ¹⁸Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden; ¹⁹Department of Medical Epidemiology and Biostatistics, Science for Life Laboratory, Karolinska Institutet, Stockholm

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