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Low-dose aspirin for PI3K-altered localised colorectal cancer

23 September 2025

September's Paper of the Month looks at a double-blind, randomised, 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.

Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer
A. Martling, I. Hed Myrberg, M. Nilbert, H. Grönberg, F. Granath, M. Eklund, T. Öresland, L.H. Iversen, C. Haapamäki, M. Janson, K. Westberg, J. Segelman, U. Ersson, M. Prytz, E. Angenete, R. Bergström, M. Mayrhofer, B. Glimelius, and J. Lindberg, for the ALASCCA Study Group. Journal: N Engl J Med 2025;393:1051-64. DOI: 10.1056/NEJMoa2504650

What is known about the subject

  • Emerging evidence suggests a role for aspirin in cancer prevention, particularly in colorectal cancer
  • Preclinical and clinical studies indicate that aspirin reduces the incidence of colorectal adenomas and cancer
  • The antineoplastic effects of aspirin are believed to occur primarily through the inhibition of cyclooxygenase-2 (COX-2), an enzyme frequently overexpressed in colorectal cancer
  • COX-2 promotes tumorigenesis by increasing the production of prostaglandin E2 (PGE2), which subsequently activates the phosphatidylinositol 3-kinase (PI3K) protein kinase B–mammalian target of rapamycin signaling pathway
  • The PI3K pathway is genetically altered in approximately one third of colorectal cancers; such alterations most commonly involve mutations in PIK3CA, PIK3R1, or PTEN

What the study adds

  • ALASCCA was a registry-based, multinational, double-blind, randomised, placebo-controlled trial integrated into the Swedish Colorectal Cancer Registry
  • 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
  • Eligibility criteria were reassessed after surgery. A total of 626 patients were randomly assigned to receive after surgery aspirin at a dose of 160 mg (157 patients with group A alterations and 156 with group B alterations) or matched placebo (157 and 156 patients, respectively) once daily
  • The estimated 3-year cumulative incidence of colorectal cancer recurrence among patients with group A alterations was 7.7% with aspirin and 14.1% with placebo
  • The hazard ratio for disease recurrence (aspirin vs. placebo) was 0.49 (95% confidence interval [CI], 0.24 to 0.98; P = 0.04).
  • Among patients with group B alterations, the estimated 3-year cumulative incidence of colorectal cancer recurrence was 7.7% with aspirin and 16.8% with placebo (hazard ratio, 0.42; 95% CI, 0.21 to 0.83)
  • The estimated disease-free survival at 3 years was 88.5% with aspirin and 81.4% with placebo (hazard ratio, 0.61; 95% CI, 0.34 to 1.08) in the cohort with group A alterations and 89.1% and 78.7%, respectively (hazard ratio, 0.51; 95% CI, 0.29 to 0.88), in the cohort with group B alterations

Implications for colorectal practice

  • In this biomarker-driven randomised trial, adjuvant aspirin led to a significantly lower incidence of recurrence among patients with resected colorectal cancer harbouring PIK3CA hotspot mutations in exon 9 or 20 than placebo over a 3-year period
  • Adjuvant aspirin appeared to have a similar benefit in patients with prespecified PIK3CA hotspot mutations and those with other somatic variants in PIK3CA, PIK3R1, or PTEN
  • Given that 1103 of the 2980 patients with complete genomic data in the current trial had somatic alterations in PI3K pathway genes, the findings provide evidence that aspirin may be an effective targeted adjuvant therapy in approximately 40% of patients with resected colorectal cancer

References

  1. A. Martling, I. Hed Myrberg, M. Nilbert, H. Grönberg, F. Granath, M. Eklund, T. Öresland, L.H. Iversen, C. Haapamäki, M. Janson, K. Westberg, J. Segelman, U. Ersson, M. Prytz, E. Angenete, R. Bergström, M. Mayrhofer,,17 B. Glimelius, and J. Lindberg, for the ALASCCA Study Group. Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer. N Engl J Med 2025;393:1051-64. DOI: 10.1056/NEJMoa2504650
  2. Rothwell PM, Wilson M, Elwin C-E, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010; 376: 1741-50.
  3. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 2007; 356: 2131-42.
  4. Cathomas G. PIK3CA in colorectal cancer. Front Oncol 2014; 4: 35
  5. Hall DCN, Benndorf RA. Aspirin sensitivity of PIK3CA-mutated colorectal cancer: potential mechanisms revisited. Cell Mol Life Sci 2022; 79: 393.