Aspirin for PI3K-altered localised colorectal cancer

PI3K and colorectal cancer

• PI3Ks belong to a family of plasma membrane-associated lipid kinases that can phosphorylate the 3′ hydroxyl group of phosphatidylinositol and phosphoinositide (1):
  • are divided into three classes, I, II, and III, based on their structures and functions
  • class IA PI3Ks, which are activated by receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and certain oncoproteins such as the small G-protein rat sarcoma virus (RAS), and class IB PI3Ks, are regulated exclusively by GPCRs
  • class I PI3Ks are the best characterized and generally coupled to extracellular stimuli
  • class 1A PI3Ks are divided into three subclasses (α, β, and δ), and class 1B is denoted as γ
    • PI3Kα and PI3Kβ are ubiquitously expressed, and PI3Kδ and PI3Kγ are mainly found in leucocytes and blood vessels
  • class IA PI3Ks have been reported to be implicated in human cancer
  • aberrant PI3K/Akt/mTOR signaling pathway is a major resistance mechanism to colorectal cancer therapy

Observational studies suggest that aspirin may improve disease-free survival after colorectal cancer diagnosis, particularly among patients with tumors harboring somatic PIK3CA mutations (2).

A study investigated the use of aspirin in colorectal cancer 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) (2):

• 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
• patients were assigned in a 1:1 ratio to receive 160 mg of aspirin or matched placebo once daily for 3 years
• primary end point was colorectal cancer recurrence
• 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
  • estimated 3-year cumulative incidence of recurrence was 7.7% with aspirin and 14.1% with placebo (hazard ratio, 0.49) among patients with group A alterations and 7.7% and 16.8%, respectively (hazard ratio, 0.42) among those with group B alterations
  • estimated 3-year disease-free survival was 88.5% with aspirin and 81.4% with placebo among patients with group A alterations and 89.1% and 78.7%, respectively, among those with group B alterations
• study authors concluded that
  • 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

Reference:

1. Leiphrakpam PD, Are C. PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment. Int J Mol Sci. 2024 Mar 9;25(6):3178.
2. Martling A et al. Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer. N Engl J Med 2025;393:1051-1064