Over The Counter Medication: A Game-Changer for PI3K-Altered Colorectal Cancer?

Sawyer Bawek, DO University at Buffalo

The latest randomized, placebo-controlled trial published in the New England Journal of Medicine evaluated the use of low-dose aspirin in individuals with stage I-III rectal or stage II or III colon cancer. The study, titled “Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer,” discusses whether a simple over the counter pill could significantly reduce the risk of colorectal cancer recurrence in individuals with PI3K pathway alterations.

What is the Significance of the PI3K Pathway?

PI3K alterations lead to hyperactivation of the PI3K-AKT-mTOR pathway, which promote tumor growth. The inhibition of COX-1 and COX-2 with aspirin helps reduce prostaglandin E2 levels, which downregulates PI3K signaling. 

  Study Design: 

• This is a multicenter, double-blind, placebo-controlled trial (NCT02647099) evaluating patients with stage I-III rectal cancer or stage II or III colon cancer with somatic alterations in PI3K pathway (PIK3CA mutation, PTEN loss, or PI3K overexpression) via next-generation sequencing (NGS) on tumor tissue.
• Eligible patients were assigned 1:1 to receive 160 mg of aspirin or a matched placebo for 3 years.
• The primary end point was colorectal cancer recurrence (Group A), with secondary end points (Group B) of disease-free survival (DFS) and safety. 

Key Findings: 

• Group A: Three-year cumulative incidence was 7.7% in the aspirin arm compared to 14.1% in the placebo arm [HR] 0.49; P = 0.04.
• Group B: Reduction from 16.8% to 7.7% (HR 0.42).
• DFS Trends: At 3 years, DFS rates were 82% in individuals who received aspirin versus 70% in those who received placebo (stage II/III patients).
• Subset Signals: Benefits were consistent across PIK3CA hotspots and PTEN-deficient tumors.
• OS Trends: Early but promising—HR: 0.68 (P = 0.06), hinting at survival gains with longer follow-up.
• Safety: Aspirin was well-tolerated, with GI bleeds in just 2.1% versus 1.4% (placebo) and no excess cardiovascular events. 

Key Takeaways for Community Oncologists

• Screen for PI3K Alterations: Routine NGS on resected CRC could benefit individuals with PI3K. 
• Patient Selection: Aspirin’s risks and benefits should be considered, particularly for those at a higher bleeding risk. 
• Cost-Effective Precision Medicine: Aspirin is a globally accessible option, helping reduce disparities in care and potentially lowering recurrence rates in community settings. 
• Easy Integration: Incorporating low-dose aspirin into adjuvant therapy protocols is straightforward, requiring minimal changes to existing workflows. It can be prescribed alongside standard treatments, with regular monitoring for side effects like GI bleeding.

Implications for Clinical Practice

The trial’s findings underscore the potential of low-dose aspirin as an adjuvant therapy for PI3K-altered colorectal cancer. For community oncologists, this presents an opportunity to enhance patient outcomes using an accessible, well-studied drug. By integrating NGS into routine practice, clinicians can identify eligible patients and include aspirin where appropriate. The consistent benefits across PIK3CA mutations and PTEN-deficient tumors.

Moreover, the safety profile supports its use in most patients, though careful monitoring for GI bleeding and other risks is essential. The early OS trends are encouraging, and ongoing follow-up data may further clarify aspirin’s role in improving long-term survival. This approach aligns with the growing emphasis on precision medicine, offering a scalable solution.