Low-Dose Aspirin Reduces Recurrence Risk in PI3K-Mutated Colorectal Cancer
In this article
Published on 17 September 2025 in one of the world's most respected medical journals, New England Journal of Medicine (NEJM), the ALASCCA trialinvestigated whether aspirin reduces colorectal cancer recurrence.
📌 Brief Summary
In colorectal cancer patients whose tumors had alterations in PI3K-related genes , daily treatment with 160 mg aspirin (approximately half a baby aspirin tablet) significantly reduced recurrence risk. After 3 years of aspirin, recurrence was approximately 8% , compared with 14–17% without aspirin.
💡 Why Does It Matter?
Despite surgery and (neo)adjuvant therapy, recurrence remains a major colorectal cancer problem. Observational data suggested aspirin was protective, but randomized controlled evidence was lacking. ALASCCA provides patients with PI3K pathway alterations with prospective, placebo-controlled evidence that low-dose aspirin can reduce recurrence. It represents the first strong evidencein this setting.
🧠 What Is the PI3K Pathway?
PI3K–AKT–mTORis a communication networkcarrying signals for cell growth, proliferation and survival. Excessive activity causes uncontrolled growth, as occurs in cancer: the pathway remains active as though the accelerator were stuck .
- PIK3CA: Encodes the PI3K enzymes' catalytic (active) component, the pathway's engine.
- PIK3R1: Produces this engine's regulatory component (p85α), keeping its speed in check.
- PTEN: Acts as a brake that naturally suppresses PI3K signaling.
Which Genomic Alterations Affect This Pathway?
In cancer, PI3K signaling is often overactive because of genetic alterations . Common examples include:
- PIK3CA mutations (common): The best-known hotspots include those in exon 9: E542K, E545K (helical domain), and in exon 20: H1047R (kinase domain). These keep the engine permanently switched on .
- PIK3R1 mutations (less common): Weaken the regulatory subunit and may leave the engine without brakes.
- PTEN loss: The braking system fails. Mutation or deletion (loss of the gene), or methylation can cause reduced or absent PTEN protein.
📊 Frequency in Colorectal Cancer (CRC)
Frequency varies with the study, stage and measurement method. Approximate ranges:
| Gene / Alteration | Typical Change | Approximate CRC Frequency | Note |
|---|---|---|---|
| PIK3CA | Hotspot mutations (E542K, E545K, H1047R) | 15–20% (12–28% in some series) | Increases activation (the engine accelerates) |
| PIK3R1 | Loss-of-function mutations (uncommon) | 2–5% (low) | Weakens regulation (less control) |
| PTEN (mutation/deletion) | Tumor suppressor loss | 8–12% (mutation/deletion); protein loss by IHC: 10–35% | Removes the brake; increases signaling |
| Overall PI3K Pathway Alterations (PIK3CA/PIK3R1/PTEN combined) | — | ~30–40% (varies by study) | NEJM-ALASCCA screening identified 37% of patients |
Interpretation: Frequencies vary by population (localized/advanced disease), test type (DNA sequencing vs immunohistochemistry) and geography.
Current Study Design (NEJM 2025; ALASCCA)
- Population: Stage I–III rectal or Stage II–III colon cancer with tumor PI3K pathway alterations (PIK3CA, PIK3R1, PTEN). Among patients with complete genomic data, 37.0%(1103/2980) had these alterations.
- Groups:
- Group A: PIK3CA exon 9/20 hotspot mutations.
- Group B: Other moderate/high-impact PIK3CA/PIK3R1/PTEN variants.
- Intervention: Aspirin 160 mg/day vs placebo, 3 years, double-blind, 1:1 randomization.
- Primary Endpoint: Colorectal cancer recurrence (time-to-event), assessed in Group A.
- Secondary: Recurrence in Group B, disease-free survival (DFS)and safety.
- Registrations: NCT02647099; EudraCT 2015-004240-19.
📊 Main Results (3 Years)
| Outcome | Aspirin | Placebo | Effect (HR, 95% CI) |
|---|---|---|---|
| Recurrence (Group A) – PIK3CA exon 9/20 | 7.7% | 14.1% | 0.49 (0.24–0.98); p=0.04 |
| Recurrence (Group B) – other PI3K/PTEN | 7.7% | 16.8% | 0.42 (0.21–0.83) |
| DFS (Group A) | 88.5% | 81.4% | HR 0.61 (0.34–1.08) |
| DFS (Group B) | 89.1% | 78.7% | HR 0.51 (0.29–0.88) |
Note: HR <1 favors aspirin; values are the estimated cumulative rates reported in the study.
⚠️ Safety and Bleeding Risk
- Serious Adverse Events: Aspirin 16.8% vs Placebo 11.6%.
- Typical risks: gastrointestinal bleeding, peptic ulcer exacerbation and, rarely, hemorrhagic stroke.
- Selection and Monitoring: Use caution with high bleeding risk, including active ulcers, anticoagulants, thrombocytopenia or older age. Consider PPI co-treatment and monitoring where appropriate.
🎯 Clinical Implications: Who, When and How?
- Target Population: Stage I–III patients whose tumors have PIK3CA exon 9/20 hotspot mutations or other significant PI3K/PTEN variants.
- Timing: After adjuvant/neoadjuvant treatment is completed, 3 years of low-dose aspirin (160 mg/day) to reduce recurrence risk may be considered.
- Prerequisite: Molecular testing to confirm PI3K pathway alterations.
- Decision-Making: Account for bleeding risk, concomitant medications and patient preferences through shared decision-making.
- Follow-Up: At clinical visits, ask about bleeding symptoms ; monitor Hb and ferritin if needed.
🧬 Possible Mechanism: Aspirin in the PI3K–COX Axis
Aspirin inhibits COX-1/COX-2, reducing prostaglandin synthesis and potentially suppressing PI3K/AKT pathway-associated proliferative signals and inflammation. PIK3CA-mutated tumors may experience a clinically meaningful effect on micrometastatic burden during adjuvant treatment when this axis is suppressed.
🔎 Limitations and Open Questions
- Dose and Duration: 160 mg/day for 3 years was studied; equivalence of lower doses remains uncertain.
- Bleeding risk varies; the net benefit–risk balance should be individualized in older patients and those taking anticoagulants.
- Further confirmatory data are needed on real-world adherence and long-term outcomes.
📚 Sources
Martling A, Myrberg IH, Nilbert M, Grönberg H, Granath F, Eklund M, Öresland T, et al. Low-Dose Aspirin for PI3K-Altered Localized Colorectal Cancer. N Engl J Med. 17 September 2025; 393:1051-1064. DOI: 10.1056/NEJMoa2504650.
Goldberg RM, Meyerhardt JA. An Aspirin a Day for Improved Colorectal Cancer Outcomes. N Engl J Med. 17 September 2025; 393:1131-1132. DOI: 10.1056/NEJMe2508634.
Was this article helpful?
Your feedback helps us improve our content.
Reader comments
Share your comment
Your name and comment are published only after administrator approval. Your email address is never shown to visitors.
Be the first to comment.