Biomarker Modulation by Aspirin and Metformin for Colorectal Cancer Prevention: Results from the ASAMET Randomized Phase II Trial

Purpose: Aspirin (Asa) and metformin (Met) have shown preventive efficacy in colorectal cancer (CRC). Preclinical data suggest convergence on NFκB/PI3K–mTOR signalling and potential synergy. The ASAMET phase II trial tested this hypothesis in patients with resected stage I–III CRC. Patients and Methods: In a 2 × 2 factorial, multicentre, double-blind study (EudraCT 2015-004824-77; NCT03047837), 51 patients were randomized to placebo, Asa 100 mg qd, Met 850 mg twice daily, or AsaMet for 12 months. Biopsies of normal colonic mucosa and fasting blood samples were obtained at baseline and 12 months. NFκB (primary endpoint), Ki67, EGFR, and pS6K were assessed by immunohistochemistry. Results: After 12 months, compared with placebo, Met reduced global NFκB by −9.04 (95% CI, −17.55 to −0.54; p = 0.04), whereas Asa alone was inactive (−3.58; 95% CI, −12.15 to 4.99; p = 0.41), and AsaMet showed a non-significant reduction (−8.88; 95% CI, −18.86 to 1.10; p = 0.08). Pooled analyses confirmed a Met-driven effect (Met vs non-Met: −7.29; 95% CI, −13.79 to −0.79; p = 0.03), with no impact of Asa (p = 0.73). Ki67 and pS6K were unchanged globally; however, AsaMet increased right-sided Ki67 (12.48; 95% CI, 0.45 to 24.51; p = 0.04). No treatment modulated pS6K. Toxicity was manageable, and no serious adverse events occurred. Conclusions: Met reduces NFκB expression in normal colorectal mucosa of CRC survivors, supporting its potential as a low-toxicity preventive agent. Aspirin did not favourably affect mucosal biomarkers. These findings support tissue-based endpoints and further evaluation of metformin for CRC prevention.