Biomarker Modulation by Aspirin and Metformin for Colorectal Cancer Prevention: Results from the ASAMET Randomized Phase II Trial
10 affiliations
- 1Division of Medical Oncology, E.O. Galliera Hospital, Genoa, Italy.
- 2Institute of Pathology, University Medical Centre, Mainz, Germany.
- 3Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, Heidelberg, Germany.
- 4Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
- 5Division of Gastroenterology, E.O. Galliera Hospital, Genoa, Italy.
- 6Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
- 7Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria.
- 8Clinical and Epidemiological Research Unit, University Hospital of Parma, Parma, Italy.
- 9Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
- 10Clinical Centre, Champalimaud Foundation, Lisbon, Portugal.
Abstract
Purpose:: Aspirin (Asa) and metformin (Met) have shown preventive efficacy in colorectal cancer. Preclinical data suggest convergence on NF-κB/PI3K–mTOR signaling and potential synergy. The ASAMET phase II trial tested this hypothesis in patients with resected stage I to III colorectal cancer.
Patients and Methods:: In a 2 × 2 factorial, multicenter, double-blind study (EudraCT 2015-004824-77; NCT03047837), 51 patients were randomized to placebo, Asa 100 mg once daily, 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. NF-κB (primary endpoint), Ki67, EGFR, and pS6K were assessed by IHC.
Results:: After 12 months, compared with placebo, Met reduced global NF-κB by −9.04 [95% confidence interval (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 nonsignificant 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, 0.45–24.51; P = 0.04). No treatment modulated pS6K. Toxicity was manageable, and no serious adverse events occurred.
Conclusions:: Met reduces NF-κB expression in normal colorectal mucosa of survivors of colorectal cancer, supporting its potential as a low-toxicity preventive agent. Asa did not favorably affect mucosal biomarkers. These findings support tissue-based endpoints and further evaluation of Met for colorectal cancer prevention.
Significance:: The ASAMET trial provides the first randomized evidence that Met significantly modulates NF-κB expression in histologically normal colorectal mucosa of survivors of colorectal cancer. This finding supports a biologically plausible mechanism of action in secondary cancer prevention that could be exploited in the postadjuvant setting. Asa, by contrast, did not favorably affect any mucosal biomarker endpoint in this population. These results may support a phase III study of Met in this setting.
Trial Registration:: ClinicalTrials.gov Identifier: NCT03047837; EudraCT number: 2015-004824-77.
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BibTeX
@article{briata2026biomarker,
title = {{Biomarker Modulation by Aspirin and Metformin for Colorectal Cancer Prevention: Results from the ASAMET Randomized Phase II Trial}},
author = {Irene M. Briata and Alessio Carbone and Sebastian Foersch and Katrin E. Tagscherer and Wilfried Roth and Dominique Scherer and Tania Buttiron Webber and Matteo Clavarezza and Jürgen Burhenne and Martino Oliva and Mauro D’Amico and Giorgia Giancarli and Massimo Oppezzi and Paola Romagnoli and Mauro Dalla Libera and Borut Stabuc and Thomas Bachleitner-Hofmann and Marilena Petrera and Laura Paleari and Matteo Puntoni and Cornelia M. Ulrich and Andrea DeCensi},
journal = {Cancer Research Communications},
year = {2026},
month = nov,
doi = {10.1158/2767-9764.crc-26-0556},
url = {https://doi.org/10.1158/2767-9764.crc-26-0556},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Biomarker Modulation by Aspirin and Metformin for Colorectal Cancer Prevention: Results from the ASAMET Randomized Phase II Trial
AU - Irene M. Briata
AU - Alessio Carbone
AU - Sebastian Foersch
AU - Katrin E. Tagscherer
AU - Wilfried Roth
AU - Dominique Scherer
AU - Tania Buttiron Webber
AU - Matteo Clavarezza
AU - Jürgen Burhenne
AU - Martino Oliva
AU - Mauro D’Amico
AU - Giorgia Giancarli
AU - Massimo Oppezzi
AU - Paola Romagnoli
AU - Mauro Dalla Libera
AU - Borut Stabuc
AU - Thomas Bachleitner-Hofmann
AU - Marilena Petrera
AU - Laura Paleari
AU - Matteo Puntoni
AU - Cornelia M. Ulrich
AU - Andrea DeCensi
PY - 2026
DA - 2026/11/04
JO - Cancer Research Communications
DO - 10.1158/2767-9764.crc-26-0556
UR - https://doi.org/10.1158/2767-9764.crc-26-0556
AB - Purpose:: Aspirin (Asa) and metformin (Met) have shown preventive efficacy in colorectal cancer. Preclinical data suggest convergence on NF-κB/PI3K–mTOR signaling and potential synergy. The ASAMET phase II trial tested this hypothesis in patients with resected stage I to III colorectal cancer. Patients and Methods:: In a 2 × 2 factorial, multicenter, double-blind study (EudraCT 2015-004824-77; NCT03047837), 51 patients were randomized to placebo, Asa 100 mg once daily, 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. NF-κB (primary endpoint), Ki67, EGFR, and pS6K were assessed by IHC. Results:: After 12 months, compared with placebo, Met reduced global NF-κB by −9.04 [95% confidence interval (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 nonsignificant 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, 0.45–24.51; P = 0.04). No treatment modulated pS6K. Toxicity was manageable, and no serious adverse events occurred. Conclusions:: Met reduces NF-κB expression in normal colorectal mucosa of survivors of colorectal cancer, supporting its potential as a low-toxicity preventive agent. Asa did not favorably affect mucosal biomarkers. These findings support tissue-based endpoints and further evaluation of Met for colorectal cancer prevention. Significance:: The ASAMET trial provides the first randomized evidence that Met significantly modulates NF-κB expression in histologically normal colorectal mucosa of survivors of colorectal cancer. This finding supports a biologically plausible mechanism of action in secondary cancer prevention that could be exploited in the postadjuvant setting. Asa, by contrast, did not favorably affect any mucosal biomarker endpoint in this population. These results may support a phase III study of Met in this setting. Trial Registration:: ClinicalTrials.gov Identifier: NCT03047837; EudraCT number: 2015-004824-77.
SN - 2767-9764
ER -