Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Study protocol

The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients

Authors: Marilena Petrera, Laura Paleari, Matteo Clavarezza, Matteo Puntoni, Silvia Caviglia, Irene Maria Briata, Massimo Oppezzi, Eva Mihajlovic Mislej, Borut Stabuc, Michael Gnant, Thomas Bachleitner-Hofmann, Wilfried Roth, Dominique Scherer, Walter-E. Haefeli, Cornelia M. Ulrich, Andrea DeCensi

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials.

Methods/design

This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year.

Discussion

A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC.

Trial registration

EudraCT Number: 2015–004824-77; ClinicalTrial.​gov Identifier: NCT03047837. Registered on February 1, 2017.
Literature
1.
2.
McArdle CS, McMillan DC, Hole DJ. Male gender adversely affects survival following surgery for colorectal cancer. Br J Surg. 2003;90:711–5.CrossRefPubMed
3.
De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, et al. Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE--5-a population-based study. Lancet Oncol. 2014;15:23–34.CrossRefPubMed
4.
Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376:1741–50.CrossRefPubMed
5.
Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012;379:1602–12.CrossRefPubMed
6.
Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379:1591–601.CrossRefPubMed
7.
Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov. 2012;2:1091–9.CrossRefPubMedPubMedCentral
8.
Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367:1596–606.CrossRefPubMedPubMedCentral
9.
Paleari L, Puntoni M, Clavarezza M, DeCensi M, Cuzick J, DeCensi A. PIK3CA mutation, aspirin use after diagnosis and survival of colorectal cancer. A systematic review and meta-analysis of epidemiological studies. Clin Oncol (R Coll Radiol) 2016; 28: 317–326.CrossRefPubMed
10.
Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–85.CrossRefPubMedPubMedCentral
11.
Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr. 2001;131:3109S–20S.CrossRefPubMed
12.
Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, et al. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2010;3:1451–61.CrossRef
13.
Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, et al. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care. 2011;34:2323–8.CrossRefPubMedPubMedCentral
14.
Hosono K, Endo H, Takahashi H, Sugiyama M, Sakai E, Uchiyama T, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila). 2010;3:1077–83.CrossRef
15.
Higurashi T, Hosono K, Takahashi H, Komiya Y, Umezawa S, Sakai E, et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016;17:475–83.CrossRefPubMed
16.
Henry WS, Laszewski T, Beca F, Beck AH, McAllister SS, et al. Aspirin suppresses growth in PI3K-mutant breast Cancer by activating AMPK and inhibiting mTORC1 signaling. Cancer Res. 2017;77:790–801.CrossRefPubMed
17.
Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122:253–70.CrossRef
18.
Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res (Phila). 2008;1:369–75.CrossRef
19.
Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology. 2012;142:1504–15.CrossRefPubMed
20.
Yue W, Yang CS, DiPaola RS, Tan XL. Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev Res (Phila). 2014;7:388–97.CrossRef
21.
Kim HG, Hien TT, Han EH, Hwang YP, Choi JH, Kang KW, et al. Metformin inhibits p-glycoprotein expression via the nf-kappab pathway and cre transcriptional activity through ampk activation. Br J Pharmacol. 2011;162:1096–108.CrossRefPubMedPubMedCentral
22.
Chen J, Stark LA. Aspirin prevention of colorectal cancer: focus on NF-κB signalling and the nucleolus. Biomedicines. 2017;5:43.CrossRefPubMedCentral
23.
Yu HG, Yu LL, Yang Y, Luo HS, Yu JP, Meier JJ, et al. Increased expression of RelA/nuclear factor-kappa B protein correlates with colorectal tumorigenesis. Oncology. 2003;65:37–45.CrossRefPubMed
24.
Bernstein C, Bernstein H, Payne CM, Dvorak K, Garewal H. Field defects in progression to gastrointestinal tract cancers. Cancer Lett. 2008;260:1–10.CrossRefPubMed
25.
Hawthorn L, Lan L, Mojica W. Evidence for field effect cancerization in colorectal cancer. Genomics. 2014;103:211–21.CrossRefPubMed
26.
ASGE. Standards of practice committee, fisher DA, maple JT, ben-Menachem T, cash BD, Decker GA et al. Complications of colonoscopy Gastrointest Endosc. 2011;74:745–52.CrossRef
27.
Epstein O. Complications of colonoscopy. BSG Guidelines in Gastroenterology. 2006.
28.
Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut. 2012;61:847–54.CrossRefPubMed
29.
Puntoni M, Branchi D, Argusti A, Zanardi S, Crosta C, Meroni E, et al. A randomized, placebo-controlled, preoperative trial of allopurinol in patients with colorectal adenoma. Cancer Prev Res (Phila). 2013;6:74–81.CrossRef
30.
Lazar AA, Cole BF, Bonetti M, Gelber RD. Evaluation of treatment-effect heterogeneity using biomarkers measured on a continuous scale: subpopulation treatment effect pattern plot. J Clin Oncol. 2010;28:4539–44.CrossRefPubMedPubMedCentral
31.
Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Lancet. 2001;357:1191–4.CrossRefPubMed
Metadata
Title
The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients
Authors
Marilena Petrera
Laura Paleari
Matteo Clavarezza
Matteo Puntoni
Silvia Caviglia
Irene Maria Briata
Massimo Oppezzi
Eva Mihajlovic Mislej
Borut Stabuc
Michael Gnant
Thomas Bachleitner-Hofmann
Wilfried Roth
Dominique Scherer
Walter-E. Haefeli
Cornelia M. Ulrich
Andrea DeCensi
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-5126-7

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

Enrichment of cancer stem cells via β-catenin contributing to the tumorigenesis of hepatocellular carcinoma

Research article

Untargeted lipidomic features associated with colorectal cancer in a prospective cohort

Research article

Cathepsin K associates with lymph node metastasis and poor prognosis in oral squamous cell carcinoma

Research article

Microenvironment dependent gene expression signatures in reprogrammed human colon normal and cancer cell lines

Research article

Colorectal cancer survivors: an investigation of symptom burden and influencing factors

Research article

ARL2 overexpression inhibits glioma proliferation and tumorigenicity via down-regulating AXL
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits