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
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2012

01-10-2012 | Clinical Trial

Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study

Authors: Saroj Niraula, Ryan J. O. Dowling, Marguerite Ennis, Martin C. Chang, Susan J. Done, Nicky Hood, Jaime Escallon, Wey Liang Leong, David R. McCready, Michael Reedijk, Vuk Stambolic, Pamela J. Goodwin

Published in: Breast Cancer Research and Treatment | Issue 3/2012

Login to get access

Abstract

Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant “window of opportunity” study of metformin in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood [fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin] attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13–40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (−0.5 kg/m2, p < 0.0001), weight (−1.2 kg, p < 0.0001), and HOMA (−0.21, p = 0.047) decreased significantly while non-significant decreases were seen in insulin (−4.7 pmol/L, p = 0.07), leptin (−1.3 ng/mL, p = 0.15) and CRP (−0.2 mg/L, p = 0.35). Ki67 staining in invasive tumor tissue decreased (from 36.5 to 33.5 %, p = 0.016) and TUNEL staining increased (from 0.56 to 1.05, p = 0.004). Short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed.
Literature
1.
Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3:1451–1461CrossRef
2.
Zhang ZJ, Zheng ZJ, Kan H, Song Y, Cui W, Zhao G, Kip KE (2011) Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care 34:2323–2328PubMedCrossRef
3.
Chlebowski RT, McTiernan A, Wactawski-Wende J, Manson JE, Aragaki AK, Rohan T, Ipp E, Kaklamani VG, Vitolins M, Wallace R, Gunter M, Phillips LS, Strickler H, Margolis K, Euhus DM (2012) Diabetes, metformin, and breast cancer in postmenopausal women. J Clin Oncol 30:2844–2852PubMedCrossRef
4.
5.
Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27:3297–3302PubMedCrossRef
6.
Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG (2008) Insulin-lowering effects of metformin in women with early breast cancer. Clin Breast Cancer 8:501–505PubMedCrossRef
7.
Duggan C, Irwin ML, Xiao L, Henderson KD, Smith AW, Baumgartner RN, Baumgartner KB, Bernstein L, Ballard-Barbash R, McTiernan A (2011) Associations of insulin resistance and adiponectin with mortality in women with breast cancer. J Clin Oncol 29:32–39PubMedCrossRef
8.
Emaus A, Veierod MB, Tretli S, Finstad SE, Selmer R, Furberg A-S, Bernstein L, Schlichting E, Thune I (2010) Metabolic profile, physical activity, and mortality in breast cancer patients. Breast Cancer Res Treat 121:651–660PubMedCrossRef
9.
Irwin ML, Duggan C, Wang CY, Smith AW, McTiernan A, Baumgartner RN, Baumgartner KB, Bernstein L, Ballard-Barbash R (2011) Fasting C-peptide levels and death resulting from all causes and breast cancer: the health, eating, activity, and lifestyle study. J Clin Oncol 29:47–53PubMedCrossRef
10.
Erickson K, Patterson RE, Flatt SW, Natarajan L, Parker BA, Heath DD, Laughlin GA, Saquib N, Rock CL, Pierce JP (2011) Clinically defined type 2 diabetes mellitus and prognosis in early-stage breast cancer. J Clin Oncol 29:54–60PubMedCrossRef
11.
Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Taylor SK, Hood N (2012) Insulin- and obesity-related variables in early-stage breast cancer: correlations and time course of prognostic associations. J Clin Oncol 30:164–171PubMedCrossRef
12.
Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R (2009) Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 230:586–623CrossRef
13.
Mulligan AM, O’Malley FP, Ennis M, Fantus IG, Goodwin PJ (2007) Insulin receptor is an independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res Treat 106:39–47PubMedCrossRef
14.
Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M (2006) Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66:10269–10273PubMedCrossRef
15.
Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67:10804–10812PubMedCrossRef
16.
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS March 31, 2003. http://​ctep.​cancer.​gov. Publish Date: 9 August 2006
17.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetology 28:412–419CrossRef
18.
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 28:2784–2795PubMedCrossRef
19.
Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118–145PubMedCrossRef
20.
Bloom HJ, Richardson WW (1957) Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 11:359–377PubMedCrossRef
21.
Elston CW, Ellis IO (1991) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410PubMedCrossRef
22.
Dowsett M, Nielsen TO, A’Hern R et al (2011) Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst 103:1656–1664PubMedCrossRef
23.
Dowsett M, Dixon JM, Horgan K, Salter J, Hills M, Harvey E (2000) Antiproliferative effects of idoxifene in a placebo-controlled trial in primary human breast cancer. Clin Cancer Res 6:2260–2267PubMed
24.
Niraula S, Stambolic V, Dowling R, Ennis M, Chang M, Done S, Hallak S, Hood N, Leong W, Escallon J, Goodwin PJ (2010) Clinical and biologic effects of metformin in early stage breast cancer. Cancer Res 70(24 Suppl):104sCrossRef
25.
Frassoldati A, Maur M, Guarneri V, Nicolini M, Conte PF (2005) Predictive value of biologic parameters for primary chemotherapy in operable breast cancer. Clin Breast Cancer 6:315–324PubMedCrossRef
26.
Archer CD, Parton M, Smith IE et al (2003) Early changes in apoptosis and proliferation following primary chemotherapy for breast cancer. Br J Cancer 89:1035–1041PubMedCrossRef
27.
Tomic T, Botton T, Cerezo M et al (2011) Metformin inhibits melanoma development through autophagy and apoptosis mechanisms. Cell Death Dis 2:e199PubMedCrossRef
28.
Yasmeen A, Beauchamp MC, Piura E, Segal E, Pollak M, Gotlieb WH (2011) Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecol Oncol 121:492–498PubMedCrossRef
29.
Malki A, Youssef A (2011) Antidiabetic drug metformin induces apoptosis in human MCF breast cancer via targeting ERK signaling. Oncol Res 19:275–285PubMedCrossRef
30.
Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE, Thor AD (2009) Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 8:2031–2040PubMedCrossRef
31.
Wang LW, Li ZS, Zou DW, Jin ZD, Gao J, Xu GM (2008) Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol 14:7192–7198PubMedCrossRef
32.
Li M, Liu J, Hu WL, Jia CH, Li HY, Wen ZH, Zou ZP, Bai XC, Luo SQ (2011) Effect of metformin on apoptosis of renal cell carcinoma cells in vitro and its mechanisms. Nan Fang Yi Ke Da Xue Xue Bao 31:1504–1508PubMed
33.
Zakikhani M, Blouin MJ, Piura E, Pollak MN (2010) Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res Treat 123:271–279PubMedCrossRef
34.
Hadad S, Iwamoto T, Jordan L et al (2011) Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial. Breast Cancer Res Treat 128:783–794PubMedCrossRef
35.
Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A, Gennari A, Trabacca MS, Galimberti V, Veronesi P, Johansson H, Aristarco V, Bassi F, Luini A, Lazzeroni M, Varricchio C, Viale G, Bruzzi P, Decensi A (2012) Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol 30:2593–2600PubMedCrossRef
36.
Ellis PA, Smith IE, Detre S, Burton SA, Salter J, A’Hern R, Walsh G, Johnston SR, Dowsett M (1998) Reduced apoptosis and proliferation and increased Bcl-2 in residual breast cancer following preoperative chemotherapy. Breast Cancer Res Treat 48:107–116PubMedCrossRef
37.
Romero Q, Bendahl PO, Klintman M, Loman N, Ingvar C, Ryden L, Rose C, Grabau D, Borgquist S (2011) Ki67 proliferation in core biopsies versus surgical samples—a model for neo-adjuvant breast cancer studies. BMC Cancer 11:341PubMedCrossRef
Metadata
Title
Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study
Authors
Saroj Niraula
Ryan J. O. Dowling
Marguerite Ennis
Martin C. Chang
Susan J. Done
Nicky Hood
Jaime Escallon
Wey Liang Leong
David R. McCready
Michael Reedijk
Vuk Stambolic
Pamela J. Goodwin
Publication date
01-10-2012
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-012-2223-1

Other articles of this Issue 3/2012

Breast Cancer Research and Treatment 3/2012 Go to the issue

Clinical trial

Reducing vasomotor symptoms with acupuncture in breast cancer patients treated with adjuvant tamoxifen: a randomized controlled trial

Preclinical Study

Is there ‘progression through grade’ in ductal invasive breast cancer?

Epidemiology

Treatment patterns and clinical outcomes in elderly patients with HER2-positive metastatic breast cancer from the registHER observational study

Review

Recommendations for the aesthetic evaluation of breast cancer conservative treatment

Brief Report

Xenografts faithfully recapitulate breast cancer-specific gene expression patterns of parent primary breast tumors

Preclinical Study

Genome-Wide Association Studies (GWAS) breast cancer susceptibility loci in Arabs: susceptibility and prognostic implications in Tunisians
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