Breast Cancer Research and Treatment

, Volume 135, Issue 3, pp 821–830 | Cite as

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

  • 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
Clinical Trial


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.


Breast cancer Metformin Neoadjuvant Ki67 TUNEL Insulin 



This research was supported by a Grant from Susan G. Komen for the Cure. Dr. Dowling is supported by a Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research.

Conflict of interest

Dr. Chang acknowledges funding from Hoffmann-LaRoche. The remaining authors declare that they have no conflicts of interest.

Ethical standards

Conduct of this study at Mount Sinai and Princess Margaret Hospitals was performed in compliance with the standards of the Ontario Cancer Research Ethics Board.


  1. 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) 3:1451–1461CrossRefGoogle Scholar
  2. 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 34:2323–2328PubMedCrossRefGoogle Scholar
  3. 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 30:2844–2852PubMedCrossRefGoogle Scholar
  4. 4.
    Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT (2012) Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat. doi: 10.1007/s10549-012-2170-x PubMedGoogle Scholar
  5. 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 27:3297–3302PubMedCrossRefGoogle Scholar
  6. 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 8:501–505PubMedCrossRefGoogle Scholar
  7. 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 29:32–39PubMedCrossRefGoogle Scholar
  8. 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 121:651–660PubMedCrossRefGoogle Scholar
  9. 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 29:47–53PubMedCrossRefGoogle Scholar
  10. 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 29:54–60PubMedCrossRefGoogle Scholar
  11. 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 30:164–171PubMedCrossRefGoogle Scholar
  12. 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 230:586–623CrossRefGoogle Scholar
  13. 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 106:39–47PubMedCrossRefGoogle Scholar
  14. 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 66:10269–10273PubMedCrossRefGoogle Scholar
  15. 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 67:10804–10812PubMedCrossRefGoogle Scholar
  16. 16.
    Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS March 31, 2003. Publish Date: 9 August 2006
  17. 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 28:412–419CrossRefGoogle Scholar
  18. 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 28:2784–2795PubMedCrossRefGoogle Scholar
  19. 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 25:118–145PubMedCrossRefGoogle Scholar
  20. 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 11:359–377PubMedCrossRefGoogle Scholar
  21. 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 19:403–410PubMedCrossRefGoogle Scholar
  22. 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 103:1656–1664PubMedCrossRefGoogle Scholar
  23. 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 6:2260–2267PubMedGoogle Scholar
  24. 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):104sCrossRefGoogle Scholar
  25. 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 6:315–324PubMedCrossRefGoogle Scholar
  26. 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 89:1035–1041PubMedCrossRefGoogle Scholar
  27. 27.
    Tomic T, Botton T, Cerezo M et al (2011) Metformin inhibits melanoma development through autophagy and apoptosis mechanisms. Cell Death Dis 2:e199PubMedCrossRefGoogle Scholar
  28. 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 121:492–498PubMedCrossRefGoogle Scholar
  29. 29.
    Malki A, Youssef A (2011) Antidiabetic drug metformin induces apoptosis in human MCF breast cancer via targeting ERK signaling. Oncol Res 19:275–285PubMedCrossRefGoogle Scholar
  30. 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 8:2031–2040PubMedCrossRefGoogle Scholar
  31. 31.
    Wang LW, Li ZS, Zou DW, Jin ZD, Gao J, Xu GM (2008) Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol 14:7192–7198PubMedCrossRefGoogle Scholar
  32. 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 31:1504–1508PubMedGoogle Scholar
  33. 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 123:271–279PubMedCrossRefGoogle Scholar
  34. 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 128:783–794PubMedCrossRefGoogle Scholar
  35. 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 30:2593–2600PubMedCrossRefGoogle Scholar
  36. 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 48:107–116PubMedCrossRefGoogle Scholar
  37. 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 11:341PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Saroj Niraula
    • 1
  • Ryan J. O. Dowling
    • 2
  • Marguerite Ennis
    • 3
  • Martin C. Chang
    • 4
    • 5
  • Susan J. Done
    • 5
    • 6
  • Nicky Hood
    • 7
  • Jaime Escallon
    • 8
    • 9
  • Wey Liang Leong
    • 9
    • 10
  • David R. McCready
    • 8
    • 9
  • Michael Reedijk
    • 9
    • 10
  • Vuk Stambolic
    • 2
  • Pamela J. Goodwin
    • 1
    • 7
  1. 1.Division of Medical Oncology and Hematology, Department of MedicineMount Sinai Hospital and Princess Margaret Hospital, University of TorontoTorontoCanada
  2. 2.Ontario Cancer Institute, University Health NetworkTorontoCanada
  3. 3.Applied StatisticianMarkhamCanada
  4. 4.Department of Pathology and Laboratory MedicineMount Sinai HospitalTorontoCanada
  5. 5.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  6. 6.Campbell Family Institute for Breast Cancer Research and Laboratory Medicine ProgramUniversity Health NetworkTorontoCanada
  7. 7.Division of Clinical EpidemiologySamuel Lunenfeld Research Institute, Mount Sinai HospitalTorontoCanada
  8. 8.Department of SurgeryMount Sinai Hospital, University of TorontoTorontoCanada
  9. 9.Department of Surgical OncologyUniversity Health Network, University of TorontoTorontoCanada
  10. 10.Campbell Family Institute for Breast Cancer ResearchPrincess Margaret HospitalTorontoCanada

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