Advertisement

Breast Cancer Research and Treatment

, Volume 126, Issue 1, pp 215–220 | Cite as

Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents

  • Pamela J. Goodwin
  • Vuk Stambolic
  • Julie Lemieux
  • Bingshu E. Chen
  • Wendy R. Parulekar
  • Karen A. Gelmon
  • Dawn L. Hershman
  • Timothy J. Hobday
  • Jennifer A. Ligibel
  • Ingrid A. Mayer
  • Kathleen I. Pritchard
  • Timothy J. Whelan
  • Priya Rastogi
  • Lois E. Shepherd
Brief Report

Abstract

Metformin, an inexpensive oral agent commonly used to treat type 2 diabetes, has been garnering increasing attention as a potential anti-cancer agent. Preclinical, epidemiologic, and clinical evidences suggest that metformin may reduce overall cancer risk and mortality, with specific effects in breast cancer. The extensive clinical experience with metformin, coupled with its known (and modest) toxicity, has allowed the traditional process of drug evaluation to be shortened. We review the rationale for a modified approach to evaluation and outline the key steps that will optimize development of this agent in breast cancer, including discussion of a Phase III adjuvant trial (NCIC MA.32) that has recently been initiated.

Keywords

Breast cancer Metformin Adjuvant Clinical testing 

References

  1. 1.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182CrossRefPubMedGoogle Scholar
  2. 2.
    Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792CrossRefPubMedGoogle Scholar
  3. 3.
    Viani GA, Alfonso SL, STafano EJ, De Fendi LI, Soares FV (2007) Adjuvant trastuzumab in the treatment of her-2 positive early breast cancer: a meta-analysis of published randomized studies. BMC Cancer; 7:153CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bedard PL, de Azambuja E, Cardoso F (2009) Beyond trastuzumab: overcoming resistance to targeted HER-2 therapy in breast cancer. Curr Cancer Drug Targets 9:148–162CrossRefPubMedGoogle Scholar
  5. 5.
    Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bowker SL, Majumdar SR, Veugelers P, Johnson JA (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29:254–258CrossRefPubMedGoogle Scholar
  7. 7.
    Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E (2009) Sulphonylureas and cancer: a case–control study. Acta Diabetol 46:279–284CrossRefPubMedGoogle Scholar
  8. 8.
    Libby G, Donnelly LA, Donnan PT, Alessi Dr, Morris AD, Evans JM (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620–1625CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777CrossRefPubMedGoogle Scholar
  10. 10.
    Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR (2010) Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 33:1304–1308CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Pasanisi P, Berrino F, De Petris M, Venturelli E, Mastroianni A, Panico S (2006) Metabolic syndrome as a prognostic factor for breast cancer recurrences. Int J Cancer 119:236–238CrossRefPubMedGoogle Scholar
  12. 12.
    Pollak MN, Chapman JW, Shepherd L, Meng D, Richardson P, Wilson C et al (2006) Insulin resistance, estimated by serum C-peptide level, is associated with reduced event-free survival for postmenopausal women in NCIC CTG MA.14 adjuvant breast cancer trial. J Clin Oncol 24(Suppl 18S):(Abstr 524)Google Scholar
  13. 13.
    Chlebowski RT, Aiello E, McTiernan A (2002) Weight loss in breast cancer patient management. J Clin Oncol 20:1128–1143CrossRefPubMedGoogle Scholar
  14. 14.
    Goodwin PJ, Pritchard KI, Ennis M, Koo J, Hood N (2009) Long-term effects of fasting insulin in early stage breast cancer patients. Eur J Cancer Suppl 7:308 (abstr P-5160)Google Scholar
  15. 15.
    Belfiore A, Frasca F (2008) IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 13:381–406CrossRefPubMedGoogle Scholar
  16. 16.
    Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM et al (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27:3297–3302CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    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 8:501–505CrossRefPubMedGoogle Scholar
  18. 18.
    Vigneri P, Frasca F, Sciacca, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Rel Cancer 16:1103–1123CrossRefGoogle Scholar
  19. 19.
    Hosono K, Endo H, Takahashi H, Sugiyama M, Sakai E, Uchiyama T et al (2010) Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res 3:1077–1083CrossRefGoogle Scholar
  20. 20.
    Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Hawley SA, Gadalla AE, Olsen GS, Hardie DG (2002) The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 51:2420–2425CrossRefPubMedGoogle Scholar
  22. 22.
    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 66:10269–10273CrossRefPubMedGoogle Scholar
  23. 23.
    Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN (2008) The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res (Phila Pa) 1:369–375CrossRefGoogle Scholar
  24. 24.
    Zhuang Y, Miskimins WK (2008) Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal 3:18CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE et al (2009) Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 8:909–915CrossRefPubMedGoogle Scholar
  26. 26.
    Hirsch HA, Iliopoulos D, Tsichlis PN (2009) Struhl K (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69:7507–7511CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA (2009) The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle 8:88–96CrossRefPubMedGoogle Scholar
  28. 28.
    Vazquez-Martin A, Oliveras-Ferraros C, del Barco S, Martin-Castillo B, Menendez JA (2009) The antidiabetic drug metformin: a pharmaceutical AMPK activator to overcome breast cancer resistance to HER2 inhibitors while decreasing risk of cardiomyopathy. Ann Oncol 20:592–595CrossRefPubMedGoogle Scholar
  29. 29.
    Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lilnd SE et al (2009) Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 8:2031–2040CrossRefPubMedGoogle Scholar
  30. 30.
    Stambolic V, Woodgett JR, Fantus IG, Pritchard KI, Goodwin PJ (2009) Utility of metformin in breast cancer treatment, is neoangiogenesis a risk factor? Breast Cancer Res Treat 114:387–389CrossRefPubMedGoogle Scholar
  31. 31.
    Phoenix KN, Vumbaca F, Claffey KP (2009) Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer Res Treat 113:101–111CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Pamela J. Goodwin
    • 1
  • Vuk Stambolic
    • 2
  • Julie Lemieux
    • 3
  • Bingshu E. Chen
    • 4
  • Wendy R. Parulekar
    • 4
  • Karen A. Gelmon
    • 5
  • Dawn L. Hershman
    • 6
  • Timothy J. Hobday
    • 7
  • Jennifer A. Ligibel
    • 8
  • Ingrid A. Mayer
    • 9
  • Kathleen I. Pritchard
    • 10
  • Timothy J. Whelan
    • 11
  • Priya Rastogi
    • 12
    • 13
  • Lois E. Shepherd
    • 4
  1. 1.Department of Medicine, Division of Clinical Epidemiology at the Samuel Lunenfeld Research InstituteMount Sinai Hospital, University of TorontoTorontoCanada
  2. 2.Division of Signaling Biology, Ontario Cancer InstituteUniversity Health NetworkTorontoCanada
  3. 3.Centre Hospitalier Affilié Universitaire de QuébecUniversité Laval Quebec CityCanada
  4. 4.NCIC Clinical Trials GroupQueen’s UniversityKingstonCanada
  5. 5.British Columbia Cancer AgencyUniversity of British ColumbiaVancouverCanada
  6. 6.Department of MedicineColumbia University Medical CenterNew YorkUSA
  7. 7.Department of OncologyMayo Clinic College of MedicineRochesterUSA
  8. 8.Dana Farber Cancer InstituteBostonUSA
  9. 9.Division of Hematology/Oncology, Department of MedicineVanderbilt University Medical CenterNashvilleUSA
  10. 10.Sunnybrook Odette Cancer CentreUniversity of TorontoTorontoCanada
  11. 11.Department of Radiation Oncology, Cancer Care OntarioJuravinski Cancer CenterHamiltonCanada
  12. 12.National Surgical Adjuvant Breast and Bowel Project (NSABP)PittsburghUSA
  13. 13.University of Pittsburgh Cancer Institute (UPCI), University of PittsburghPittsburghUSA

Personalised recommendations