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Published in: Breast Cancer Research and Treatment 1/2011

01-02-2011 | Brief Report

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

Authors: 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

Published in: Breast Cancer Research and Treatment | Issue 1/2011

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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.
Literature
1.
go back to reference 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 235:177–182CrossRefPubMed 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 235:177–182CrossRefPubMed
2.
go back to reference 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 344:783–792CrossRefPubMed 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 344:783–792CrossRefPubMed
3.
go back to reference 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; 7:153CrossRefPubMedPubMedCentral 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; 7:153CrossRefPubMedPubMedCentral
4.
go back to reference Bedard PL, de Azambuja E, Cardoso F (2009) Beyond trastuzumab: overcoming resistance to targeted HER-2 therapy in breast cancer. Curr Cancer Drug Targets 9:148–162CrossRefPubMed Bedard PL, de Azambuja E, Cardoso F (2009) Beyond trastuzumab: overcoming resistance to targeted HER-2 therapy in breast cancer. Curr Cancer Drug Targets 9:148–162CrossRefPubMed
5.
6.
go back to reference 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 29:254–258CrossRefPubMed 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 29:254–258CrossRefPubMed
7.
go back to reference Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E (2009) Sulphonylureas and cancer: a case–control study. Acta Diabetol 46:279–284CrossRefPubMed Monami M, Lamanna C, Balzi D, Marchionni N, Mannucci E (2009) Sulphonylureas and cancer: a case–control study. Acta Diabetol 46:279–284CrossRefPubMed
8.
go back to reference 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 32:1620–1625CrossRefPubMedPubMedCentral 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 32:1620–1625CrossRefPubMedPubMedCentral
9.
go back to reference Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777CrossRefPubMed Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777CrossRefPubMed
10.
go back to reference 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 33:1304–1308CrossRefPubMedPubMedCentral 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 33:1304–1308CrossRefPubMedPubMedCentral
11.
go back to reference 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 119:236–238CrossRefPubMed 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 119:236–238CrossRefPubMed
12.
go back to reference 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) 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)
13.
go back to reference Chlebowski RT, Aiello E, McTiernan A (2002) Weight loss in breast cancer patient management. J Clin Oncol 20:1128–1143CrossRefPubMed Chlebowski RT, Aiello E, McTiernan A (2002) Weight loss in breast cancer patient management. J Clin Oncol 20:1128–1143CrossRefPubMed
14.
go back to reference 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) 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)
15.
go back to reference Belfiore A, Frasca F (2008) IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 13:381–406CrossRefPubMed Belfiore A, Frasca F (2008) IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 13:381–406CrossRefPubMed
16.
go back to reference 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 27:3297–3302CrossRefPubMedPubMedCentral 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 27:3297–3302CrossRefPubMedPubMedCentral
17.
go back to reference 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 8:501–505CrossRefPubMed 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 8:501–505CrossRefPubMed
18.
go back to reference Vigneri P, Frasca F, Sciacca, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Rel Cancer 16:1103–1123CrossRef Vigneri P, Frasca F, Sciacca, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Rel Cancer 16:1103–1123CrossRef
19.
go back to reference 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 3:1077–1083CrossRef 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 3:1077–1083CrossRef
20.
go back to reference 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 108:1167–1174CrossRefPubMedPubMedCentral 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 108:1167–1174CrossRefPubMedPubMedCentral
21.
go back to reference 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 51:2420–2425CrossRefPubMed 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 51:2420–2425CrossRefPubMed
22.
go back to reference 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 66:10269–10273CrossRefPubMed 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 66:10269–10273CrossRefPubMed
23.
go back to reference 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) 1:369–375CrossRef 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) 1:369–375CrossRef
24.
go back to reference 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 3:18CrossRefPubMedPubMedCentral 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 3:18CrossRefPubMedPubMedCentral
25.
go back to reference 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 8:909–915CrossRefPubMed 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 8:909–915CrossRefPubMed
26.
go back to reference 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 69:7507–7511CrossRefPubMedPubMedCentral 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 69:7507–7511CrossRefPubMedPubMedCentral
27.
go back to reference 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 8:88–96CrossRefPubMed 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 8:88–96CrossRefPubMed
28.
go back to reference 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 20:592–595CrossRefPubMed 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 20:592–595CrossRefPubMed
29.
go back to reference 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 8:2031–2040CrossRefPubMed 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 8:2031–2040CrossRefPubMed
30.
go back to reference 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 114:387–389CrossRefPubMed 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 114:387–389CrossRefPubMed
31.
go back to reference 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 113:101–111CrossRefPubMed 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 113:101–111CrossRefPubMed
Metadata
Title
Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents
Authors
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
Publication date
01-02-2011
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-010-1224-1

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