Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR)

Jisun Kim, Woosung Lim, Eun-Kyu Kim, Min-Kyoon Kim, Nam-Sun Paik, Sang-Seol Jeong, Jung-Han Yoon, Chan Heun Park, Sei Hyun Ahn, Lee Su Kim, Sehwan Han, Seok Jin Nam, Han-Sung Kang, Seung Il Kim, Young Bum Yoo, Joon Jeong, Tae Hyun Kim, Taewoo Kang, Sung-Won Kim, Yongsik Jung, Jeong Eon Lee, Ku Sang Kim, Jong-Han Yu, Byung Joo Chae, So-Youn Jung, Eunyoung Kang, Su Yun Choi, Hyeong-Gon Moon, Dong-Young Noh, Wonshik Han, Jisun Kim, Woosung Lim, Eun-Kyu Kim, Min-Kyoon Kim, Nam-Sun Paik, Sang-Seol Jeong, Jung-Han Yoon, Chan Heun Park, Sei Hyun Ahn, Lee Su Kim, Sehwan Han, Seok Jin Nam, Han-Sung Kang, Seung Il Kim, Young Bum Yoo, Joon Jeong, Tae Hyun Kim, Taewoo Kang, Sung-Won Kim, Yongsik Jung, Jeong Eon Lee, Ku Sang Kim, Jong-Han Yu, Byung Joo Chae, So-Youn Jung, Eunyoung Kang, Su Yun Choi, Hyeong-Gon Moon, Dong-Young Noh, Wonshik Han

Abstract

Background: Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in patients with postmenopausal breast cancer. Preclinical and clinical studies have shown that the antidiabetic drug metformin has anti-tumor activity. This prospective, multicenter, phase II randomized, placebo controlled trial was designed to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with estrogen-receptor (ER) positive breast cancer.

Methods/design: Patients meeting the inclusion criteria and providing written informed consent will be randomized to 24 weeks of neoadjuvant treatment with letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Target accrual number is 104 patients per arm. The primary endpoint will be clinical response rate, as measured by calipers. Secondary endpoints include pathologic complete response rate, breast conserving rate, change in Ki67 expression, breast density change, and toxicity profile. Molecular assays will be performed using samples obtained before treatment, at week 4, and postoperatively.

Discussion: This study will provide direct evidence of the anti-tumor effect of metformin in non-diabetic, postmenopausal patients with ER-positive breast cancer.

Trial registration: ClinicalTrials.gov Identifier NCT01589367.

Figures

Figure 1
Figure 1
Scheme of the METEOR trial. Patients meeting the inclusion criteria will be 1:1 randomized to 24 weeks of letrozole plus metformin or letrozole plus placebo. Core needle biopsies will be recommended after 4 weeks of treatment. Surgery will be performed within 2 weeks after the end of the 24 week treatment period.

References

    1. Goodwin PJ, Stambolic V, Lemieux J, Chen BE, Parulekar WR, Gelmon KA, Hershman DL, Hobday TJ, Ligibel JA, Mayer IA, Pritchard KI, Whelan TJ, Rastogi P, Shepherd LE. Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res Treat. 2011;126(1):215–220. doi: 10.1007/s10549-010-1224-1.
    1. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Can Res. 2011;71(9):3196–3201. doi: 10.1158/0008-5472.CAN-10-3471.
    1. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27(20):3297–3302. doi: 10.1200/JCO.2009.19.6410.
    1. Garcia A, Tisman G. Metformin, B(12), and enhanced breast cancer response to chemotherapy. J Clin Oncol. 2010;28(2):e19. doi: 10.1200/JCO.2009.25.7857. author reply e20.
    1. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–1174. doi: 10.1172/JCI13505.
    1. Hawley SA, Gadalla AE, Olsen GS, Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes. 2002;51(8):2420–2425. doi: 10.2337/diabetes.51.8.2420.
    1. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006;66(21):10269–10273. doi: 10.1158/0008-5472.CAN-06-1500.
    1. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8(12):915–928. doi: 10.1038/nrc2536.
    1. Goodwin PJ, Ligibel JA, Stambolic V. Metformin in breast cancer: time for action. J Clin Oncol. 2009;27(20):3271–3273. doi: 10.1200/JCO.2009.22.1630.
    1. Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG. Insulin-lowering effects of metformin in women with early breast cancer. Clin Breast Cancer. 2008;8(6):501–505. doi: 10.3816/CBC.2008.n.060.
    1. 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. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol. 2012;30(21):2593–2600. doi: 10.1200/JCO.2011.39.3769.
    1. Martin M, Marais R. Metformin: a diabetes drug for cancer, or a cancer drug for diabetics? J Clin Oncol. 2012;30(21):2698–2700. doi: 10.1200/JCO.2012.42.1677.
    1. Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, Melnikova OA, Paltuev RM, Kletzel A, Berstein LM. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007;110(2):244–254. doi: 10.1002/cncr.22789.
    1. Mlineritsch B, Tausch C, Singer C, Luschin-Ebengreuth G, Jakesz R, Ploner F, Stierer M, Melbinger E, Menzel C, Urbania A, Fridrik M, Steger G, Wohlmuth P, Gnant M, Greil R. Austrian Breast, Colorectal Cancer Study Group(ABCSG) Exemestane as primary systemic treatment for hormone receptor positive post-menopausal breast cancer patients: a phase II trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-17) Breast Cancer Res Treat. 2008;112(1):203–213. doi: 10.1007/s10549-007-9843-x.
    1. Eiermann W, Paepke S, Appfelstaedt J, Llombart-Cussac A, Eremin J, Vinholes J, Mauriac L, Ellis M, Lassus M, Chaudri-Ross HA, Dugan M, Borgs M. Letrozole Neo-Adjuvant Breast Cancer Study Group. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol. 2001;12(11):1527–1532. doi: 10.1023/A:1013128213451.
    1. Baselga J, Semiglazov V, van Dam P, Manikhas A, Bellet M, Mayordomo J, Campone M, Kubista E, Greil R, Bianchi G, Steinseifer J, Mollow B, Tokaji E, Gardner H, Phillips P, Stumm M, Lane HA, Dixon JM, Jonat W, Rugo HS. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27(16):2630–2637. doi: 10.1200/JCO.2008.18.8391.
    1. Goldenberg N, Glueck CJ, Loftspring M, Sherman A, Wang P. Metformin-diet benefits in women with polycystic ovary syndrome in the bottom and top quintiles for insulin resistance. Metabolism. 2005;54(1):113–121. doi: 10.1016/j.metabol.2004.08.007.
    1. Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC, Esserman LJ, Unzeitig GW, Margenthaler J, Babiera GV, Marcom PK, Guenther JM, Watson MA, Leitch M, Hunt K, Olson AJ. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z103. J Clin Oncol. 2011;29(17):2342–2349. doi: 10.1200/JCO.2010.31.6950.
    1. Kim J, Han W, Moon HG, Ahn SK, Shin HC, You JM, Han SW, Im SA, Kim TY, Koo HR, Chang JM, Cho N, Moon WK, Noh DY. Breast density change as a predictive surrogate for response to adjuvant endocrine therapy in hormone receptor positive breast cancer. Breast Cancer Res. 2012;14(4):R102. doi: 10.1186/bcr3221.
    1. Nie K, Chen JH, Chan S, Chau MK, Yu HJ, Bahri S, Tseng T, Nalcioglu O, Su MY. Development of a quantitative method for analysis of breast density based on three-dimensional breast MRI. Med Phys. 2008;35(12):5253–5262. doi: 10.1118/1.3002306.
    1. Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL, McBurnie W, Fleming S, Alessi DR. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008;412(2):211–221. doi: 10.1042/BJ20080557.
    1. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Kovalenko IG, Poroshina TE, Semenchenko AV, Provinciali M, Re F, Franceschi C. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol. 2005;40(8–9):685–693.
    1. Anisimov VN, Egormin PA, Bershtein LM, Zabezhinskii MA, Piskunova TS, Popovich IG, Semenchenko AV. Metformin decelerates aging and development of mammary tumors in HER-2/neu transgenic mice. Bull Exp Biol Med. 2005;139(6):721–723. doi: 10.1007/s10517-005-0389-9.
    1. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. American Diabetes A. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193–203. doi: 10.2337/dc08-9025.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren