Phase I trial of exemestane in combination with metformin and rosiglitazone in nondiabetic obese postmenopausal women wi
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ORIGINAL ARTICLE
Phase I trial of exemestane in combination with metformin and rosiglitazone in nondiabetic obese postmenopausal women with hormone receptor–positive metastatic breast cancer Francisco J. Esteva • Stacy L. Moulder • Ana M. Gonzalez-Angulo • Joe Ensor • James L. Murray • Marjorie C. Green • Kimberly B. Koenig Mong-Hong Lee • Gabriel N. Hortobagyi • Sai-Ching Yeung
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Received: 27 April 2012 / Accepted: 13 September 2012 / Published online: 28 September 2012 Ó Springer-Verlag Berlin Heidelberg 2012
Abstract Purpose Obese women with breast cancer have worse prognosis than women with normal body mass index. Endocrine therapy resistance is in part mediated by insulin resistance in obese women with breast cancer. We investigated the tolerability and pharmacokinetics of exemestane in combination with metformin and rosiglitazone in nondiabetic overweight and obese postmenopausal women with hormone receptor–positive metastatic breast cancer. Methods Patients had previously received chemotherapy and endocrine therapy for breast cancer. Exemestane was given as 25 mg orally per day. Metformin (M) and rosiglitazone (R) were given twice daily. Dose level 1 consisted of M 1,500 mg/day and R 6 mg/day. Dose level 2 consisted
F. J. Esteva (&) S. L. Moulder A. M. Gonzalez-Angulo J. L. Murray M. C. Green K. B. Koenig G. N. Hortobagyi Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1354, Houston, TX 77030, USA e-mail: [email protected] J. Ensor Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA M.-H. Lee Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA S.-C. Yeung Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA S.-C. Yeung Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
of M 2,000 mg/day and R 8 mg/day. Plasma concentrations of exemestane were measured on days 1, 8, and 15. Results Twenty patients were enrolled. Fourteen patients received exemestane, metformin, and rosiglitazone. Six patients received exemestane with metformin only (2,000 mg/day). Both regimens were well tolerated at the highest doses tested, and there were no notable changes in plasma exemestane levels. Six patients (30 %) had stable disease for 6 months or longer. Conclusions Oral daily administration of exemestane (25 mg) and metformin (2,000 mg) with and without rosiglitazone (8 mg) daily was well tolerated. Exemestane pharmacokinetics were not altered by metformin and rosiglitazone. Keywords Breast neoplasm Exemestane Metformin Rosiglitazone Phase I trial
Introduction Obesity is associated with an increased risk of developing postmenopausal breast cancer and is an independent prognostic factor in patients who have been diagnosed with breast cancer [23]. Up to 50 % of postmenopausal breast cancer deaths in the Uni
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