Phase I trial of exemestane in combination with metformin and rosiglitazone in nondiabetic obese postmenopausal women with hormone receptor-positive metastatic breast cancer.
OBJECTIVE
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 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.
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. fjesteva@mdanderson.org
Francisco J
FJ
Esteva
Stacy L
SL
Moulder
Ana M
AM
Gonzalez-Angulo
Joe
J
Ensor
James L
JL
Murray
Marjorie C
MC
Green
Kimberly B
KB
Koenig
Mong-Hong
MH
Lee
Gabriel N
GN
Hortobagyi
Sai-Ching
SC
Yeung
D000284:Administration, Oral; D000368:Aged; D000730:Androstadienes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008687:Metformin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009765:Obesity / Q000503:physiopathology*; D050177:Overweight / Q000503:physiopathology; D017698:Postmenopause; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors
D000730:Androstadienes; D000970:Antineoplastic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008687:Metformin; C056516:exemestane