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Phase I trial of exemestane in combination with metformin and rosiglitazone in nondiabetic obese postmenopausal women with hormone receptor–positive metastatic breast cancer

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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 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.

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References

  1. Alimova IN, Liu B, Fan Z et al (2009) Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 8:909–915

    Article  PubMed  CAS  Google Scholar 

  2. Anisimov VN, Berstein LM, Egormin PA et al (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40:685–693

    Article  PubMed  CAS  Google Scholar 

  3. Benson JR, Jatoi I, Keisch M et al (2009) Early breast cancer. Lancet 373:1463–1479

    Article  PubMed  Google Scholar 

  4. Brewster AM, Hortobagyi GN, Broglio KR et al (2008) Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst 100:1179–1183

    Article  PubMed  Google Scholar 

  5. Corona G, Elia C, Casetta B et al (2009) A liquid chromatography-tandem mass spectrometry method for the simultaneous determination of exemestane and its metabolite 17-dihydroexemestane in human plasma. J Mass Spectrom 44:920–928

    Article  PubMed  CAS  Google Scholar 

  6. Dirix LY, Ignacio J, Nag S et al (2008) Treatment of advanced hormone-sensitive breast cancer in postmenopausal women with exemestane alone or in combination with celecoxib. J Clin Oncol 26:1253–1259

    Article  PubMed  CAS  Google Scholar 

  7. Elstner E, Williamson EA, Zang C et al (2002) Novel therapeutic approach: ligands for PPARgamma and retinoid receptors induce apoptosis in bcl-2-positive human breast cancer cells. Breast Cancer Res Treat 74:155–165

    Article  PubMed  CAS  Google Scholar 

  8. Esteva FJ (2004) Monoclonal antibodies, small molecules, and vaccines in the treatment of breast cancer. Oncologist 9:4–9

    Article  PubMed  CAS  Google Scholar 

  9. Esteva FJ, Glaspy J, Baidas S et al (2003) Multicenter phase II study of oral bexarotene for patients with metastatic breast cancer. J Clin Oncol 21:999–1006

    Article  PubMed  CAS  Google Scholar 

  10. Esteva FJ, Hortobagyi GN (1999) Locally advanced breast cancer. Hematol Oncol Clin North Am 13:457–472

    Article  PubMed  CAS  Google Scholar 

  11. Esteva FJ, Hortobagyi GN (2004) Prognostic molecular markers in early breast cancer. Breast Cancer Res 6:109–118

    Article  PubMed  CAS  Google Scholar 

  12. Esteva FJ, Hortobagyi GN (2006) Comparative assessment of lipid effects of endocrine therapy for breast cancer: implications for cardiovascular disease prevention in postmenopausal women. Breast 15:301–312

    Article  PubMed  CAS  Google Scholar 

  13. Esteva FJ, Sahin AA, Cristofanilli M et al (2002) Molecular prognostic factors for breast cancer metastasis and survival. Semin Radiat Oncol 12:319–328

    Article  PubMed  Google Scholar 

  14. Fonseca V, Rosenstock J, Patwardhan R et al (2000) Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 283:1695–1702

    Article  PubMed  CAS  Google Scholar 

  15. Han C, Zhang HT, Du L et al (2005) Serum levels of leptin, insulin, and lipids in relation to breast cancer in China. Endocrine 26:19–24

    Article  PubMed  CAS  Google Scholar 

  16. Hankinson SE, Schernhammer ES (2003) Insulin-like growth factor and breast cancer risk: evidence from observational studies. Breast Dis 17:27–40

    PubMed  CAS  Google Scholar 

  17. Hutson PR, Love RR, Havighurst TC et al (2005) Effect of exemestane on tamoxifen pharmacokinetics in postmenopausal women treated for breast cancer. Clin Cancer Res 11:8722–8727

    Article  PubMed  CAS  Google Scholar 

  18. Jaffe CC (2006) Measures of response: RECIST, WHO, and new alternatives. J Clin Oncol 24:3245–3251

    Article  PubMed  Google Scholar 

  19. Jin Q, Esteva FJ (2008) Cross-talk between the ErbB/HER family and the type i insulin-like growth factor receptor signaling pathway in breast cancer. J Mammary Gland Biol Neoplasia 13:485–498

    Article  PubMed  Google Scholar 

  20. Jiralerspong S, Palla SL, Giordano SH et al (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27:3297–3302

    Article  PubMed  CAS  Google Scholar 

  21. Johannessen DC, Engan T, Di Salle E et al (1997) Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study. Clin Cancer Res 3:1101–1108

    PubMed  CAS  Google Scholar 

  22. Kamdem LK, Flockhart DA, Desta Z (2011) In vitro cytochrome P450-mediated metabolism of exemestane. Drug Metab Dispos 39:98–105

    Article  PubMed  CAS  Google Scholar 

  23. Key TJ, Verkasalo PK, Banks E (2001) Epidemiology of breast cancer. Lancet Oncol 2:133–140

    Article  PubMed  CAS  Google Scholar 

  24. Lawlor DA, Smith GD, Ebrahim S (2004) Hyperinsulinaemia and increased risk of breast cancer: findings from the British Women’s Heart and Health Study. Cancer Causes Control 15:267–275

    Article  PubMed  Google Scholar 

  25. Lenihan DJ, Esteva FJ (2008) Multidisciplinary strategy for managing cardiovascular risks when treating patients with early breast cancer. Oncologist 13:1224–1234

    Article  PubMed  CAS  Google Scholar 

  26. Leverve XM, Guigas B, Detaille D et al. (2003) Mitochondrial metabolism and type-2 diabetes: a specific target of metformin. Diabetes Metab 29:6S88–6S94

    Google Scholar 

  27. Lu M, Sarruf DA, Talukdar S et al (2011) Brain PPAR-gamma promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat Med 17:618–622

    Article  PubMed  CAS  Google Scholar 

  28. Majuri A, Santaniemi M, Rautio K et al (2007) Rosiglitazone treatment increases plasma levels of adiponectin and decreases levels of resistin in overweight women with PCOS: a randomized placebo-controlled study. Eur J Endocrinol 156:263–269

    Article  PubMed  CAS  Google Scholar 

  29. Mauras N, Lima J, Patel D et al (2003) Pharmacokinetics and dose finding of a potent aromatase inhibitor, Aromasin (exemestane), in young males. J Clin Endocrinol Metab 88:5951–5956

    Article  PubMed  CAS  Google Scholar 

  30. Morris PG, Hudis CA, Giri D et al (2011) Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev Res (Phila) 4:1021–1029

    Article  CAS  Google Scholar 

  31. Nahta R, Hortobagyi GN, Esteva FJ (2003) Growth factor receptors in breast cancer: potential for therapeutic intervention. Oncologist 8:5–17

    Article  PubMed  CAS  Google Scholar 

  32. Park JY, Kim KA, Shin JG et al (2004) Effect of ketoconazole on the pharmacokinetics of rosiglitazone in healthy subjects. Br J Clin Pharmacol 58:397–402

    Article  PubMed  CAS  Google Scholar 

  33. Petrelli JM, Calle EE, Rodriguez C et al (2002) Body mass index, height, and postmenopausal breast cancer mortality in a prospective cohort of US women. Cancer Causes Control 13:325–332

    Article  PubMed  Google Scholar 

  34. Rivera E, Valero V, Syrewicz L et al (2001) Phase I study of stealth liposomal doxorubicin in combination with gemcitabine in the treatment of patients with metastatic breast cancer. J Clin Oncol 19:1716–1722

    PubMed  CAS  Google Scholar 

  35. Rose DP, Komninou D, Stephenson GD (2004) Obesity, adipocytokines, and insulin resistance in breast cancer. Obes Rev 5:153–165

    Article  PubMed  CAS  Google Scholar 

  36. Sirtori CR, Franceschini G, Galli-Kienle M et al (1978) Disposition of metformin (N, N-dimethylbiguanide) in man. Clin Pharmacol Ther 24:683–693

    PubMed  CAS  Google Scholar 

  37. Sturgeon CM, Duffy MJ, Stenman UH et al (2008) National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 54:e11–e79

    Article  PubMed  CAS  Google Scholar 

  38. Tian YF, Chu CH, Wu MH et al (2007) Anthropometric measures, plasma adiponectin, and breast cancer risk. Endocr Relat Cancer 14:669–677

    Article  PubMed  CAS  Google Scholar 

  39. Traina TA, Poggesi I, Robson M et al (2008) Pharmacokinetics and tolerability of exemestane in combination with raloxifene in postmenopausal women with a history of breast cancer. Breast Cancer Res Treat 111:377–388

    Article  PubMed  CAS  Google Scholar 

  40. Yager JD, Davidson NE (2006) Estrogen carcinogenesis in breast cancer. N Engl J Med 354:270–282

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a PROMISE grant from the Susan G. Komen for the Cure and by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant (CA016672). The authors thank Bryan Tutt from the Department of Scientific Publications at MD Anderson Cancer Center for editorial assistance. We also thank Martijn Hilhorst and Thomas Thompson from PRA International (Lenexa, KS) for measurements of exemestane in human plasma and interpretation of pharmacokinetics data, respectively. The pharmacokinetics sampling was performed in the U.T. MD Anderson Cancer Center Clinical and Translational Research Center (CTRC) and was supported by the Center for Clinical and Translational Sciences, which is funded by National Institutes of Health Clinical and Translational Science Award UL1 RR024148 and by the National Institutes of Health Cancer Center Support Grant (CCSG) award CA016672 to MD Anderson Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The Susan G. Komen for the Cure and the National Institutes of Health had no influence on the design, conduct, and interpretation of the results of this study.

Conflict of interest

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Authors and Affiliations

  1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1354, Houston, TX, 77030, USA

    Francisco J. Esteva, Stacy L. Moulder, Ana M. Gonzalez-Angulo, James L. Murray, Marjorie C. Green, Kimberly B. Koenig & Gabriel N. Hortobagyi

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Joe Ensor

  3. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Mong-Hong Lee

  4. Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sai-Ching Yeung

  5. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sai-Ching Yeung

Authors
  1. Francisco J. Esteva
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  2. Stacy L. Moulder
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  3. Ana M. Gonzalez-Angulo
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  4. Joe Ensor
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  5. James L. Murray
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  6. Marjorie C. Green
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  7. Kimberly B. Koenig
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  8. Mong-Hong Lee
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  9. Gabriel N. Hortobagyi
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  10. Sai-Ching Yeung
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Correspondence to Francisco J. Esteva.

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Esteva, F.J., Moulder, S.L., Gonzalez-Angulo, A.M. et al. Phase I trial of exemestane in combination with metformin and rosiglitazone in nondiabetic obese postmenopausal women with hormone receptor–positive metastatic breast cancer. Cancer Chemother Pharmacol 71, 63–72 (2013). https://doi.org/10.1007/s00280-012-1977-9

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  • DOI: https://doi.org/10.1007/s00280-012-1977-9

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