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Investigational New Drugs

, Volume 37, Issue 2, pp 345–351 | Cite as

Efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal patients with metastatic, hormone receptor-positive, HER2-negative breast cancer: a phase II study

  • Clinton Yam
  • Francisco J. Esteva
  • Miral M. Patel
  • Akshara S. Raghavendra
  • Naoto T. Ueno
  • Stacy L. Moulder
  • Kenneth R. Hess
  • Girish S. Shroff
  • Silvia Hodge
  • Kimberly H. Koenig
  • Mariana Chavez Mac Gregor
  • Robin L. Griner
  • Sai-Ching J. Yeung
  • Gabriel N. Hortobagyi
  • Vicente ValeroEmail author
PHASE II STUDIES

Summary

Background Increased adiposity is thought to result in worse clinical outcomes in patients with breast cancer through increased estrogen production, hyperinsulinemia, insulin resistance, and activation of the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Thus, we hypothesized that the addition of metformin to everolimus and exemestane, could lead to better outcomes in overweight and obese patients with metastatic, hormone receptor-positive, HER2-negative breast cancer. We conducted a phase II trial to evaluate the efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal women with metastatic, hormone receptor-positive, HER2-negative breast cancer. Methods Twenty-two patients with a body mass index ≥25 kg/m2 were treated with metformin 1000 mg twice daily, everolimus 10 mg daily and exemestane 25 mg daily. Median progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results Median PFS and OS were 6.3 months (95% confidence interval [CI]: 3.8–11.3 months) and 28.8 months (95% CI: 17.5–59.7 months), respectively. Five patients had a partial response and 7 had stable disease for ≥24 weeks yielding a clinical benefit rate of 54.5%. Compared with overweight patients, obese patients had an improved PFS on univariable (p = 0.015) but not multivariable analysis (p = 0.215). Thirty-two percent of patients experienced a grade 3 treatment-related adverse event (TRAE). There were no grade 4 TRAEs and 7 patients experienced a grade 3 TRAE. Conclusion The combination of metformin, everolimus and exemestane was safe and had moderate clinical benefit in overweight and obese with patients metastatic, hormone receptor-positive, HER2-negative breast cancer.

Keywords

Metformin Everolimus Exemestane Obesity Metastatic breast cancer 

Notes

Acknowledgements

This work was supported by a PROMISE grant from Susan G. Komen for the Cure (to FJE, SCJY and VV), the Breast Cancer Research Foundation (to FJE), the National Institutes of Health through MD Anderson’s Cancer Center Support Grant (NCI P30 CA016672). Dr. Yam is supported by the Allison and Brian Grove Endowed Fellowship for Breast Medical Oncology, the Susan Papizan Dolan Fellowship in Breast Oncology, and the 2018 Gianni Bonadonna Breast Cancer Research Fellowship. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the sponsors. The authors thank Jeanie F. Woodruff, BS. ELS, for editorial support.

Funding

This work was supported by a PROMISE grant from Susan G. Komen for the Cure (to FJE, SCJY and VV), the Breast Cancer Research Foundation (to FJE), the National Institutes of Health through MD Anderson’s Cancer Center Support Grant (NCI P30 CA016672). Dr. Yam is supported by the Allison and Brian Grove Endowed Fellowship for Breast Medical Oncology, the Susan Papizan Dolan Fellowship in Breast Oncology, and the 2018 Gianni Bonadonna Breast Cancer Research Fellowship. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the sponsors.

Compliance with ethical standards

Conflict of interest

FJE has received honoraria from Novartis and Pfizer for consultancy. MCM has received honoraria for serving on the advisory boards of Roche and Pfizer and has received institutional research funding from Novartis. SCJY has received research funding and grant support from Bristol-Myers Squibb and DepoMed. GNH was the principal investigator of the BOLERO-2 trial and received research funding from Norvatis for conducting the trial and honoraria for chairing the protocol steering committee. VV has received honoraria from Novartis for consultancy. All other authors declare no relevant potential conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Clinton Yam
    • 1
  • Francisco J. Esteva
    • 1
  • Miral M. Patel
    • 2
  • Akshara S. Raghavendra
    • 1
  • Naoto T. Ueno
    • 1
  • Stacy L. Moulder
    • 1
  • Kenneth R. Hess
    • 3
  • Girish S. Shroff
    • 2
  • Silvia Hodge
    • 1
  • Kimberly H. Koenig
    • 1
  • Mariana Chavez Mac Gregor
    • 1
  • Robin L. Griner
    • 1
  • Sai-Ching J. Yeung
    • 4
    • 5
  • Gabriel N. Hortobagyi
    • 1
  • Vicente Valero
    • 1
    Email author
  1. 1.Department of Breast Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Diagnostic RadiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of BiostatisticsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Department of Endocrine Neoplasia and Hormonal DisordersThe University of Texas MD Anderson Cancer CenterHoustonUSA
  5. 5.Department of Emergency MedicineThe University of Texas MD Anderson Cancer CenterHoustonUSA

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