Randomized phase II trial of fulvestrant alone or in combination with bortezomib in hormone receptor-positive metastatic breast cancer resistant to aromatase inhibitors: a New York Cancer Consortium trial.

Journal: NPJ breast cancer
Published Date: Dec 14, 2016

Abstract

The proteasome inhibitor bortezomib enhances the effect of the selective estrogen receptor (ER) downregulator (SERD) fulvestrant by causing accumulation of cytoplasmic ER aggregates in preclinical models. The purpose of this trial was to determine whether bortezomib enhanced the effectiveness of fulvestrant. One hundred eighteen postmenopausal women with ER-positive metastatic breast cancer resistant to aromatase inhibitors (AIs) were randomized to fulvestrant alone (Arm A-500 mg intramuscular (i.m.) day -14, 1, 15 in cycle 1, and day 1 of additional cycles) or in combination with bortezomib (Arm B-1.6 mg/m intravenous (i.v.) on days 1, 8, 15 of each cycle). The study was powered to show an improvement in median progression-free survival (PFS) from 5.4 to 9.0 months and compare PFS rates at 6 and 12 months (=0.10, =0.10). Patients with progression on fulvestrant could cross over to the combination (arm C). Although there was no difference in median PFS (2.7 months in both arms), the hazard ratio for PFS in Arm B versus Arm A (referent) was 0.73 (95% confidence interval (CI)=0.49, 1.09, =0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (=0.03, 1-sided -test; 95% CI for difference (14.5%)=-0.06, 29.1%). Of 27 patients on arm A who crossed over to the combination (arm C), 5 (18%) were progression-free for at least 24 weeks. Bortezomib likely enhances the effectiveness of fulvestrant in AI-resistant, ER-positive metastatic breast cancer by reducing acquired resistance, supporting additional evaluation of proteasome inhibitors in combination with SERDs.

Authors

  • Kerin Adelson
    Yale Cancer Center and Smilow Cancer Hospital, Yale University School of Medicine, New Haven, CT, USA.
  • Bhuvaneswari Ramaswamy
    The Ohio State Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
  • Joseph A Sparano
    Department of Oncology, Montefiore Medical Center, Bronx, NY, USA.
  • Paul J Christos
    Department of Healthcare Policy & Research, Weill Cornell Medical Center, New York, NY, USA.
  • John J Wright
    Investigational Drug Branch, Cancer Therapy and Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • George Raptis
    Department of Medicine, Northwell Health, Lake Success NY and Hofstra Northwell School of Medicine, Hempstead, NY, USA.
  • Gang Han
    Department of Orthopaedics, General Hospital of Chinese PLA, Beijing, 100853, P.R.China.
  • Miguel Villalona-Calero
    Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
  • Cynthia X Ma
    Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
  • Dawn Hershman
    Department of Medicine and Epidemiology New York Presbyterian-Columbia University Medical Center, New York, NY, NY, USA.
  • Joseph Baar
    Department of Medicine, Division of Hematology/Oncology, Seidman Cancer Center of the University Hospitals of the Cleveland Medical Center, Cleveland, OH, USA.
  • Paula Klein
    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY, USA.
  • Tessa Cigler
    Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical Center, New York, NY, USA.
  • G Thomas Budd
    Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Center, Cleveland, OH, USA.
  • Yelena Novik
    Perlmutter Cancer Center, NYU Langone Medical Center, New York University School of Medicine, New York, NY, USA.
  • Antoinette R Tan
    Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
  • Susan Tannenbaum
    Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA.
  • Anupama Goel
    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY, USA.
  • Ellis Levine
    Roswell Park Cancer Institute, Jacobs School of Medicine and Biomedical Science, State University of New York at Buffalo, Buffalo, NY, USA.
  • Charles L Shapiro
    The Ohio State Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.
  • Eleni Andreopoulou
    Department of Oncology, Montefiore Medical Center, Bronx, NY, USA.
  • Michael Naughton
    Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
  • Kevin Kalinsky
    Department of Medicine, Division of Hematology and Oncology, New York Presbyterian-Columbia University Medical Center, New York, NY, USA.
  • Sam Waxman
    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY, USA.
  • Doris Germain
    Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, NY, USA.

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