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

Kerin Adelson, Bhuvaneswari Ramaswamy, Joseph A. Sparano, Paul J. Christos, John J. Wright, George Raptis, Gang Han, Miguel Villalona-Calero, Cynthia X. Ma, Dawn Hershman, Joseph Baar, Paula Klein, Tessa Cigler, G. Thomas Budd, Yelena Novik, Antoinette R. Tan, Susan Tannenbaum, Anupama Goel, Ellis Levine, Charles L. ShapiroEleni Andreopoulou, Michael Naughton, Kevin Kalinsky, Sam Waxman, Doris Germain

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 2 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 (α = 0.10, β = 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, P = 0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 α level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P = 0.03, 1-sided χ 2 -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.

Original languageEnglish (US)
Article number16037
Journalnpj Breast Cancer
Volume2
Issue number1
DOIs
StatePublished - Dec 14 2016
Externally publishedYes

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Aromatase Inhibitors
Disease-Free Survival
Estrogen Receptors
Hormones
Breast Neoplasms
Proteasome Inhibitors
Neoplasms
Confidence Intervals
Cytoplasmic and Nuclear Receptors
Survival Rate
Bortezomib
fulvestrant

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology (medical)

Cite this

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. / Adelson, Kerin; Ramaswamy, Bhuvaneswari; Sparano, Joseph A.; Christos, Paul J.; Wright, John J.; Raptis, George; Han, Gang; Villalona-Calero, Miguel; Ma, Cynthia X.; Hershman, Dawn; Baar, Joseph; Klein, Paula; Cigler, Tessa; Budd, G. Thomas; Novik, Yelena; Tan, Antoinette R.; Tannenbaum, Susan; Goel, Anupama; Levine, Ellis; Shapiro, Charles L.; Andreopoulou, Eleni; Naughton, Michael; Kalinsky, Kevin; Waxman, Sam; Germain, Doris.

In: npj Breast Cancer, Vol. 2, No. 1, 16037, 14.12.2016.

Research output: Contribution to journalArticle

Adelson, K, Ramaswamy, B, Sparano, JA, Christos, PJ, Wright, JJ, Raptis, G, Han, G, Villalona-Calero, M, Ma, CX, Hershman, D, Baar, J, Klein, P, Cigler, T, Budd, GT, Novik, Y, Tan, AR, Tannenbaum, S, Goel, A, Levine, E, Shapiro, CL, Andreopoulou, E, Naughton, M, Kalinsky, K, Waxman, S & Germain, D 2016, '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', npj Breast Cancer, vol. 2, no. 1, 16037. https://doi.org/10.1038/npjbcancer.2016.37
Adelson, Kerin ; Ramaswamy, Bhuvaneswari ; Sparano, Joseph A. ; Christos, Paul J. ; Wright, John J. ; Raptis, George ; Han, Gang ; Villalona-Calero, Miguel ; Ma, Cynthia X. ; Hershman, Dawn ; Baar, Joseph ; Klein, Paula ; Cigler, Tessa ; Budd, G. Thomas ; Novik, Yelena ; Tan, Antoinette R. ; Tannenbaum, Susan ; Goel, Anupama ; Levine, Ellis ; Shapiro, Charles L. ; Andreopoulou, Eleni ; Naughton, Michael ; Kalinsky, Kevin ; Waxman, Sam ; Germain, Doris. / 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. In: npj Breast Cancer. 2016 ; Vol. 2, No. 1.
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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 2 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 (α = 0.10, β = 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, P = 0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 α level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6{\%} and 28.1{\%} (P = 0.03, 1-sided χ 2 -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.",
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AU - Adelson, Kerin

AU - Ramaswamy, Bhuvaneswari

AU - Sparano, Joseph A.

AU - Christos, Paul J.

AU - Wright, John J.

AU - Raptis, George

AU - Han, Gang

AU - Villalona-Calero, Miguel

AU - Ma, Cynthia X.

AU - Hershman, Dawn

AU - Baar, Joseph

AU - Klein, Paula

AU - Cigler, Tessa

AU - Budd, G. Thomas

AU - Novik, Yelena

AU - Tan, Antoinette R.

AU - Tannenbaum, Susan

AU - Goel, Anupama

AU - Levine, Ellis

AU - Shapiro, Charles L.

AU - Andreopoulou, Eleni

AU - Naughton, Michael

AU - Kalinsky, Kevin

AU - Waxman, Sam

AU - Germain, Doris

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N2 - 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 2 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 (α = 0.10, β = 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, P = 0.06, 1-sided log-rank test, significant at the prespecified 1-sided 0.10 α level). At 12 months, the PFS proportion in Arm A and Arm B was 13.6% and 28.1% (P = 0.03, 1-sided χ 2 -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.

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