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/m2 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 χ2-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.
Highlights
Endocrine therapy prolongs survival in patients with metastatic breast cancer whose tumors express the estrogen receptor (ER) and is better tolerated than chemotherapy
Fulvestrant is a selective estrogen receptor (ER) downregulator (SERD) that binds, inhibits, and degrades the estrogen receptor (ER). It binds with 100-fold greater affinity than tamoxifen, and more effectively inhibits estrogen signaling than either tamoxifen or AIs6–8 suggesting that it may be a better platform for combining with agents targeting other pathways
One hundred eighteen patients were enrolled from 17 institutions between June 2010 and October 2013, including 59 patients randomized to fulvestrant alone and 59 patients randomized to fulvestrant plus bortezomib (Arm B)
Summary
Endocrine therapy prolongs survival in patients with metastatic breast cancer whose tumors express the estrogen receptor (ER) and is better tolerated than chemotherapy. Resistance to endocrine therapy is a major clinical challenge.[2]. Several agents have been shown to enhance the effectiveness of hormonal modulation, including the mTor inhibitor everolimus,[3] the CDK 4/6 inhibitor palbociclib,[4] and the histone deacetylase inhibitor entinostat,[5] indicating that it may be feasible to abrogate endocrine resistance with rational combinations of endocrine and non-endocrine agents, including those that have only modest activity when used alone. Fulvestrant is a SERD that binds, inhibits, and degrades the estrogen receptor (ER) It binds with 100-fold greater affinity than tamoxifen, and more effectively inhibits estrogen signaling than either tamoxifen or AIs6–8 suggesting that it may be a better platform for combining with agents targeting other pathways.
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