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.
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.
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DOI：
10.1038/npjbcancer.2016.37
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发表时间：
2016
影响因子：
5.9
通讯作者：
Germain D
中科院分区：
文献类型：
--
作者：
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
蛋白酶体抑制剂硼替佐米通过在临床前模型中引起细胞质ER聚集体蓄积，增强选择性雌激素受体（ER）下调剂（SERD）氟维司群的作用。本试验的目的是确定硼替佐米是否增强氟维司群的有效性。将118名患有对芳香酶抑制剂（AI）耐药的ER阳性转移性乳腺癌的绝经后女性随机分配至氟维司群单独治疗组（A组-500 mg肌内（i.m.）第1周期第-14、1、15天，以及其他周期的第1天）或与硼替佐米联合（B组-1.6 mg/m2静脉内（i. v.）在每个周期的第1、8、15天）。该研究的把握度显示中位无进展生存期（PFS）从5.4个月改善至9.0个月，并比较6个月和12个月的PFS率（α=0.10，β=0.10）。接受氟维司群治疗后发生进展的患者可交叉至联合治疗组（C组）。尽管中位PFS无差异（两组均为2.7个月），但B组与A组（参照组）相比PFS的风险比为0.73（95%置信区间（CI）=0.49，1.09，P=0.06，单侧对数秩检验，在预先规定的单侧0.10 α水平下具有显著性）。12个月时，A组和B组的PFS比例分别为13.6%和28.1%（P=0.03，单侧χ2检验;差异（14.5%）的95% CI =−0.06，29.1%）。在A组27例交叉至联合治疗组（C组）的患者中，5例（18%）至少24周无进展。硼替佐米可能通过降低获得性耐药性增强氟维司群在AI耐药、ER阳性转移性乳腺癌中的有效性，支持对蛋白酶体抑制剂与SERD联合治疗的额外评价。
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.