SAN ANTONIO—Targeting the proteasome might help prevent tumor resistance to endocrine therapy, suggest findings from a randomized phase 2 trial presented at the 2014 San Antonio Breast Cancer Symposium.

“The addition of bortezomib to fulvestrant significantly reduced the rate of disease progression (hazard ratio [HR] 0.73; P=0.06 [below the predetermined study protocol threshold P value of 0.10]),” reported lead study author Kerin B. Adelson, MD, of the Yale Cancer Institute at the Yale University School of Medicine in New Haven, CT. “It significantly improved 12-month PFS from 14% to 28% but did not improve 6-month PFS or median PFS.”

Fulvestrant promotes estrogen receptor (ER) degradation in cell nuclei and promotes the accumulation of insoluble and potentially toxic ER protein aggregates in cytoplasm, she noted. “Our group reasoned that combining fulvestrant with the proteasome inhibitor bortezomib may enhance the efficacy of fulvestrant,” she said.

The researchers enrolled women with ER-positive (ER+) metastatic breast cancer that had exhibited resistance to aromatase inhibitor, and randomly assigned to receive fulvestrant alone (59 patients; cycle 1: 500 mg on days -14, 1, and 15; cycle 2 and beyond: on day 1 of each 28-day cycle) or with bortezomib (59 patients, 2 of whom never received treatment; 1.6 mg/m2 bortezomib on days 1, 8, and 15 of each 28-day cycle). Patients in the first group were allowed to cross over to receive bortezomib upon progression.

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Median PFS was 2.72 months for the fulvestrant and bortezomib group and 2.69 months for the fulvestrant group, a insignificant difference, Dr. Adelson reported. “We had estimated the median PFS in the fulvestrant arm would be 5.4 months, but the observed median PFS of 2.7 months suggests a more hormone-resistant population than expected,” she noted.

At follow-up after 12 months, PFS among participants in the fulvestrant arm was 13.6%, compared to 28 months in the fulvestrant and bortezomib group (P=0.03). “PFS in the two study arms significantly diverge after 3 months,” she noted.

Adverse events included low-grade nausea, vomiting, headache, sensory neuropathy, and thrombocytopenia, “but [there was] little grade 3 and no attributable grade 4 toxicity—suggesting the regimen is well tolerated,” she reported.

The study provides “proof of principle that targeting the proteasome may prevent and/or delay the emergence of acquired resistance to endocrine therapy with fulvestrant,” she concluded. The team is working to identify response predictors.


  1. Adelson KB, Ramaswamy B, Sparano JA, et al. S6-03. Presented at: San Antonio Breast Cancer Symposium 2014. Dec. 9-13, 2014; San Antonio, TX.