A phase II study of the combination of endocrine treatment and bortezomib in patients with endocrine-resistant metastatic breast cancer.
The majority of patients with hormone receptor-positive metastatic breast             cancer die from disease progression despite different types of anti-hormonal treatments.             Preclinical studies have indicated that resistance to anti-hormonal therapies             may be the result of an activated NF-κB signalling pathway in breast cancer. Bortezomib             is a proteasome inhibitor that blocks the NF-κB pathway. Recent pharmacodynamic             and pharmaco-kinetic xenograft studies have shown that drug exposure may be a             crucial factor for the efficacy of bortezomib in solid tumours. The aim was to             investigate whether the addition of bortezomib to anti-hormonal therapy would             result in regained antitumour activity in patients with progressive and measurable             disease being treated with an endocrine agent. Clinical benefit was defined as             patients obtaining stable disease, partial response or complete response after             2 cycles, lasting for at least another five weeks. Bortezomib was administered             on days 1, 8, 15 and 22 of a 5-week regimen (1.6 mg/m2). Eight patients received             an aromatase inhibitor and bortezomib, while one received tamoxifen and bortezomib.             There were 3 grade 3 gastrointestinal toxicities. Median time to treatment failure             was 69 days (range, 35-140). Two out of the 9 patients had stable disease for             more than 10 weeks. Despite an effective target inhibition, suggested in peripheral             blood mononuclear cells and available tumour samples, no objective antitumour             responses were observed. Addition of a proteasome inhibitor to anti-hormonal therapy             resulted in a clinical benefit rate of 22% in a limited number of patients with             endocrine resistant and progressive metastatic breast cancer. The demonstrated             proteasome inhibition in tumour tissue provides evidence that the lack of clinical             responses is not attributed to deficient drug exposure.