A Phase II Study of the Combination of Endocrine Treatment and Bortezomib in Patients with Endocrine Resistant Metastatic Breast Cancer.

Background: The introduction of anti-hormonal treatment has been a major revolution in breast cancer management. The majority of patients with metastatic hormone receptor-positive breast cancer eventually suffer from progression of their disease despite different types of anti-hormonal treatment. Preclinical studies have indicated bidirectional inhibitory interactions between ER and NF-kappaB, governing in part endocrine-resistance and enhanced growth. The hypothesis that inhibition of NF-kappaB activation by a proteasome inhibitor might reverse the sensitivity to endocrine therapy was the rationale to initiate a phase II trial. Aim, Material and Methods: The aim is to investigate whether the addition of open label bortezomib to either a SERM or an AI will result in documented activity in patients with progressive and measurable disease on the identical endocrine agent. This endpoint is evaluated according to RECIST criteria every 8 weeks. The patients are stratified into 2 treatment groups, according to their current endocrine treatment either tamoxifen or an AI. Bortezomib is administered on days 1, 8, 15, 21 of a 6 week regimen at a dose of 1.6 mg/sqm on each treatment day. Consecutive tumour biopsies (if accessible) and blood samples are collected for translational purposes. Clinical benefit was predefined by the patients obtaining at least either stable disease, or a partial or a complete response according to RECIST criteria, lasting for at least four weeks. A two-stage statistical approach showed that this should at least occur in 1 patient in the first cohort of 14 patients, prior to further accrual. Results: At present N=9 patients have been enrolled. Eight patients received AI+bortezomib, while one received TAM+bortezomib. N=5/9 patients had progressive disease, N=4/9 patients had stable disease of which two patients (N=2/9) had stable disease continuing for more than 4 weeks. There were no objective antitumour responses observed. N=4/9 had grade III diarrhoea. Median time to treatment failure was 69 days [35-140], either due to toxicity (N=3/9) or (eventual) progression (N=6/9). Conclusions: Preliminary results shows that the clinical benefit rate is 22% (N=2/9). Although preliminary, these results warrant further accrual and suggest that the biological hypothesis seems clinically valid. Further recruitment is ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4099.