Phase I study of apoptosis gene modulation with oblimersen within preoperative chemotherapy in patients with primary breast cancer

Abstract

e11576 Background: The expression of the Bcl-2 protein confers resistance to chemotherapy mediated apoptotic signals in patients with breast cancer. The development of chemo sensitizing drugs may result in new treatment options. We investigated the effects of Bcl-2 down-regulation by the Bcl-2 antisense oligodeoxynucleotide oblimersen in breast tumor biopsies. Oblimersen targets Bcl-2 mRNA, thereby down regulates Bcl-2 protein translation, and enhances the antitumor effects of sub therapeutic doses of docetaxel. Methods: Within a phase I trial we administered escalating doses of oblimersen (3/5/7mg/kg/day) as continuous infusion on day 1–7 in combination with standard dosed docetaxel, doxorubicin, cyclophosphamide (TAC) on day 5 as preoperative chemotherapy in 28 patients with T2–4 breast cancers. Effects of oblimersen were evaluated in tumor biopsies and peripheral blood mononuclear cells (PBMCs) 4 days after start of oblimersen continuous infusion and before TAC treatment by quantitative microfluidic real-time polymerase chain reaction (RT-PCR). Read-outs consisted in measurement of Bcl-2 mRNA modulations and of 18 other putative predictive markers. Results: Two out of 13 patients showed a diminution of Bcl-2 transcripts after 4 days of treatment with oblimersen 5 mg/kg/day. PBMCs could not be evaluated as a surrogate tissue, because no qualified RNA could be isolated. Conclusions: Nevertheless, we demonstrated the feasibility to process clinical samples and to obtain good quality RNA from tumor biopsies, and indicated the potential of oblimersen to lower Bcl-2 mRNA in breast cancer. No significant financial relationships to disclose.