Another issue was that, at least to date, tumor molecular profiles differed between the two trials. For example, only 25% of patients in the phase III trial had basal-like disease, compared with more than 40% in the phase II trial. Both trials had some patients with luminal A type, which usually corresponds to estrogen receptor–positive disease. This suggests that triple-negative phenotype alone is unlikely to be an adequate selection strategy for PARP inhibition and that we need trials with tissue analysis.
Finally, it turns out we weren’t really giving a PARP inhibitor in these trials. Iniparib at the doses that were delivered does not inhibit PARP. Efforts are now underway to study escalation. And the actual mechanism of action of this drug remains to be determined.
Antiangiogenic Agents
Agents that interfere with angiogenesis, such as bevacizumab (Avastin), are of interest in triple-negative breast cancer to target the hypoxia signature that is characteristic of this and other rapidly proliferating tumors.
We know that bevacizumab adds to clinical efficacy of chemotherapy in breast cancer. But it’s been hard to show specific subsets that benefit, and that’s our current quandary. A meta-analysis of the first-line trials in triple-negative disease suggested patients with triple-negative disease had similar improvements in outcomes from the addition of bevacizumab as did other subsets of patients (SABCS 2010 meeting. Abstract P6-12-03).
In the second-line RIBBON 2 trial, adding bevacizumab to chemotherapy appeared to have greater benefit in the triple-negative subset of patients compared with the whole group, but numbers were too small to draw definitive conclusions (ASCO 2011 Breast Cancer Symposium. Abstract 290).
Other Targeted Agents
A variety of other targeted agents are being evaluated for activity in triple-negative breast cancer. Tigatuzumab, an antibody to TRAIL receptor 2, one of the so-called death receptors, had impressive results in preclinical testing. It is now being evaluated in a randomized phase II trial in which patients with metastatic triple-negative breast cancer are treated with nanoparticle albumin–bound (nab)-paclitaxel (Abraxane) with or without tigatuzumab (NCT01307891).
An interesting finding has been that approximately 5% of patients with triple-negative disease have upregulation of the androgen receptor. Thus, another phase II trial is testing bicalutamide (Casodex) in patients whose tumors have these receptors but neither estrogen nor progesterone receptors (NCT00468715). This is a fascinating approach and could be of great benefit for this small subset of patients, as some patients have had stable disease for a year on bicalutamide therapy, which has minimal toxicity.