Using multiple targeted therapies in oncology: considerations for use, and progress to date in breast cancer

There has been significant progress in our basic understanding of drugs and targets in the management of breast cancer. Recent breast cancer clinical trials have examined whether combinations of drugs targeting transmembrane receptors or their downstream effectors involved in cell signal transduction can increase response rates and overcome acquired and/or de novo drug resistance compared to a single targeted agent with or without systemic chemotherapy. We reviewed published clinical trials and conference proceedings examining combinations of targeted therapies across different breast cancer subtypes. Improvements in pathological complete response (pCR) rates and progression free survival (PFS) in preoperatively treated and metastatic human epidermal growth factor 2 (HER2)-positive breast cancer, respectively, have been observed with combinations of anti-HER2 therapies given concomitantly. Promising results were also observed in estrogen receptor (ER)-positive, HER2-negative breast cancer using a mammalian target of rapamycin inhibitor with tamoxifen or an aromatase inhibitor (AI) in the preoperative setting and for patients with metastatic breast cancer that had previously progressed on endocrine therapy alone. A recent phase II trial reported a statistically significant improvement in PFS with the addition of an oral inhibitor of cyclin-dependent kinase 4/6 to letrozole compared to letrozole alone (26.1 versus 7.5 months). A phase III study is planned for early 2013. On the basis of preclinical data, clinical trials have examined combinations of hormonal agents such as fulvestrant with an AI. However, the results are conflicting. Early data indicated that poly (ADP-ribose) polymerase (PARP) inhibitors exploiting the concept of synthetic lethality would offer improved outcomes for patients with ER-negative, progesterone receptor (PR)-negative, HER2-negative breast cancer often referred to as triple negative breast cancer (TNBC); however, data in the phase III setting failed to confirm these findings but this may be because the drug was not a true PARP inhibitor. Chemotherapy continues to be the mainstay of treatment for TNBC until specific drugs and their associated targets are identified. As advances in medical technologies continue to identify multiple molecularly distinct breast cancer subgroups that are predicted to respond to combinations of targeted agents new challenges have arisen. In particular, how do we evaluate the safety and efficacy of these new drug combinations in relatively small subgroups of patients? Novel clinical trial designs will be required and increasingly regulatory agencies will require companion diagnostic tests that can identify the subgroups likely to respond to these therapies. The US Food and Drug Administration is assessing the role of pCR in breast cancer studies as a surrogate endpoint to predict clinical benefit in the accelerated drug approval process.