The Role of mTOR Inhibitors in Breast Cancer

Abstract

Despite minimal activity as single agents, mTOR inhibitors are currently in advanced phases of clinical development in the treatment of breast cancer, and everolimus (Afinitor®, Novartis) has already received regulatory approval in combination with exemestane for the treatment of aromatase inhibitor-refractory metastatic hormone receptor-positive breast cancer. In combination with endocrine agents, mTOR inhibitors contribute to overcoming the resistance mediated by the PI3K-Akt-mTOR pathway, and positive data has also been generated in combination with tamoxifen. Trials have started enrolling patients with hormone receptor-positive breast cancer in the early setting. In the treatment of HER-2+ breast cancer, they are thought to reverse resistance to anti-HER-2 agents. Proof-of-concept trials have already been reported, and everolimus has reached phase 3 development in combination with chemotherapy and trastuzumab upfront or in the trastuzumab-resistant setting. The BOLERO-3 testing the combination of vinorelbine, trastuzumab, and everolimus has already been reported. However, mTOR inhibitors face competition generated by the advent of novel anti-HER-2 agents such as pertuzumab and T-DM1. In the treatment of triple-negative breast cancer, mTOR inhibitors inhibit multiple targets and pathways involved in the pathogenesis of the disease: DNA repair pathways, angiogenesis, EGFR, stem cells, etc. Nevertheless, this setting remains an unmet medical need. Main adverse events are stomatitis, rash, and cytopenias when combined with chemotherapy. Predictive biomarkers are therefore necessary and are being explored using next-generation sequencing in order to better identify the patients who will derive significant benefit from treatment. New agents targeting the same pathway with presumably a better target specificity are now in advanced development phases such as pan-PI3K inhibitors and PI3K alpha subunit-specific inhibitors.