Abstract ES3-3: Integration of novel targeted agents with endocrine therapy

An unfortunate problem with all antiestrogens is that breast cancer cells become resistant to their action over time. Studies in cell lines and human xenografts have shown that growth factor receptor signaling pathways, in particular those which converge on phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK/ERK), can mediate resistance to all forms of endocrine therapy. Therefore, combining two or more targeted agents with endocrine therapy may be required for a more optimal approach to ER+ breast cancer treatment, since combination of “complementary” pathway inhibitors would potentially maximize efficacy, and would minimize therapeutic resistance. Numerous experimental approaches seek to identify “targets” in ER+ breast cancer: PI3K or mTOR inhibitors, CDK4/6 inhibitors, histone deacetylase inhibitors, and FGFR inhibitors, are a few of the agents under consideration or currently being investigated in the clinical setting against this disease. However, for the majority of targeted therapies in development, there are still no clinical tools to determine which patients are most likely to benefit or, alternatively, be resistant de novo to these novel agents or drug combinations. The study of biomarkers of drug exposure and sensitivity in metastatic tumors, although feasible, is not easy due to the inherent difficulty of obtaining sequential tumor samples only for research purposes. Neoadjuvant endocrine therapy studies for ER+ breast cancer are a great opportunity to develop insights into the biologic basis for the efficacy of ER-targeting agents, alone or in combination. Additionally, the comprehensive molecular analysis of cancers remaining in the breast after therapy provides a unique opportunity to discover, in unbiased fashion, the molecular mechanisms of resistance to estrogen deprivation ± a targeted inhibitor. These mechanisms, in turn, may represent actionable molecular targets that can be the focus of future drug discovery efforts and/or translational/clinical investigation in ER+ breast cancers. In neoadjuvant trials, a variety of endpoints have been used, such as pathological response rate, clinical response rate, breast conserving surgery rate, preoperative endocrine prognostic index (PEPI) score and Ki67 variation. Pathological response rate is generally expected to be low with endocrine therapy alone and not predictive of clinical benefit. However, considering that certain targeted agents, such as PI3K inhibitors, lead to increased cell death in vitro, it is reasonable to assume that a combination of endocrine therapy with a PI3K inhibitor could lead to an increased pathologic response in vivo, by eliciting tumor apoptosis. An enhanced rate of pathologic response as evidence for the activation of a cell death process that would more effectively delete ER+ breast cancer cells before the acquisition of resistance to endocrine therapy, or an increased rate of PEPI score 0 following neoadjuvant therapy are not only reproducible endpoints, but can be used as a “proving ground” to test the efficacy of new endocrine therapy approaches for breast cancer. Currently, three phase II neoadjuvant trials exploring the addition of inhibitors of the PI3K/ AKT/ mTOR pathway to endocrine therapy are under way. Citation Format: Ingrid A. Mayer. Integration of novel targeted agents with endocrine therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES3-3.