Abstract ES8-2: Future Directions in Endocrine Therapy for Advanced HR+/HER2- Breast Cancer

The majority of metastatic breast cancer is hormone receptor positive (HR+), HER2 negative. Substantial advances over the prior decades have demonstrated the efficacy of endocrine monotherapies, including aromatase inhibitors, tamoxifen, and fulvestrant, in controlling disease and prolonging survival. More recently, the introduction of targeted therapies used in concert with endocrine therapy have further improved outcomes. The CDK4/6 inhibitors (CDK4/6i): palbociclib, abemaciclib, and ribociclib, have uniformly demonstrated efficacy in the first-line and pretreated settings in prolonging progression free survival, with hazard ratios across at least 8 randomized trials (PALOMA, MONARCH, MONALEESA series) ranging from 0.50-0.55. Recent reports from these trials also support prolongation in overall survival with the use of CDK4/6i in combination with an endocrine backbone. Since initial approval in 2015, CDK4/6i in combination with an endocrine partner have become a mainstay of treatment for metastatic HR+ HER-2 negative breast cancer. Additionally, in the setting of endocrine resistance, a deeper understanding of resistance signaling, such as the mTOR/PI3kinase/AKT pathway, has led to the development and approval of active therapies, including everolimus and alpelisib, with further agents in development. Despite substantial progress, a major challenge within the current landscape is to better identify mechanisms of resistance to these therapies, with a goal of utilizing a personalized approach to tailor subsequent treatment options. Significant ongoing work focuses on the post-CDK4/6i space, to identify molecular mechanisms of resistance, and whether resistance extends exclusively to CDK4/6i, or to endocrine therapy as well. Examination of tumor and blood samples post-CDK4/6i exposure has suggested a heterogenous mutational landscape. Loss of Rb is a rare observation, however other important events include alterations in AKT1, aurora kinase A (AURKA), FGFR1, cyclin E2 (CCNE2), ESR1, and RAS. Agents of interest post-CDK4/6i thus include SERDs (selective estrogen receptor down regulators), AKT inhibtors, FGFR1 antagonists, as well as aurora kinase inhibitors. In conclusion, the area of empiric endocrine monotherapy has become a notion of the past. The advent of CDK4/6i has changed paradigms of therapy and introduced improved survival outcomes. Substantial ongoing work attempts to characterize the heterogenous genomic alternations which underlie resistance to endocrine and targeted therapies, and novel agents matched to these specific mutations are in development. Moving beyond CDK4/6i, we are now entering a new era of personalized and targeted therapy for metastatic HR+ HER-2 negative breast cancer, with the potential to provide significant benefit to the many patients with this disease. Citation Format: E Mayer. Future Directions in Endocrine Therapy for Advanced HR+/HER2- Breast Cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES8-2.