Abstract TF1-1: Leveraging our most contemporary understanding of estrogen signaling in breast cancer to inform the development of next generation endocrine therapies
Authors: McDonnell DP 
Published: March 2022

Abstract
Endocrine therapies designed to block estrogen-dependent activation of the estrogen receptor (ER) signaling pathway have, and will continue to be, the cornerstone of therapeutic approaches to treat luminal breast cancer. These agents work by either inhibiting the synthesis of gonadal/extragonadal estrogens or by directly blocking the activity of ER and have had a very significant impact on mortality and morbidity in patients with breast cancer, when used in the preventative, adjuvant, or treatment settings. However, as with most targeted therapies, de novo and acquired resistance remain impediments to durable clinical responses. Whereas the mechanisms underlying resistance to endocrine therapies are complex and multifactorial, most can be attributed to changes in the biochemical properties of the receptor or to adaptive changes in cancer cells that alter the way ER-ligand complexes are recognized. Mutations in ER that permit it to activate transcription in a ligand-independent manner and/or which enable pathological neomorphic activities have received considerable attention of late. These mutations, which occur infrequently in primary tumors are present in ~30-40% of metastatic lesions. Whereas it remains to be determined if these mutations are causally responsible for endocrine therapy failure their presence is at least a surrogate for the acute ER dependence of a tumor. Notable also are emerging data suggesting that ~1-2% of lesions from patients with advanced disease harbor gene arrangements that result in the formation of pathological ESR1-fusions. There is abundant evidence from both preclinical and clinical studies that resistance to endocrine therapies may result from changes in the absolute expression or activity of receptor-associated coregulators (coactivators or corepressors) and/or to dysregulated activity of signaling pathways that converge on ER-coregulator complexes. These activities negate the inhibitory effects of aromatase inhibitors and competitive antagonists like tamoxifen. A key feature of the primary resistance mechanisms that have been described to date is the continued dependence of tumors on ER signaling. This observation, together with the positive clinical activity of first generation Selective Estrogen Receptor Downregulators (SERDs), has encouraged the development of the next generation of endocrine therapies. Currently, there are 13 SERDs in clinical development for breast cancer, several of which have already shown efficacy in early clinical studies. It is likely that several of these SERDs, which accomplish ER downregulation/degradation by different mechanisms, will be approved for clinical use and that it will be issues associated with tolerability, effects on bone and cognitive function, and the ability to manage off-target activities which will differentiate these drugs. In addition to these drugs which target ER directly there is considerable enthusiasm for emerging new classes of drugs that directly target ER-coregulators or exploit collateral vulnerabilities that emerge in cancer cells as they become therapy resistant. Most endocrine therapies have been developed with the goal of inhibiting the cancer cell intrinsic actions of ER. However, we believe that it is important to consider that drugs of this class also inhibit cancer cell extrinsic actions of ER (a) in stromal cells within tumors and (b) at sites distal to the tumor (i.e. bone), that may impact tumor biology. Understanding these complexities. will inform the best use of current medicines and will be instructive as to the development of the next generation of endocrine therapies.
Citation Format: DP McDonnell. Leveraging our most contemporary understanding of estrogen signaling in breast cancer to inform the development of next generation endocrine therapies. [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr TF1-1.