LAUSR

Aromatase inhibitors (AIs), the Estrogen Receptor (ER) modulator tamoxifen and the full ER antagonist fulvestrant each target ER signaling and constitute the backbone of standard of care for ER+ breast cancer. The growing appreciation of liabilities associated with each of these modalities, which may limit their clinical potential, has triggered a wave of activity around next-generation ER therapeutics, and there are currently more than 10 new molecular entities targeting ER being evaluated in Phase 1 clinical trials. In addition to a collection of ER-targeted therapeutics either approved or under evaluation, the emergence of CDK4/6 inhibitors as combination partners has meaningfully contributed to the oncologist’s tool box for the treatment of breast cancer, while also adding complexity to the treatment landscape. Although direct ER antagonists are expected to be superior to AIs in patients with tumors expressing constitutively activating ER mutations (e.g. ER.Y537S), it is currently unclear if a subset of ER wildtype patients may likewise derive superior benefit from direct ER targeting. It is also unclear which ER+ tumors require CDK4/6 inhibitor/ER antagonist combinations for maximal anti-tumor activity, versus those where single-agent ER antagonist treatment may achieve full cell cycle control. To address these key questions, we used a panel of 22 ER+ cell lines to evaluate the relative anti-proliferative and cytotoxic effects of estrogen (E2) withdrawal (modeling AIs), ER modulation, and full ER inhibition, as single agents and in combination with the CDK4/6 inhibitor Palbociclib. We find a number of cell lines in which direct ER antagonism is superior to E2 withdrawal and is associated with E2-independent ER signaling not attributable to ER mutations. The impact of E2 withdrawal on cell cycle control and proliferation is significantly enhanced by concurrent CDK4/6 inhibition, in line with clinical observations, however, direct ER antagonism in combination with CDK4/6 inhibition remains most efficacious. We are integrating our cell response data with detailed molecular analyses and transcriptional profiling to 1) identify cellular contexts, beyond ER mutations, where direct ER antagonism is superior to targeting E2 synthesis, 2) identify tumors where full cell cycle control and anti-tumor efficacy is achievable through single-agent ER targeting, and 3) better understand the basis for the co-operativity of endocrine suppression with CDK4/6 inhibition. Deconvolution of the ER+ breast cancer response to distinct modes of ER signaling inhibition alone and in combination with CDK4/6 inhibitors has the potential to guide clinical decision-making for personalized patient care. Citation Format: Wei Zhou, Jane Guan, Georgia Hatzivassiliou, Anneleen Daemen, Marc Hafner, Ciara Metcalfe. Leveraging an expanding tool box for ER+ breast cancer: exploring breast cancer dependencies to support optimal therapeutic strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1004.