Abstract SoA3-01: SERMs versus SERDs for targeting ESR1 mutations

Abstract Estrogen receptor positive (ER+) breast cancers are effectively treated with adjuvant endocrine therapies, with or without the addition of CDK4/6 inhibitors. However, many patients develop resistance and progress to ER+ metastatic disease (MBC). Acquired mutations in ESR1, which encodes estrogen receptor alpha (ERa), contribute to 20-40% of endocrine therapy resistant MBC. An emerging, unanswered and controversial question is the best choice of ER-targeted therapy for ET-resistant mutant ER+ MBC, recognizing that for most patients, a balance between compliance, effectiveness and quality of life are competing issues. To partially address some of these issues, we have tested and compared a relatively nontoxic SERM, lasofoxifene, to a complete estrogen receptor antagonist (CERAN), OP1250, in a mutant ERa (MCF-7 Y537S ERa) MBC endocrine therapy resistant xenograft tumor model (MIND = Mammary intraductal) to examine the efficacy of both drugs in a metastatic context in which a frequently observed, aggressive mutant ERa is expressed. As single agents, both Lasofoxifene and OP1250 inhibited primary tumor growth as well as metastasis to the lung, liver, brain and bone, with greater effect at higher doses of each drug, and both were substantially more effective than fulvestrant, the current gold standard for treating progressive disease. When combined with palbociclib, an additional decrease in metastasis was observed, compared to lasofoxifene, OP1250 or palbociclib as single agents. In total, these results demonstrate that lasofoxifene, a SERM, is as effective as OP-1250, a complete ER antagonist and SERD in a xenograft MIND model of mutant ER+ metastatic breast cancer. The potential use of lasofoxifene or OP1250, both alone and in combination with CDK4/6 inhibitors, to reduce tumor growth and metastasis in patients with ET-resistant metastatic breast cancer, is being tested in clinical trials to determine whether either drug is a preferred therapy versus current standard of care for mutant ER+ MCB. Citation Format: G. Greene. SERMs versus SERDs for targeting ESR1 mutations abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr SoA3-01.