Abstract 1012: Selective estrogen receptor downregulators and immune checkpoint inhibitors in breast cancer immunotherapy

Breast cancers (BC) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diagnosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important intervention for BCs that express ERα, and it remains one of the most effective targeted treatments. However, substantial numbers of patients with localized disease, and almost all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents a class of ERα antagonists that elicit selective ER downregulation (SERDs), an action that helps overcome several resistance mechanisms. Unfortunately, full antitumor efficacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC cells in vitro, we find that these compounds suppress ERα protein levels with efficacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell proliferation in vitro even in the presence of estradiol-17β. In vivo, SERD-128 significantly inhibits tumor growth in MCF-7 xenograft models in a dose-dependent manner (P Citation Format: Diana C. Marquez-Garban, Gang Deng, Begonya Comin-Anduix, Alejandro J. Garcia, Emelyine Diers, Gaoyuan Ma, Nalo Hamilton, Michael E. Jung, Richard J. Pietras. Selective estrogen receptor downregulators and immune checkpoint inhibitors in breast cancer immunotherapy [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 1012.