Oral Selective Estrogen Receptor Degraders (SERDs) in Breast Cancer: Advances, Challenges, and Current Status

Teesha Downton,1,2 Fiona Zhou,1,2 Davendra Segara,1 Rinath Jeselsohn,3,* Elgene Lim1,2,* 1Garvan Institute of Medical Research, Sydney, NSW, Australia; 2School of Clinical Medicine, St Vincent’s Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; 3Dana-Farber Cancer Institute, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Elgene Lim, Tel +61 2 9355 5600, Fax +61 2 9355 5602, Email e.lim@garvan.org.auAbstract: Several endocrine therapies are currently available for the treatment of estrogen receptor (ER) positive breast cancer, but the clinical benefit of these agents is limited by endocrine therapy drug resistance. A common mechanism of endocrine therapy resistance is ESR1 mutations. The first-generation selective estrogen receptor degrader (SERD) fulvestrant has activity against ESR1 mutant tumors but requires intramuscular injection and has poor bioavailability that precludes optimal drug dosing. This led to the development of second-generation SERDs which are potent and have improved oral bioavailability and pharmacokinetics. Several of these oral SERDs are now in phase III trials in both the early and advanced ER positive breast cancer settings. This review summarizes the background of oral SERD development, the current status and future perspectives.Keywords: selective estrogen receptor degraders, breast cancer, estrogen receptor