Caution over haste: why novel endocrine therapy in early lines should wait in Estrogen receptor positive human epidermal growth factor receptor 2 negative breast cancer

Abstract The rapid development of novel endocrine therapies (ETs), such as selective estrogen receptor degraders (SERDs), proteolysis targeting chimeras (PROTACs), selective estrogen receptor covalent antagonists (SERCAs), and complete estrogen receptor antagonists (CERANs) has generated enthusiasm for their use in earlier treatment lines in advanced estrogen receptor-positive (ER+) human epidermal receptor 2-negative (HER2-) breast cancer (BC). Multiple phase III trials have demonstrated progression-free survival (PFS) benefit for novel ETs, especially in patients harboring ESR1 mutations. However, their broader use may be limited by toxicity concerns, adherence challenges, need for combination therapy, and financial burden. In this manuscript, we provide a concise review of key clinical trial outcomes for novel ETs with a focus on SERDs and critically evaluate their use in earlier lines of therapy. We also examine the design of ongoing adjuvant and first-line trials and explore the clinical implications of circulating tumor DNA (ctDNA)-guided treatment strategies.