Hormone receptor-positive breast cancer is the most common breast cancer subtype, and for decades its treatment rested on a relatively stable pharmacological foundation. That foundation is now shifting rapidly — with implications not just for metastatic disease but potentially for earlier-stage treatment where cure, not control, is the goal.
This review in Clinical Breast Cancer maps the evolving landscape of oral estrogen receptor (ER)-targeting agents for ER-positive, HER2-negative breast cancer. Two FDA-approved selective estrogen receptor degraders (SERDs) — elacestrant and imlunestrant — are examined alongside vepdegestrant, a first-in-class proteolysis-targeting chimera (PROTAC) that recently cleared FDA approval. Unlike traditional SERDs, which block and degrade ER protein, PROTACs commandeer the cell's own ubiquitin-proteasome system to eliminate the receptor entirely, offering a mechanistically distinct approach to ER suppression. The review also covers pipeline agents including complete estrogen receptor antagonists (CERANs) and selective estrogen receptor covalent antagonists (SERCAs), each exploiting different binding modes to overcome resistance mutations — particularly the ESR1 mutation that commonly emerges after aromatase inhibitor therapy and drives endocrine resistance.
The clinical importance of this proliferation of drug classes lies in the resistance problem that has long plagued endocrine therapy. ESR1 mutations, detected in circulating tumor DNA, are now actionable biomarkers that can guide sequential drug selection — a precision oncology approach gaining real traction. The PROTAC mechanism is particularly noteworthy: by degrading rather than merely inhibiting the ER, it may suppress receptor activity even when mutations alter the ligand-binding domain. However, most data reviewed here come from metastatic settings, and translation to curative-intent early-stage disease requires dedicated trial evidence. The clinical community should also watch for combinability data — how these agents pair with CDK4/6 inhibitors and PI3K-pathway drugs will likely determine their ultimate place in therapy. Overall, this is a confirmatory but consequential review charting a genuinely expanding toolkit.