Loss of luminal lineage drives resistance to next-generation ERα antagonists in pretreated ER+ HER2- locally-advanced or metastatic breast cancer.

Next-generation selective estrogen receptor-α (ERα) antagonist/degraders (SERDs) are being developed for ER-positive breast cancer (ER+ BC), with intentions of improving outcomes for patients. In recent clinical trials of metastatic ER+ BC, next-generation SERDs demonstrated clinical activity, and elacestrant received an approval for advanced ESR1-mutant disease. However, responses to these drugs were highly heterogeneous: across trials and independent of ESR1 status, 30-50% of patients progressed by their first follow-up scan while other patients sustained benefit for 2 years or more. Here, we interrogate the basis for heterogeneous responses by comparing biopsies from non-responding patients (NR; progression-free survival <2 months) and responding patients (Resp; PFS ≥ 2 months) who received the next-generation SERD giredestrant. While Resp tumors maintain high dependency on ERα signaling, NR tumors exhibit loss of luminal lineage identity and by extension, ERα dependence. NR tumors instead up-regulate multiple ERα-independent proliferative pathways, such as EGFR/MAPK and Hippo/TEAD, which may represent targetable dependencies in NR disease. Modeling resistance and lineage plasticity in vitro, we find that giredestrant-resistant ER+ BC cell lines exhibit profound shifts in chromatin accessibility, with the transcription factors, FOXA1 and FOXM1, implicated in gene expression of NR-upregulated proliferative pathways.