A liquid biopsy assay of estrogen receptor activity predicts response to giredestrant in ER+/HER2− advanced breast cancer

Background: Endocrine resistance limits benefit durability in ER+/HER2− advanced breast cancer (aBC), particularly after CDK4/6 inhibition. Prior studies have shown that tumor RNA-based estrogen receptor (ER) activity predicts response to the oral SERD giredestrant and serves as a pharmacodynamic (PD) biomarker of ER pathway suppression. However, tumor RNA profiling requires serial biopsies which are often challenging in aBC. The Precede ER Dependence Index (PERDI) quantifies ER-driven cis-regulatory enhancer activity from circulating chromatin, enabling noninvasive monitoring of ER pathway dependence and treatment response. Methods: 87 patients (pts) with ER+/HER2− aBC received second or third line giredestrant, alone or in combination. One milliliter of plasma from 87 pre-treatment (tx) and 9 on-tx samples was profiled using Precede's comprehensive epigenomic liquid biopsy assay. PERDI scores were evaluable for 80 pre-tx and 8 on-tx samples. Baseline ESR1 mutation (m) status was determined using the FoundationOne®Liquid CDx assay. PERDI concordance was assessed against tissue ER activity from matched RNA-seq. Plasma-based gene expression was inferred using Precede's algorithms that integrate enhancer, promoter and DNA methylation features. Results: Plasma PERDI strongly correlated with tumor tissue ER activity in pts without detectable ESR1 m and effectively discriminated ESR1 m status. Plasma-derived predictions of ER signaling-related genes were concordant with tumor RNA-seq results, with identified genes offering biological insights into clinical response. At baseline, PERDI distinguished RECIST 1.1-evaluated responders well compared to tumor ER activity or ctDNA level. Similar to tumor ER activity, a median split of PERDI demonstrated strong predictive power (HR=0.43; CI: 0.20-0.93), with median PFS of 11.4 months in the PERDI-high group and 2.0 months in the PERDI-low group. The effect size was further enhanced when comparing the top versus bottom PERDI tertiles (HR=0.19; CI: 0.07-0.52). PERDI complemented ESR1 m status and ctDNA levels in predicting response, identifying rapid progressors with ESR1 m as well as durable responders despite high ctDNA or absent ESR1 m. PERDI declined on-tx in all partial responders (3/3), suggesting pathway-specific modulation beyond ctDNA effects. Conclusions: PERDI quantifies plasma-based ER activity and predicts giredestrant benefit, particularly when integrated with ESR1 genotype or ctDNA tumor fraction. PERDI also showed early evidence of PD change directly from plasma, mitigating the need for serial tumor biopsies. cfDNA-based gene expression modeling enables noninvasive assessment of ER dependence and response-associated transcriptional programs, offering a scalable framework for monitoring endocrine response and adaptation in ER+/HER2− aBC.