Abstract PO1-05-07: Circulating tumor DNA dynamics in acelERA Breast Cancer: a Phase II study of giredestrant for estrogen receptor-positive, HER2-negative, previously treated advanced breast cancer
Authors: Collier Ann , Bardia Aditya , Sohn Joo Hyuk , Lim Elgene , Chavez Marianna , Martín Miguel , Martinalbo Jorge , Perez-Moreno Pablo , Moore Heather 
Published: May 2024

BACKGROUND Giredestrant (GIR) is a highly potent, oral, selective estrogen receptor antagonist and degrader (SERD) that exhibits robust estrogen receptor (ER) occupancy. The Phase II, randomized, open-label acelERA Breast Cancer (BC) study (NCT04576455) assessed GIR vs physician’s choice of endocrine therapy (PCET) in second- or third-line ER-positive, HER2-negative advanced BC (ER+, HER2– aBC). The study did not reach statistical significance for the primary endpoint of investigator-assessed progression-free survival (PFS); however, the benefit of GIR was of larger magnitude among patients (pts) with ESR1-mutated tumors (ESR1m; a common cause of acquired resistance to endocrine therapy [ET]). We present an exploratory biomarker analysis of circulating tumor (ct)DNA dynamics. METHODS Pts (n = 303) were randomized 1:1 to GIR or PCET (75% of pts had fulvestrant [FUL]; 25%, an aromatase inhibitor). Partial response (PR), stable disease (SD), and progressive disease (PD) were categorized by RECIST v1.1. Plasma samples taken at Cycle 1, Day 1 (C1D1; n = 229), while on treatment (tx) at C2D1 (n = 220), and at the end of therapy (EOT; n = 155) were evaluated with the FoundationOne Liquid CDx next-generation sequencing assay. Gene mutations were defined as variants with known or likely impact on protein function. Composite tumor fraction (cTF) was defined as the total estimated tumor ctDNA content in each sample, and was only evaluable for a subset of samples (137 C1D1; 136 C2D1; 99 EOT). cTF or ESR1 mutant allele frequency (MAF) changes were calculated as a percent change from C1D1. ESR1m clonality was estimated as variant tumor fraction/estimated tumor fraction. Statistical significance was evaluated using the Mann–Whitney test. RESULTS The overall mutation landscape remained relatively unchanged with GIR tx at C2D1 or EOT, except for ESR1m prevalence, which declined from 43% at C1D1 to 26% on tx and 27% at EOT. With PCET, ESR1m prevalence decreased from 34% at C1D1 to 29% on tx, but increased to 43% by EOT. There were no concordant changes for other top mutated genes in this study, including PIK3CA, TP53, or DNMT3A. cTF decreased on tx in 38/65 (59%) and 32/59 (54%) of evaluable pts with GIR and PCET, respectively; the median change from C1D1 was –23% with GIR compared with –5% with PCET or –15% with FUL. The median change in cTF levels on tx with GIR was significantly greater in pts with a PR (–88%) vs PD (+6%, p = 0.002) or SD (–19%, p = 0.004). The degree of cTF decline on tx with GIR was significantly higher in pts with baseline ESR1m (median change –58%) vs no ESR1m detected (+5%, p = 0.012). Pts with a clonal ESR1m had higher levels of cTF decline on tx vs pts with subclonal ESR1m, suggesting cTF dynamics are a function of tumor heterogeneity. ESR1 MAF decreased on tx in 93% of pts with baseline ESR1m on GIR, vs 60% with PCET and 70% with FUL. ESR1 MAF decline on tx was significantly higher with GIR vs PCET at both C2D1 and EOT (p &lt; 0.0001). The average ESR1 MAF decline on tx with GIR was greater in pts with a PR (–97%) vs PD (–54%, p = 0.025) or SD (–48%, p = 0.051), and all seven GIR-treated pts with a PR showed a near or total loss of ESR1 MAF by C2D1. The ESR1m variants D538G and Y537X had a significantly greater decline in MAF on tx with GIR vs PCET or FUL (p &lt; 0.0001). CONCLUSIONS Data show that cTF and ESR1m ctDNA dynamics were associated with clinical response to GIR in ER+, HER2– aBC. ESR1 MAF decline was significantly greater with GIR vs PCET or FUL. ESR1 MAF declined to a greater degree with GIR compared with cTF, which is consistent with the larger magnitude of PFS benefit seen with GIR in pts with ESR1m tumors. The specific ESR1 variants D538G and Y537X showed greater sensitivity to GIR compared with PCET or FUL.

Citation Format: Ann Collier, Aditya Bardia, Joo Hyuk Sohn, Elgene Lim, Marianna Chavez, Miguel Martín, Jorge Martinalbo, Pablo Perez-Moreno, Heather Moore. Circulating tumor DNA dynamics in acelERA Breast Cancer: a Phase II study of giredestrant for estrogen receptor-positive, HER2-negative, previously treated advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-07.