Abstract 2043: Circulating tumor DNA (ctDNA) mutation analysis at baseline (BSL) and end of treatment (EOT) with sacituzumab govitecan (SG) and clinical impact on efficacy in patients (pts) with HR+/HER2- metastatic breast cancer (mBC): Biomarker res

Abstract Background: SG is approved in pretreated HR+/HER2- mBC based on the TROPiCS-02 study (NCT03901339). Mutations in specific genes may affect efficacy of SG, including PIK3CA/TP53 (common in BC, may impact outcomes) and TACSTD2/TOP1 (may confer resistance to Trop-2-directed ADCs like SG). We assessed specific mutations at BSL and EOT in TROPiCS-02 to identify genes that may be involved in acquired SG resistance. Methods: Randomized pts received SG or chemotherapy treatment of physician’s choice (TPC). Plasma samples were collected at BSL and EOT, and ctDNA was analyzed using Guardant Health’s Infinity RUO ctDNA panel. Specific genes were analyzed to determine association with clinical outcomes (progression-free survival [PFS] and overall survival [OS]). Unbiased analysis at EOT was used to identify genes associated with SG resistance. Results: Pt characteristics, PFS, and OS were similar between the intent-to-treat (ITT; N=543) and ctDNA (46% of ITT) populations. PFS and OS benefit was observed with SG vs TPC regardless of PIK3CA or TP53 mutation status (Table). At BSL and EOT, no TACSTD2 mutations were observed in the SG arm. At BSL, 3 TOP1 mutations (I435V, D122H, M319I) were detected in 2 pts, and at EOT, 1 new TOP1 mutation (G717V) was detected in the SG arm (184 days treatment). At BSL 64% of pts had ≥1 deleterious variant in the 69-gene DDR panel. No clear expansion or clearance of individual DDR genes or variants was observed at EOT. Conclusions: Survival benefit was observed with SG vs TPC in pts with and without PIK3CA and TP53 mutations, similar to the ITT population. Our matched BSL to EOT analyses did not identify any genes that were clear drivers of SG resistance in pretreated HR+/HER2- mBC. Future analyses would benefit from paired biopsies at BSL and at disease progression to identify potential drivers of SG resistance. Citation Format: Hope S. Rugo, Yi Zhang, Shan Tang, Frederik Marmé, Peter Schmid, Javier Cortés, Sara M. Tolaney, Oh Kyu Yoon, Wendy Verret, Meghna Das Thakur, Aditya Bardia. Circulating tumor DNA (ctDNA) mutation analysis at baseline (BSL) and end of treatment (EOT) with sacituzumab govitecan (SG) and clinical impact on efficacy in patients (pts) with HR+/HER2- metastatic breast cancer (mBC): Biomarker results from TROPiCS-02. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2043.