Abstract Background: Primary resistance to sacituzumab govitecan (SG) was reported in 24% of patients treated in the ASCENT trial. This retrospective study aims to explore biomarkers associated with primary resistance to SG in metastatic triple negative breast cancer (mTNBC) in a real world cohort. Methods: Patients (pts) with mTNBC treated with SG (2021-2024) at Gustave Roussy were eligible for this study if they had a formalin-fixed-paraffin-embedded tissue sample collected at any time before SG administration available. Trop-2 immunohistochemistry, multiplex immunofluorescence (MIF) for characterization of immune TME, targeted genomic panel and whole transcriptomic analysis using next-generation sequencing were performed and compared between patients with PFS on SG ≤ 3 vs 3 months. p values were adjusted for multiple testing. Results: 55 pts were included. Median age was 54 years (range 32-80). 12 (21.8%) pts had de novo mTNBC, 13 (23.6%) had more than 3 lines of therapy before SG, 13 (23.6%) had received 1st line immune checkpoint inhibitor, and 35 (63.6%) had visceral metastases. 17 pts had a PFS on SG ≤ 3 months. 36 samples were from metastatic sites (65.5%) and 19 from primary tumor (34.5%). Table below shows the results relevant to Trop-2 H-score and immune TME analyzed by MIF. Differential expression analysis of patients with PFS 3 months (versus ≤ 3 months) showed that the top 5 genes with the highest log2FC (3.75 - 2.59) were IGLV2-23, IGLV3-19, IGLV4-60, SFTPB, and IGHV1-2 (p-adj 0.05). In contrast, the 5 significant genes with the lowest log2FC (-2.22 - -3.16) were KRT6C, KCNT1, BRINP2, HMGA2, and KCNH7 (p-adj 0.05). Gene set enrichment analysis (GSEA) using the Gene Ontology, Biological Process database showed that patients with PFS 3 months were enriched for the “molecular mediator of immune response” geneset (p-adj 0.05) and suppressed for the “negative regulation of double-strand break repair via nonhomologous end joining” (p-adj 0.05) and the “pre-miRNA processing” (p-adj 0.05) genesets. Conclusion: Primary resistance to SG in pts with mTNBC seems to be derived by both an interplay between the tumor and immune microenvironment, and DNA repairing damage mechanisms. Genomic analysis will be also presented. Citation Format: E. Rassy, J. Paparo, B. Job, M. Triki-Lacroix, L. Lacroix, F. Mosele, P. Kannouche, F. Papa, C. Roussel-Simonin, L. Bordelet, N. Signolle, A. Viansone, J. Zeghondy, T. Grinda, C. Bousrih, N. Joyon, T. Ben Ahmed, T. Henry, V. Goldbarg, J. Ribeiro, S. Delaloge, F. Andre, S. Michiels, B. Pistilli. Biomarkers of primary resistance to sacituzumab govitecan in metastatic triple negative breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD3-10.
Rassy et al. (Tue,) studied this question.