Abstract PR08: Intratumoral heterogeneity drives resistance to Antibody Drug Conjugate therapy: Analysis of the NeoSTAR trial of neoadjuvant Sacituzumab govitecan for localized TNBC

Abstract Antibody Drug Conjugates (ADCs) are proving to be groundbreaking therapeutics for all breast cancer subtypes. Sacituzumab govitecan (SG), an ADC targeting the TROP2 tumor antigen and harboring a topoisomerase 1 inhibitor payload, improves overall survival in advanced Hormone Receptor positive (HR+) and Triple Negative Breast Cancer (TNBC). However, SG has not been tested in early-stage breast cancer, and response predictors and mechanisms of resistance to SG in any setting remain to be defined. We thus designed the NeoSTAR trial, a Phase 2 study of response-guided neoadjuvant SG for localized TNBC, in which 50 patients received single-agent SG followed by imaging and tumor bed biopsy, with subsequent therapy determined by clinical and pathologic response. We collected fresh pre-treatment and post-SG biopsies and carried out analysis employing single-cell RNAseq, exome sequencing, and spatial analysis. As anticipated, cell composition of TNBCs between subjects was highly heterogenous but revealed non-tumor cell types predictive of pathologic complete response (pCR) to SG alone. As in the metastatic setting, tumor cell TROP2 levels were variable both within and between TNBCs, and were not predictive of response to SG. In contrast, we identified tumor cell-intrinsic pathways predictive of response that were the same as those identified in parallel genome-wide CRISPR screens for SG response pathways in TNBC. Analysis of matched pre/post treatment specimens demonstrated substantial clonal selection and clonal evolution post SG. Of particular interest were small subpopulations of tumor cells with shared properties that were present in multiple tumors in very small numbers pre-treatment but dramatically expanded post-treatment, suggesting the presence of a common resistance phenotype. Ongoing work to be presented focuses on defining the nature of the shared resistant subpopulations, and on comprehensively assessing the genomic correlates of response to SG versus standard chemotherapy. In summary, detailed single-cell and genomic analysis of single-agent ADC therapy in treatment-naïve primary TNBC reveals how intratumoral heterogeneity and subclonal resistance phenotypes shape the landscape of treatment response. These observations provide new insights relevant to the clinical application of this complex class of therapeutics. Citation Format: Laura M. Spring, Bogang Wu, Ting Liu, Jacob Geisberg, Simona Cristea, Veerle Bossuyt, Rachel Occhiogrosso Abelman, Nicole Peiris, James Coates, Siang-Boon Koh, Mengran Zhang, Lianne Ryan, Beverly Moy, Steven J. Isakoff, Sara M. Tolaney, Franziska Michor, Aditya Bardia, Leif W. Ellisen. Intratumoral heterogeneity drives resistance to Antibody Drug Conjugate therapy: Analysis of the NeoSTAR trial of neoadjuvant Sacituzumab govitecan for localized TNBC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR08.