Abstract 1497: Longitudinal response and selection under neoadjuvant systemic therapy (NAST) in triple-negative breast cancer (TNBC): Profiling results from a randomized trial (ARTEMIS; NCT02276443)

Background: The heterogeneity of TNBC results in a spectrum of responses to NAST: 30-40% of patients (pts) have a pathologic complete response (pCR) with an excellent prognosis. Several methods have been used to measure and evaluate residual disease, including ultrasound, MRI scans, histo-pathology. In addition to these, we hypothesize that comprehensive molecular profiling of longitudinal biopsies, with an integrative evaluation of sub-clonal selection and changes in molecular pathways, will serve as a critical biomarker for chemotherapy, and subsequent targeted therapy trials. Methods: Pts with stage I-III TNBC began a planned 4 cycles of Adriamycin-based chemo (AC). Biopsies were performed pre (mandatory) and post (optional) AC. Volumetric change by ultrasound (VUS) at completion of AC (or progression) was calculated. Pts with sensitive disease received subsequent taxane-based (T) therapy. Pts with insensitive disease were offered phase II trials. Pathologic response was assessed at surgical resection in 85 pts (Training N=55, Validation N=30). Matched samples, pre and post AC (N = 85 pts) underwent transcriptomic and genomic profiling. Samples were classified into six previously identified ARTEMIS subtypes of TNBC (ART-Type) and immune deconvolution and estimation were performed using RNA-Seq profiles. Multiplex IHC using the Vectra platform is being used to validate results from bulk RNASeq experiments. Somatic mutations and copy-number changes were evaluated using, Mutect2, Sequenza (and FACETs), and PhyloWGS (and PyClone). Results: Predominately, tumors reacted to AC in 4 different patterns with variation in immune and EMT related pathways. Enrichment of EMT (Group 4) was associated with poor prognosis and higher RCB (10.3% vs 42% pCR rates, p