Abstract P2-16-08: Longitudinal response and selection under neoadjuvant systemic therapy (NAST) in triple-negative breast cancer (TNBC): Profiling results from a randomized, TNBC enrolling trial to confirm molecular profiling improves survival (ARTEMIS; NCT02276443)
Authors: Seth Sahil , Huo Lei , Vasaikar Suhas , Rauch Gaiane , Lim Bora , White Jason , Adrada Beatriz , Piwnica-Worms Helen , Ueno Naoto T , Thompson Alastair Mark , Mittendorf Elizabeth , Tripathy Debashish , Litton Jennifer Keating , Symmans William Fraser , Draetta Giulio , Futreal Andrew , Chang Jeffrey , Moulder Stacy 
Published: March 2020

Abstract
Background: The heterogeneity of TNBC results in a spectrum of responses to NAST: 30-40% of patients (pts) have pathologic complete response (pCR) with excellent prognosis. Several methods have been used to measure and evaluate residual disease, including ultrasound, MRI scans, histo-pathology and transcriptional profiling (Seth, ASCO 2019). In addition, we hypothesize that integrative understanding of sub-clonal selection and changes in molecular pathways would lead to better stratification as a 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 55 pts. Matched samples, pre and post AC (N = 55 pts) underwent transcriptomic and genomic profiling. Samples were classified into six previously identified ARTEMIS subtypes of TNBC (ART-Type) and immune deconvolution and estimation was performed using RNA-Seq profiles. Somatic mutations and copy-number changes were evaluated using, Mutect, FACETS, 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&lt;0.05). The global changes in transcription led to ART-Type switching in all subtypes (44% of pts), except LAR subtype. MYC amplification was more prevalent (40%) in Group 4, associated with higher EMT and poor prognosis than other groups (28%). Phylogenetic evaluation of selection revealed, sub-clonal selection in 22% of evaluable cases with pre and post biopsies. Conclusions: Molecular profiling of longitudinal TNBC samples reveals distinct response patterns in tumors and their micro-environments upon treatment with AC. Integrative analysis of genomic and transcriptomic changes can lead to better stratification of response to NAST. These patterns were indicative of pathologic response in this cohort; however, they require validation in a separate cohort.
Citation Format: Sahil Seth, Lei Huo, Suhas Vasaikar, Gaiane Rauch, Bora Lim, Jason White, Beatriz Adrada, Helen Piwnica-Worms, Naoto T Ueno, Alastair Mark Thompson, Elizabeth Mittendorf, Debashish Tripathy, Jennifer Keating Litton, William Fraser Symmans, Giulio Draetta, Andrew Futreal, Jeffrey Chang, Stacy Moulder. Longitudinal response and selection under neoadjuvant systemic therapy (NAST) in triple-negative breast cancer (TNBC): Profiling results from a randomized, TNBC enrolling trial to confirm molecular profiling improves survival (ARTEMIS; NCT02276443) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-08.