Abstract PD7-02: Transcriptomic profiling of the tumor microenvironment indicates differential response to neoadjuvant chemotherapy with and without pembrolizumab in early TNBC

Abstract Background: Neoadjuvant chemotherapy (CT) with pembrolizumab (P) has significantly improved pathologic complete response (pCR) and survival outcomes compared to CT alone in patients (pts) with stage II-III TNBC. Predictive markers of response to the addition of P to CT are lacking. We compared tumor microenvironment (TME) composition inferred by gene expression at baseline (BL) and post-treatment (if residual disease, RD) in pts who received neoadjuvant CT vs CT-P. Methods: From the prospective DFCI Multicenter TNBC Registry, FFPE research or archival BL biopsies and surgical samples (if RD) from pts who received neoadjuvant CT or CT-P were reviewed for tumor content. RNA expression was quantified using whole transcriptome sequencing (WTS) of isolated RNA. TME cell type abundance was estimated using TIMER3 deconvolution methods. Comparison between groups was performed using linear models with tumor abundance as a covariate and paired samples as a random effect intercept. Associations with recurrence free (RFS) and overall survival (OS) used a Cox proportional hazards model adjusted for stage and pCR and a likelihood ratio test. Results: From 5/2019-1/2024, 125 pts with TNBC were identified: 50 CT, 75 CT-P. Median age at diagnosis was 51 (IQR: 42-61). Anatomic stage I, II and III was 13 (26.0%), 32 (64.0%) and 5 (10.0%) in the CT group; 5 (6.7%), 53 (70.7%) and 17 (22.7%) in the CT-P group. Neoadjuvant regimens included an anthracycline in 41/50 and 63/75, taxane in 50/50 and 73/75, and platinum in 10/50 and 72/75 pts, respectively. Germline BRCA1/2 status was known in 109 pts: 5/46 (10.9%) CT and 14/63 (22.2%) CT-P had pathogenic variants. BL biopsies were analyzed with WTS in 104 pts; 20/37 (54.1%) CT and 39/67 (58.2%) CT-P had pCR. Among 45 pts with RD, 43 RD samples were analyzed (35 with paired BL biopsy). Pts who experienced pCR had higher BL abundance of almost exclusively proinflammatory TME cell types (FDR