Predictive Markers of Response to Neoadjuvant Durvalumab with Nab-Paclitaxel and Dose-Dense Doxorubicin/Cyclophosphamide in Basal-Like Triple-Negative Breast Cancer

Purpose: We examined gene expression, germline variant, and somatic mutation features associated with pathologic response to neoadjuvant durvalumab plus chemotherapy in basal-like tripleExperimental Design: Germline and somatic whole-exome DNA and RNA sequencing, programmed death ligand 1 (PD-L1) IHC, and stromal tumor-infiltrating lymphocyte scoring were performed on 57 patients. We validated our results using 162 patients from the GeparNuevo randomized trial. Results: Gene set enrichment analysis showed that pathways signaling, cancer drivers, cell cycle, apoptosis, and DNA repair were enriched in cases with pathologic complete response (pCR), whereas epithelial-mesenchymal transition, extracellular matrix, and TGFI3 pathways were enriched in cases with residual disease (RD). Immune-rich bTNBC with RD was enriched in CCL-3,-4,-5, -8,-23, CXCL-1,-3,-6,-10, and IL1,-23,-27,-34, and had higher expression of macrophage markers compared with immune-rich cancers with pCR that were enriched in IFNy, IL2,-12,-21, chemokines CXCL-9,-13, CXCR5, and activated T-and B-cell markers (GZMB, CD79A). In the validation cohort, an immune-rich five-gene signature showed higher expression in pCR cases in the durvalumab arm (P = 0.040) but not in the placebo arm (P = 0.923) or in immune-poor cancers. Independent of immune mar-kers, tumor mutation burden was higher, and PI3K, DNA damage repair, MAPK, and WNT/I3-catenin signaling pathways were enriched in germline and somatic mutations in cases with pCR. Conclusions: The TGFI3 pathway is associated with immune-poor phenotype and RD in bTNBC. Among immune-rich bTNBC RD, macrophage/neutrophil chemoattractants dominate the cyto-kine milieu, and IFNy and activated B cells and T cells dominate immune-rich cancers with pCR.