Abstract 6438: Decoding the archetypes and ecotypes of triple-negative breast cancer in responses to chemotherapy

Abstract Triple-negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer. The pillar of treatment is chemotherapy, but only half of the patients have a complete response and good survival. To resolve inter- and intra-tumoral heterogeneity and determine their clinical associations, we performed single-cell RNA-sequencing and spatial transcriptomics methods including Visium and Xenium on treatment-naïve samples of TNBC patients in the ARTEMIS clinical trial. We find that TNBC was classified into 4 major archetypes at patient level: luminal secretory-associated, basal-associated, immunoreactive, and luminal androgen receptor. At cell level, cancer cells exhibited intratumoral heterogeneity in 13 gene expression metaprograms. The TNBC tumor microenvironment (TME) consisted of 49 distinct immune and stromal cell states, many of which were reprogrammed relative to normal breast tissues from disease-free women. We further identified 8 ecotypes of cancer cells and TME cell states that co-occurred among patients and were associated with specific archetypes and chemotherapy response groups. In contrast to previous work on T-cells, our data showed the importance of macrophage cell states and cancer cell metaprograms for interferon signaling, HLA expression and cell cycle activity that were associated with chemotherapy response. To facilitate a clinical application, we developed a 13-gene-based model to predict response. Collectively, this study provides new insights into the natural biology of untreated TNBC tumors and their association with chemotherapy response. Citation Format: Yun Yan, Yiyun Lin, Tapsi Kumar, Shanshan Bai, Aatish Thennavan, Jianzhuo Li, Tuan Tran, Min Hu, Mitchell Rao, Anna Casasent, Elizabeth Ravenberg, Gaiane Margishvili Rauch, Alyson Clayborn, Debu Tripathy, Alastair Thompson, Bora Lim, Lei Huo, Stacy Moulder, Clinton Yam, Nicholas Navin. Decoding the archetypes and ecotypes of triple-negative breast cancer in responses to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6438.