Abstract 3311: Tumor cell total mRNA level predicts disease progression across multi-ethnic patient cohorts with triple-negative breast cancer

Abstract

Abstract Tumor heterogeneity presents a major challenge in the clinical management of breast cancers by impacting patient’s prognosis, therapeutic response, and clinical outcomes. Triple-negative breast cancer (TNBC) carries the worst prognosis among all the breast cancer intrinsic subtypes and has limited treatment options. Currently, TNBC subtypes are mainly refined into four categories: basal-like (BL1 and BL2), luminal androgen receptor (LAR) and mesenchymal (M). Although each of these tumor-specific subtypes represent different gene expression profiles, response to standard treatments and prognosis, further studies did not confirm a prognostic value for these subtypes. Given the distinct outcomes of TNBC patients, there is an urgent need to stratify their prognosis and identify patients who may benefit from potential targeted therapy. TNBC tumors often harbor cancer cells with different features in both genomic and transcriptomic level. With deconvolution of existing genomic and transcriptomic data, we derived a mathematical definition of breast cancer cell plasticity at a patient level. With a total of 765 TNBC patients from The Cancer Genome Atlas (TCGA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), Fudan University Shanghai Cancer Center (FUSCC) and Sweden Cancerome Analysis Network-Breast project (SCAN-B), we measured tumor-cell total mRNA expression scores (TmS) through an integrative deconvolution method with matched DNAseq and RNAseq data. In our previous study (Cao et al. Nature Biotechnology 2022), high TmS value is significantly associated with favorable prognosis in both TCGA (n=108) and METABRIC (n=214). We now validated this finding in both FUSCC from Han Chinese (n=245) and SCAN-B from Swedes (n=198). With TmS as a patient-level phenotypic feature, we performed differential expression analysis and gene set enrichment analysis to understand the biological functions indicated by TmS. In all four TNBC cohorts, patients with lower TmS are associated with epithelial to mesenchymal and TGFβ signaling hallmark pathways, with the latter presenting potential molecular targets for TNBC. Gene ontology enrichment revealed patients with higher TmS overexpress genes that are related with immune activities such as B cell and lymphocyte activation. Our results suggest a unique utility of tumor-specific total mRNA level in identifying high-risk TNBC patients across multi-ethnic cohorts and tailoring treatment on individual basis to maximize clinical benefit. Citation Format: Yaoyi Dai, Shaolong Cao, Bora Lim, Johan Staaf, Gloria V. Echeverria, Wenyi Wang. Tumor cell total mRNA level predicts disease progression across multi-ethnic patient cohorts with triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3311.