Abstract 4628: Profiling the tumor microenvironments of triple- and quadruple-negative breast cancers
Authors: Saini Geetanjali , Rupji Manali , Bhargava Mahak , Badve Sunil , Aneja Ritu 
Published: April 2023

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype that lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Approximately 15%-20% of breast cancers are triple-negative. Based on expression of the androgen receptor (AR), TNBC can be categorized as AR-positive (AR+ TNBC) or AR-negative (quadruple-negative breast cancer, QNBC). Studies have reported that the loss of AR expression is associated with poor prognoses. Recent evidence suggests that QNBCs disproportionately affect women of African descent and contributes to poor overall survival. QNBC is a more aggressive disease compared to TNBC, and patients with QNBC currently have no treatment options beyond chemotherapy. Data from interrogating public databases such as TCGA indicates that QNBC is distinct from TNBC in molecular makeup, particularly in immune tumor microenvironment. Currently, QNBC is not considered distinct from the broader TNBC subtype, hence a comprehensive molecular characterization is lacking. We aim to examine differences between the TNBC and QNBC tumor microenvironments that consist of both immune and stromal components. We analyzed RNA expression data from the METABRIC (TNBC= 11, QNBC= 185) and TCGA (TNBC= 29, QNBC= 103) datasets. Based on AR transcript expression, patients with TNBC were stratified into AR-low (considered QNBC) and AR-high (deemed ‘true’ TNBC) groups. The analytical immune tools - CIBERSORTx and xCELL were used to analyze the RNA-Seq data. CIBERSORTx can distinguish 22 mature human hematopoietic populations and provides abundance of member cell types in a mixed cell population, from gene expression data. xCELL is a gene signature-based method that can perform cell type enrichment analysis from gene expression for 64 immune and stromal cell types. Thus, xCell can discriminate between closely related cell types. Using these immune tools, the tumor microenvironments of the TNBC and QNBC groups were compared. Correlations between individual immune and stromal components with patient survival probability were assessed. Significant differences (p-value &lt;0.05) in several immune and stromal cell types were noted when comparing the TNBC and QNBC groups within these datasets. CIBERSORTx and xCELL yielded both unique and common sets of cell types. Notably, significant differences in the stroma score (a composite score of stromal cell types provided by xCELL) were observed between TNBC and QNBC in both the METABRIC and TCGA datasets. These immune tools are based on different methodologies and our results show that they can provide complementary information. Our data suggest that QNBC and TNBC have distinct tumor microenvironments, and that QNBC should be considered as an independent breast cancer subtype that warrants comprehensive characterization.

Citation Format: Geetanjali Saini, Manali Rupji, Mahak Bhargava, Sunil Badve, Ritu Aneja. Profiling the tumor microenvironments of triple- and quadruple-negative breast cancers. [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 4628.