Abstract 2039: High mesothelin expressing triple negative breast cancer is associated with enhanced cell proliferation but without impact on survival outcomes

Abstract Introduction: Mesothelin (MSLN) is a cell surface glycoprotein commonly expressed on several types of cancer including breast cancer (BC). Despite lacking an intracellular signaling domain or known physiologic function, MSLN is implicated in aggressive tumor behavior. Although known for high MSLN prevalence, its biological role in triple-negative breast cancer (TNBC) remains largely unexplored. We utilized multiple independent large patient cohorts with comprehensive gene expression profile and clinical variables to unravel the functional and clinical implications of MSLN expression in TNBC. Methods: Clinical variables and transcriptome of a total of 628 TNBC patients were gathered from three independent cohorts: The Cancer Genome Atlas (TCGA, n=160), the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n=313), and The Sweden Cancerome Analysis Network - Breast (SCAN-B, GSE96058, n=155). Four neoadjuvant chemotherapy (NAC) cohorts; GSE32603, GSE25066, GSE163882, and GSE123845 were also analyzed. Results: Using single-cell sequence cohorts, SCP1039 and SCP1106, we found that MSLN is exclusively expressed in cancer epithelial cells, and its expression is associated with less stromal cells (adipocytes and fibroblasts) in the TNBC tumor microenvironment. High expression of MSLN was associated with the TNBC subtype and advanced lymph node metastasis in BC of TCGA, METABRIC, and SCAN-B cohorts (all p < 0.001). Unexpectedly, MSLN expression was not associated with Disease-Free, Disease-Specific, nor Overall Survival in any of the TNBC cohorts analyzed (all p > 0.05). MSLN expression was significantly higher in TNBC that achieved pathological complete response after neoadjuvant chemotherapy in the GSE25066 cohort (p < 0.001), although there was no survival difference by MSLN expression in this cohort, either. Consistent with its immunological role, MSLN-high tumors exhibited a pro-inflammatory microenvironment, including higher Cancer-Testis Antigen (CTA) scores and increased activity of immune cells, notably immature dendritic cells (iDCs) and M1 macrophages (all p < 0.05). Biologically, MSLN expression was linked to elevated cellular proliferation, as evidenced by correlation with Ki67 gene expressions and histological grade consistently in TCGA, METABRIC and SCAN-B. Hallmark cell proliferation-related gene sets, G2M checkpoint, E2F targets, and Mitotic Spindle were significantly enriched in MSLN-high TNBC in METABRIC and SCAN-B (all FDR < 0.25). Conclusion: MSLN-high TNBC is characterized by enhanced cell proliferation and a pro-inflammatory microenvironment, showing better response to neoadjuvant chemotherapy without significant impact on long-term survival outcomes. These data may be useful for future studies in MSLN-targeted therapies. Citation Format: Takumi Sato, Brendan Hagerty, Rongrong Wu, Takashi Ishikawa, Kazuaki Takabe. High mesothelin expressing triple negative breast cancer is associated with enhanced cell proliferation but without impact on survival outcomes [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 2039.