Comprehensive Profiling of Poor-Risk Paired Primary and Recurrent Triple-Negative Breast Cancers Reveals Immune Phenotype Shifts
| Autor: | Yuan Yuan, Radia M. Johnson, Daniel Schmolze, Katherine E. Hutchinson, Adrian R. Carr, Daniel L. Halligan, Ching-Wei Chang, Paul R. McAdam, Susan E. Yost, Jackson Liang, Chun-Chieh Chang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Breast Neoplasms Triple Negative Breast Neoplasms Biology Article Transcriptome 03 medical and health sciences Lymphocytes Tumor-Infiltrating 0302 clinical medicine Germline mutation Gene expression Biomarkers Tumor Tumor Microenvironment Humans KEGG Gene Exome sequencing Phenotype 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: Emerging data suggest immune checkpoint inhibitors have reduced efficacy in heavily pretreated triple-negative breast cancers (TNBC), but underlying mechanisms are poorly understood. To better understand the phenotypic evolution of TNBCs, we studied the genomic and transcriptomic profiles of paired tumors from patients with TNBC. Experimental Design: We collected paired primary and metastatic TNBC specimens from 43 patients and performed targeted exome sequencing and whole-transcriptome sequencing. From these efforts, we ascertained somatic mutation profiles, tumor mutational burden (TMB), TNBC molecular subtypes, and immune-related gene expression patterns. Stromal tumor-infiltrating lymphocytes (stromal TIL), recurrence-free survival, and overall survival were also analyzed. Results: We observed a typical TNBC mutational landscape with minimal shifts in copy number or TMB over time. However, there were notable TNBC molecular subtype shifts, including increases in the Lehmann/Pietenpol-defined basal-like 1 (BL1, 11.4%–22.6%) and mesenchymal (M, 11.4%–22.6%) phenotypes, and a decrease in the immunomodulatory phenotype (IM, 31.4%–3.2%). The Burstein-defined basal-like immune-activated phenotype was also decreased (BLIA, 42.2%–17.2%). Among downregulated genes from metastases, we saw enrichment of immune-related Kyoto Encyclopedia of Genes and Genomes pathways and gene ontology (GO) terms, and decreased expression of immunomodulatory gene signatures (P < 0.03) and percent stromal TILs (P = 0.03). There was no clear association between stromal TILs and survival. Conclusions: We observed few mutational shifts, but largely consistent transcriptomic shifts in longitudinally paired TNBCs. Transcriptomic and IHC analyses revealed significantly reduced immune-activating gene expression signatures and TILs in recurrent TNBCs. These data may explain the observed lack of efficacy of immunotherapeutic agents in heavily pretreated TNBCs. Further studies are ongoing to better understand these initial observations. See related commentary by Savas and Loi, p. 526 |
| Databáze: | OpenAIRE |
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