Molecular Subtyping of Triple‐Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance. (1st June 2020)

• Record Type: Journal Article
• Authors: Zhao, Shen; Ma, Ding; Xiao, Yi; Li, Xiao‐Mei; Ma, Jian‐Li; Zhang, Han; Xu, Xiao‐Li; Lv, Hong; Jiang, Wen‐Hua; Yang, Wen‐Tao; Jiang, Yi‐Zhou; Zhang, Qing‐Yuan; Shao, Zhi‐Ming
• Is Part Of: Oncologist. Volume 25:Number 10(2020)
• Page Start: e1481
• Page End: e1491
• Publication Date: 2020-06-01
• Subjects: Triple‐negative breast cancer -- Molecular classification -- Immunohistochemistry -- Precision medicine; Oncology -- Periodicals; Tumors -- Periodicals; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Oncology; Tumors; Neoplasms; Electronic journals; Periodicals; Periodicals; 616.994
• DOI: 10.1634/theoncologist.2019-0982
• Languages: English
• ISSNs: 1083-7159

Abstract

Abstract: Background: Molecular subtyping of triple‐negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs. Materials and Methods: By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) ( n = 360) and The Cancer Genome Atlas data set ( n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC‐based classifier, and applied it to another two cohorts ( n = 183 and 214). Results: We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC‐based luminal androgen receptor (IHC‐LAR; AR‐positive [+]), (b) IHC‐based immunomodulatory (IHC‐IM; AR‐negative [−], CD8+), (c) IHC‐based basal‐like immune‐suppressed (IHC‐BLIS; AR−, CD8−, FOXC1+), (d) IHC‐based mesenchymal (IHC‐MES; AR−, CD8−, FOXC1−, DCLK1+), and (e) IHC‐based unclassifiable (AR−, CD8−, FOXC1−, DCLK1−). The κ statistic indicated substantial agreement between the IHC‐based classification and mRNA‐based classification. Multivariate survival analysis suggested that our IHC‐based classification was an independent prognostic factor for relapse‐free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC‐LAR subtype showed relative activation of HER2 pathway. The IHC‐IM subtype tended to exhibit an immune‐inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC‐BLIS subtype showed high expression of a VEGF signature. The IHC‐MES subtype displayed activation of JAK/STAT3 signaling pathway. Conclusion: We developed an IHC‐based approach to classify TNBCs into molecular subtypes. This IHC‐based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes. Abstract : This article describes an immunohistochemistry‐based approach to classification of triple‐negative breast cancers into molecular subtypes for purposes of the translation of TNBC molecular classification into clinical practice.