根据免疫组化对三阴性乳腺癌分子分型
根据基因表达分析三阴性乳腺癌分子亚型，对于深入了解该异质性疾病的分子本质以及指导个体化治疗至关重要。不过，并非任何医院都有条件进行基因测序，可是大多数医院都有条件进行免疫组织化学（免疫组化）检查，故有必要通过免疫组化对三阴性乳腺癌分子亚型进行分析。
2020年5月14日，美国转化肿瘤学会《肿瘤学家》在线发表复旦大学附属肿瘤医院赵珅、马丁、肖毅、徐晓丽、吕泓、蒋文华、杨文涛、江一舟、邵志敏、哈尔滨医科大学附属肿瘤医院李晓梅、马健力、张翰、张清媛等学者的研究报告，设计了一种基于免疫组化对三阴性乳腺癌进行分子亚型分析的临床实用方法。
该研究首先对2007～2017年复旦大学附属肿瘤医院360例三阴性乳腺癌和美国癌症基因组图谱数据库158例三阴性乳腺癌的核糖核酸（RNA）测序数据进行回顾分析，确定可以识别的特定分子亚型标记。随后对其中210例三阴性乳腺癌肿瘤切片进行免疫组化染色，基于免疫组化建立分类方法，并且将其用于2007～2014年复旦大学附属肿瘤医院183例三阴性乳腺癌和2011～2014年哈尔滨医科大学附属肿瘤医院214例三阴性乳腺癌进行验证。
结果，雄激素受体AR、杀伤型T淋巴细胞膜受体CD8、转录因子复制叉头部区FOXC1、丝氨酸苏氨酸蛋白质激酶DCLK1被选择作为免疫组化标记，并且根据染色结果将三阴性乳腺癌分为五种亚型：
基于免疫组化的雄激素受体管腔亚型：AR阳性
基于免疫组化的免疫调节亚型：雄激素受体阴性、CD8阳性
基于免疫组化的基底样免疫抑制亚型：雄激素受体阴性、CD8阴性、FOXC1阳性
基于免疫组化的间充质样亚型：雄激素受体阴性、CD8阴性、FOXC1阴性、DCLK1阳性
基于免疫组化的无法分类亚型：雄激素受体阴性，CD8阴性，FOXC1阴性，DCLK1阴性
κ系数表明，根据免疫组化与根据信使核糖核酸（mRNA）测序的分类结果基本吻合。
多因素生存分析表明，免疫组化分类是无复发生存的独立预后因素。
转录组数据和病理观察结果表明，针对不同亚型的治疗策略不同：
基于免疫组化的雄激素受体管腔亚型：HER2信号传导通路相对活跃，对HER2靶向治疗可能有效
基于免疫组化的免疫调节亚型：倾向于出现免疫炎症的表现型，其特征为CD8阳性T淋巴细胞浸润至肿瘤实质，对免疫治疗可能有效
基于免疫组化的基底样免疫抑制亚型：血管内皮生长因子VEGF特征高表达，对VEGF靶向治疗可能有效
基于免疫组化的间充质样亚型：JAK→STAT3信号传导通路激活，对JAK或STAT3靶向治疗可能有效
因此，该研究结果表明，对于没有条件开展基因测序的基层医院，可以根据免疫组化将三阴性乳腺癌初步分为不同的分子亚型，为复发预测或生存预后提供额外信息，有助于大型临床研究将三阴性乳腺癌患者分为不同亚组，对某些亚型的个体化靶向治疗效果进行评估，并且有望被常规用于指导三阴性乳腺癌患者的临床治疗决策。
相关链接
Oncologist. 2020 May 14. Online ahead of print.
Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance.
Zhao S, Ma D, Xiao Y, Li XM, Ma JL, Zhang H, Xu XL, Lv H, Jiang WH, Yang WT, Jiang YZ, Zhang QY, Shao ZM.
Fudan University Shanghai Cancer Center, Shanghai, China; Harbin Medical University Cancer Hospital, Harbin, China.
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 (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 (LAR; AR-positive [+]), (b) IHC-based immunomodulatory (IM; AR-negative [-], CD8+), (c) IHC-based basal-like immune-suppressed (BLIS; AR-, CD8-, FOXC1+), (d) IHC-based mesenchymal (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 large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes. It has potential to be routinely used to guide treatment decisions for patients with TNBC.
IMPLICATIONS FOR PRACTICE: We developed an immunohistochemistry (IHC)-based classification approach for triple-negative breast cancer (TNBC), which exhibited substantial agreement with the mRNA expression-based classification. The implications for practice are as follows. Our IHC-based classification (a) allows for subgrouping of TNBC patients in large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes, (b) will contribute to the practical application of subtype-specific treatment for patients with TNBC, and (c) can provide additional information beyond traditional prognostic factors in relapse prediction.
KEYWORDS: Immunohistochemistry Precision medicine; Molecular classification; Triple-negative breast cancer.
PMID: 32406563
DOI: 10.1634/theoncologist.2019-0982