基于免疫组织化学的肌层浸润性膀胱癌分子亚型：与 HER2 和 EGFR 改变、新辅助化疗反应和生存的关联。
Immunohistochemical based molecular subtypes of muscle-invasive bladder cancer: association with HER2 and EGFR alterations, neoadjuvant chemotherapy response and survival.
机构信息
Pathology Department, Faculty of Medicine, Tanta University, Tanta, 31527, Egypt.
Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
出版信息
Diagn Pathol. 2023 Feb 3;18(1):11. doi: 10.1186/s13000-023-01295-y.
Muscle-invasive bladder cancers (MIBCs) is a group of molecularly heterogonous diseases that could be stratified into subtypes with distinct clinical courses and sensitivities to chemotherapy. Clinical application of molecular subtypes could help in prediction of neoadjuvant chemotherapy (NAC) responders. Immunohistochemical (IHC) markers such as GATA3, cytokeratin (CK) 5/6, and p53 are associated with these subtypes and are widely available. Human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) are mutated in multiple cancers including MIBC and are potential therapeutic targets. HER2/EGFR status of MIBC subtypes has not been investigated. Tissue microarrays (TMAs) were constructed from transurethral resection of the bladder tumor (TURB) specimens and stained with GATA3,CK5/6,p53 and HER2 in addition to Quantitative Reverse Transcription PCR for detection of EGFR gene. Of the total cases, 45% were luminal, 36.7% basal and 18.3% p53 wild subtype (p53-WT). Univariate analysis showed that overall survival (OS) and disease-free progression survival (DFS) were significantly longer for luminal subtype. In multivariate analysis, molecular subtype, HER2 status and LV invasion were independent prognostic factors for DFS and OS. Basal subtype showed a significantly better response to NAC. HER2 expression was significantly higher in luminal while EGFR expression was significantly higher in basal subtype. Kaplan-Meier survival curves revealed a significant longer OS and DFS for HER2 negative than positive cases. MIBC can be stratified using a simple IHC panel [GATA3,CK5/6,P53] into clinically relevant prognostic molecular subtypes. Basal tumors are aggressive and respond well to NAC while luminal have better OS. P53-WT tumors are chemoresistant and require further treatments. HER2 and EGFR are potential therapeutic targets for molecular subtypes of MIBC where luminal tumors are more likely to benefit from HER2 and basal from EGFR directed therapies.
肌层浸润性膀胱癌（MIBC）是一组分子异质性疾病，可以分为具有不同临床过程和对化疗敏感性的亚型。分子亚型的临床应用有助于预测新辅助化疗（NAC）的反应者。免疫组织化学（IHC）标志物，如 GATA3、细胞角蛋白（CK）5/6 和 p53，与这些亚型相关，并且广泛可用。人表皮生长因子受体 2（HER2）和表皮生长因子受体（EGFR）在包括 MIBC 在内的多种癌症中发生突变，是潜在的治疗靶点。MIBC 亚型的 HER2/EGFR 状态尚未得到研究。从经尿道膀胱肿瘤切除术（TURB）标本构建组织微阵列（TMA），并用 GATA3、CK5/6、p53 和 HER2 染色，此外还进行定量逆转录 PCR 检测 EGFR 基因。在总病例中，45%为 luminal 型，36.7%为基底型，18.3%为 p53 野生型（p53-WT）。单因素分析显示，luminal 型的总生存（OS）和无病进展生存（DFS）显著更长。多因素分析显示，分子亚型、HER2 状态和 LV 浸润是 DFS 和 OS 的独立预后因素。基底型对 NAC 的反应明显更好。在 luminal 型中 HER2 表达明显更高，而在基底型中 EGFR 表达明显更高。Kaplan-Meier 生存曲线显示 HER2 阴性病例的 OS 和 DFS 明显更长。MIBC 可以使用简单的 IHC 面板[GATA3、CK5/6、P53]进行分层，分为具有临床相关预后的分子亚型。基底肿瘤侵袭性强，对 NAC 反应良好，而 luminal 肿瘤的 OS 更好。p53-WT 肿瘤对化疗耐药，需要进一步治疗。HER2 和 EGFR 是 MIBC 分子亚型的潜在治疗靶点，其中 luminal 肿瘤可能受益于 HER2，而基底型受益于 EGFR 靶向治疗。
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