Background: Recent data suggests that HER2-targeted treatment is efficacious in urothelial carcinoma (UC). We investigated the genomic, transcriptomic, and immune landscapes and clinical outcomes in UC segmented byERBB2expression. Methods: NextGen DNA/RNA sequencing was performed for 4743 UC tumors. A total of 3% (124/4125) of tumors had HER2 IHC and whole transcriptome sequencing (WTS) data.ERRB2-high and -low tumors were defined by ≥75th and <25th percentiles ofERBB2expression, respectively. PD-L1 (SP142) positive staining was defined as ≥2+ and ≥5%. HER2 (4B5) positive staining was defined as ≥3+ and >10% or 2+ and >10% with positive HER2 in situ hybridization (ISH). Results: Of the patients who wereERBB2-high, 79% (61/77) were HER2 positive via IHC. Tumors from lower tract UC had higherERBB2expression compared to upper tract UC (50 v 40 median TPM (mTPM),p< 0.001).ERBB2expression was similar between primary and metastatic tumors (47 v 47 mTPM,p= 0.95).ERBB2-high tumors had a higher prevalence of pathogenic mutations inpTERT,ERBB2, andELF3versusERBB2-low tumors,p< 0.001.ERBB2-high tumors had higher expressions of ADC target genesNECTIN4(12 v 8 mTPM) andTACSTD2(366 v 74 mTPM) versusERBB2-low (p< 0.001), as well as better overall survival from time of tissue sampling thanERBB2-low (HR 1.71,p< 0.001). Conclusion: Our study demonstrated a high concordance between HER2 expression by IHC andERBB2gene expression by WTS in UC. Differences in ADC target expression betweenERBB2-high vs.ERBB2-low UC may provide a rationale for combination treatment strategies with HER2-ADC. The association between highERBB2expression and survival advantage warrants further investigation.
背景：近期数据显示，HER2靶向治疗在尿路上皮癌（UC）中具有疗效。本研究通过ERBB2表达水平对UC进行分层，探讨其基因组、转录组及免疫微环境特征与临床结局的关联。方法：对4743例UC肿瘤组织进行新一代DNA/RNA测序。其中3%（124/4125）的肿瘤同时具备HER2免疫组化（IHC）和全转录组测序（WTS）数据。ERBB2高表达与低表达组分别定义为ERBB2表达水平≥第75百分位数和<第25百分位数。PD-L1（SP142）阳性定义为染色强度≥2+且阳性细胞比例≥5%。HER2（4B5）阳性定义为染色强度≥3+且阳性细胞>10%，或强度2+且阳性细胞>10%同时HER2原位杂交（ISH）阳性。结果：在ERBB2高表达患者中，79%（61/77）经IHC检测为HER2阳性。下尿路UC肿瘤的ERBB2表达水平高于上尿路UC（中位TPM值50 vs 40，p<0.001）。原发灶与转移灶的ERBB2表达水平无显著差异（中位TPM值47 vs 47，p=0.95）。与ERBB2低表达组相比，高表达组在pTERT、ERBB2和ELF3基因的致病性突变发生率更高（p<0.001）。ERBB2高表达组的ADC靶点基因NECTIN4（12 vs 8 mTPM）和TACSTD2（366 vs 74 mTPM）表达水平显著高于低表达组（p<0.001），且组织取样后的总生存期更优（HR 1.71，p<0.001）。结论：本研究证实UC中HER2蛋白表达（IHC）与ERBB2基因表达（WTS）具有高度一致性。ERBB2高表达与低表达UC之间ADC靶点表达的差异，为HER2-ADC联合治疗策略提供了理论依据。ERBB2高表达与生存优势的关联值得进一步研究。
The Genomic Landscape of Urothelial Carcinoma with High and LowERBB2Expression
肿瘤(癌症)患者之家