Hadadi Agreen, Krause Harris B, Elliott Andrew, Brown Jacqueline T, Nazha Bassel, Harik Lara R, Carthon Bradley C, Miron Benjamin, Nabhan Chadi, Barata Pedro C, Saleh Mohamed, Yang Yuanquan, McKay Rana R, Bilen Mehmet A
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
CARIS Life Sciences, Inc., Irving, TX 75039, USA.
Cancers (Basel). 2023 Dec 6;15(24):5721. doi: 10.3390/cancers15245721.
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 by expression.
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. -high and -low tumors were defined by ≥75th and <25th percentiles of expression, 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).
Of the patients who were -high, 79% (61/77) were HER2 positive via IHC. Tumors from lower tract UC had higher expression compared to upper tract UC (50 v 40 median TPM (mTPM), < 0.001). expression was similar between primary and metastatic tumors (47 v 47 mTPM, = 0.95). -high tumors had a higher prevalence of pathogenic mutations in , , and versus -low tumors, < 0.001. -high tumors had higher expressions of ADC target genes (12 v 8 mTPM) and (366 v 74 mTPM) versus -low ( < 0.001), as well as better overall survival from time of tissue sampling than -low (HR 1.71, < 0.001).
Our study demonstrated a high concordance between HER2 expression by IHC and gene expression by WTS in UC. Differences in ADC target expression between -high vs. -low UC may provide a rationale for combination treatment strategies with HER2-ADC. The association between high expression and survival advantage warrants further investigation.
近期数据表明，HER2靶向治疗在尿路上皮癌（UC）中有效。我们研究了按HER2表达进行分类的UC的基因组、转录组和免疫图谱以及临床结局。
对4743例UC肿瘤进行了二代DNA/RNA测序。共有3%（124/4125）的肿瘤有HER2免疫组化（IHC）和全转录组测序（WTS）数据。HER2高表达和低表达肿瘤分别定义为HER2表达的第75百分位数及以上和第25百分位数以下。程序性死亡受体配体1（PD-L1，SP142）阳性染色定义为≥2+且≥5%。HER2（4B5）阳性染色定义为≥3+且>10%或2+且>10%同时HER2原位杂交（ISH）阳性。
在HER2高表达的患者中，79%（61/77）通过IHC检测为HER2阳性。下尿路UC的肿瘤与上尿路UC相比HER2表达更高（中位转录每百万映射读取数（mTPM）分别为50和40，P<0.001）。原发性和转移性肿瘤之间的HER2表达相似（mTPM分别为47和47，P = 0.95）。与HER2低表达肿瘤相比，HER2高表达肿瘤中PIK3CA、RB1和FGFR3的致病突变发生率更高，P<0.001。与HER2低表达肿瘤相比，HER2高表达肿瘤中ADC靶基因TUBB3（mTPM为12 vs 8）和CLDN18.2（mTPM为366 vs 74）的表达更高（P<0.001），并且从组织采样时间起的总生存期也更好（风险比1.71，P<0.001）。
我们的研究表明，UC中IHC检测的HER2表达与WTS检测的HER2基因表达高度一致。HER2高表达与低表达UC之间ADC靶标表达的差异可能为HER2抗体药物偶联物（HER2-ADC）联合治疗策略提供理论依据。HER2高表达与生存优势之间存在关联，值得进一步研究。
