Lee Hyun Jung, Gulati Roman, Sayar Erolcan, Patel Radhika A, Itagi Pushpa, Richards Helen M, Persse Thomas, Arora Sonali, Coleman Ilsa, Adil Mohamed, Schuster Samantha L, Shokri Farinaz, Wright Jonathan L, Yu Evan Y, True Lawrence D, Chambers Meagan, Hawley Jessica E, Cheng Heather H, Schweizer Michael T, Grivas Petros, Nelson Peter S, Montgomery R Bruce, Hsieh Andrew C, Vakar-Lopez Funda, Morrissey Colm, Lam Hung-Ming, Ha Gavin, Tretiakova Maria S, Haffner Michael C, Raychaudhuri Ruben
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington.
Department of Pathology, Pusan National University School of Medicine, Yangsan, Korea.
Cancer Res Commun. 2025 Aug 1;5(8):1419-1428. doi: 10.1158/2767-9764.CRC-25-0069.
UNLABELLED: HER2 is an oncogenic driver in multiple cancers and a predictive biomarker for HER2-targeted therapies. Although HER2-directed therapies like fam-trastuzumab deruxtecan are approved for HER2-positive breast and other solid tumors, the landscape of HER2 expression in advanced prostate cancer and urothelial carcinoma remains inadequately characterized. We evaluated HER2 protein expression in metastatic prostate cancer and urothelial carcinoma using a validated IHC assay on tissue microarrays constructed from the University of Washington Tissue Acquisition Necropsy Program. HER2 expression was scored using standardized gastric cancer criteria. Genomic analysis of ERBB2 alterations was conducted on a subset of samples. HER2 expression heterogeneity and its relationship with other surface markers were also evaluated. In the prostate cancer cohort (n = 52 patients, 1-19 tumors per patient), HER2 expression was low, with no 3+ expression observed and only five (10%) patients exhibiting 2+ expression. Low-level ERBB2 copy-number gains were observed in some tumors but did not correlate with HER2 protein expression (P = 0.2). In urothelial carcinoma (n = 20, 2-6 tumors per patient), HER2 expression was more frequent, with ≥2+ expression observed in six (30%) cases and 3+ expression observed in three (15%) cases in at least one tumor. Urothelial carcinoma samples showed less heterogeneity, with more consistent expression across metastases. HER2 overexpression is rare and heterogeneous in metastatic prostate cancer, limiting its utility as a therapeutic target. HER2 expression is more prevalent and uniform in urothelial carcinoma. These findings underscore the importance of comprehensive HER2 assessment in advanced urothelial carcinoma and suggest that success of HER2-directed therapies in prostate cancer will require careful case selection. SIGNIFICANCE: This study demonstrates that HER2 is rarely overexpressed in metastatic prostate cancer but is more common and consistent in urothelial carcinoma. These findings highlight the need for HER2 testing in urothelial cancer and suggest that HER2-targeted therapies in prostate cancer will require careful patient selection.
未标记：HER2是多种癌症中的致癌驱动因子，也是HER2靶向治疗的预测生物标志物。尽管像fam-曲妥珠单抗德鲁替康这样的HER2导向疗法已被批准用于HER2阳性乳腺癌和其他实体瘤，但晚期前列腺癌和尿路上皮癌中HER2表达的情况仍未得到充分描述。我们使用经过验证的免疫组织化学（IHC）检测方法，对由华盛顿大学组织采集尸检项目构建的组织微阵列上的转移性前列腺癌和尿路上皮癌进行HER2蛋白表达评估。HER2表达采用标准化的胃癌标准进行评分。对一部分样本进行了ERBB2改变的基因组分析。还评估了HER2表达的异质性及其与其他表面标志物的关系。在前列腺癌队列（n = 52例患者，每位患者1 - 19个肿瘤）中，HER2表达较低，未观察到3+表达，仅有5例（10%）患者表现为2+表达。在一些肿瘤中观察到低水平的ERBB2拷贝数增加，但与HER2蛋白表达无关（P = 0.2）。在尿路上皮癌（n = 20例，每位患者2 - 6个肿瘤）中，HER2表达更为常见，在至少一个肿瘤中，6例（30%）病例观察到≥2+表达，3例（15%）病例观察到3+表达。尿路上皮癌样本的异质性较小，转移灶之间的表达更一致。HER2过表达在转移性前列腺癌中罕见且具有异质性，限制了其作为治疗靶点的效用。HER2表达在尿路上皮癌中更普遍且更一致。这些发现强调了在晚期尿路上皮癌中进行全面HER2评估的重要性，并表明HER2导向疗法在前列腺癌中的成功应用需要谨慎选择病例。 意义：本研究表明，HER2在转移性前列腺癌中很少过表达，但在尿路上皮癌中更常见且更一致。这些发现凸显了在尿路上皮癌中进行HER2检测的必要性，并表明前列腺癌中HER2靶向疗法需要谨慎选择患者。
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