BACKGROUND In patients with rare histologies of bladder cancer, including adenocarcinoma of the bladder (ACB) and squamous-cell carcinoma (SCC), there are limited standard therapy options, defining an unmet medical need. OBJECTIVE In this comparative comprehensive genomic profiling (CGP) study, genomic alterations (GAs), and immuno-oncology (IO) biomarkers have been analyzed. DESIGN, SETTING, AND PARTICIPANTS Within the Foundation Medicine database, 143 cases with centrally reviewed pure ACB, 2142 with pure urothelial carcinoma (UC), and 83 with pure SCC were subjected to CGP. All patients developed advanced disease following a primary diagnosis of bladder cancer. INTERVENTION CGP using a hybrid capture-based assay and immunohistochemistry (IHC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. Programmed cell-death ligand-1 (PD-L1) expression was determined by IHC (Ventana SP-142 assay), with >1% tumor cells (TCs) or tumor-infiltrating lymphocytes (TILs) scoring positive. RESULTS AND LIMITATIONS Pure ACB patients were younger and more often female than pure UC and pure SCC patients. UC and SCC had a significantly higher median TMB than ACB (p < 0.001). Rare CD274 (PD-L1) amplification cases were more frequently seen in SCC than in UC (5% vs 1%), and were not seen in ACB. MSI high status was very uncommon in all tumor types (0-1%). The frequencies of PD-L1 expression in both TCs and TILs was higher in UC and SCC (both 30%) than in ACB (18%). The results are limited by their retrospective nature and lack of clinical data annotation. CONCLUSIONS Deep sequencing revealed significant differences in IO biomarkers among the three major subtypes of bladder carcinomas. UC and SCC revealed higher frequencies of PD-L1 expression and higher TMB than ACB, and SCC has the highest frequency of CD274 amplification. The presence of pure SCC features should not disqualify patients for inclusion in IO trials. PATIENT SUMMARY Tumor samples from patients diagnosed with advanced pure adenocarcinoma of the bladder (ACB) or pure squamous-cell carcinoma (SCC) have been analyzed in terms of frequency of putative immunotherapy biomarkers. The results indicated that pure SCC of the bladder was characterized by genomic features that portend similar response possibilities to immunotherapy compared with the classical pure urothelial carcinoma. Conversely, for pure ACB there might be different therapeutic opportunities, such as targeted therapies against peculiar genomic alterations in selected patients.

中文翻译：

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腺癌、尿路上皮癌和膀胱鳞状细胞癌中免疫肿瘤学生物标志物的综合评估。

背景 在具有罕见组织学膀胱癌的患者中，包括膀胱腺癌 (ACB) 和鳞状细胞癌 (SCC)，标准治疗选择有限，定义了未满足的医疗需求。目的 在这项比较全面的基因组分析 (CGP) 研究中，对基因组改变 (GA) 和免疫肿瘤学 (IO) 生物标志物进行了分析。设计、设置和参与者 在 Foundation Medicine 数据库中，143 例集中审查的纯 ACB、2142 例纯尿路上皮癌 (UC) 和 83 例纯 SCC 接受了 CGP。所有患者在初步诊断为膀胱癌后均发展为晚期疾病。使用基于混合捕获的测定和免疫组织化学 (IHC) 的干预 CGP。结果测量和统计分析 肿瘤突变负荷 (TMB) 在 1. 在 114 个基因座上确定了 1 Mbp 的 DNA 测序和微卫星不稳定性 (MSI)。程序性细胞死亡配体-1 (PD-L1) 表达由 IHC（Ventana SP-142 测定）确定，>1% 的肿瘤细胞 (TC) 或肿瘤浸润淋巴细胞 (TIL) 评分为阳性。结果和局限性 与纯 UC 和纯 SCC 患者相比，纯 ACB 患者更年轻，女性更常见。UC 和 SCC 的中位 TMB 显着高于 ACB（p < 0.001）。罕见的 CD274 (PD-L1) 扩增病例在 SCC 中比在 UC 中更常见（5% 对 1%），而在 ACB 中未见。MSI 高状态在所有肿瘤类型中都非常罕见 (0-1%)。UC 和 SCC 中 TC 和 TIL 中 PD-L1 表达的频率（均为 30%）高于 ACB（18%）。结果受到回顾性和缺乏临床数据注释的限制。结论 深度测序揭示了膀胱癌三种主要亚型之间 IO 生物标志物的显着差异。UC 和 SCC 显示出比 ACB 更高的 PD-L1 表达频率和更高的 TMB，并且 SCC 具有最高频率的 CD274 扩增。单纯 SCC 特征的存在不应取消患者纳入 IO 试验的资格。患者总结 来自被诊断患有晚期纯膀胱腺癌 (ACB) 或纯鳞状细胞癌 (SCC) 的患者的肿瘤样本已根据推定的免疫治疗生物标志物的频率进行了分析。结果表明，与经典的纯尿路上皮癌相比，膀胱的纯 SCC 的特征在于基因组特征，预示着对免疫治疗的相似反应可能性。反过来，