Abstract

BACKGROUND:

Immune checkpoint inhibitors are an important therapeutic option for urothelial carcinoma, but durable responses are achieved in a minority of patients. Identifying pre-treatment biomarkers that may predict response to these therapies or who exhibit intrinsic resistance, is of paramount importance.

OBJECTIVE:

To explore the prevalence of PD-L1 copy number alteration in urothelial carcinoma and correlate with response to immune checkpoint inhibitors.

METHODS:

We analyzed a cohort of 1050 carcinomas of the bladder and upper urinary tract that underwent targeted next generation sequencing, prospectively. We assessed PD-L1 protein expression, copy number status (next generation sequencing/FISH), and detailed treatment response.

RESULTS:

We identified 9 tumors with PD-L1 amplification and 9 tumors with PD-L1 deletion. PD-L1 protein expression was the highest in PD-L1 amplified tumors. Of the 9 patients whose tumors harbored PD-L1 amplification, 6 received immunotherapy with 4 deriving clinical benefit, and two achieving durable response. Of the 9 patients whose tumors had PD-L1 copy number losses, 4 received immunotherapy with 3 experiencing disease progression.

CONCLUSIONS:

PD-L1 copy number alterations may serve as potential biomarkers of response to immunotherapy in urothelial carcinoma patients, if validated in larger cohorts.

中文翻译：

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CD274 (PD-L1) 拷贝数变化（增益）和对泌尿道癌免疫检查点阻断治疗的反应

摘要

背景：

免疫检查点抑制剂是尿路上皮癌的重要治疗选择，但在少数患者中实现了持久反应。识别可以预测对这些疗法的反应或表现出内在耐药性的治疗前生物标志物至关重要。

客观的：

探讨PD-L1拷贝数改变在尿路上皮癌中的普遍性，并与对免疫检查点抑制剂的反应相关。

方法：

我们前瞻性地分析了接受靶向下一代测序的 1050 例膀胱癌和上尿路癌的队列。我们评估了 PD-L1 蛋白表达、拷贝数状态（下一代测序/FISH）和详细的治疗反应。

结果：

我们鉴定了 9 个具有PD-L1扩增的肿瘤和 9 个具有PD-L1缺失的肿瘤。PD-L1 蛋白表达在PD-L1扩增的肿瘤中最高。在 9 名肿瘤携带PD-L1扩增的患者中，6 名接受了免疫治疗，其中 4 名获得了临床益处，2 名获得了持久反应。在 9 名肿瘤出现PD-L1拷贝数丢失的患者中，4 名接受了免疫治疗，3 名出现疾病进展。

结论：

如果在更大的队列中得到验证， PD-L1拷贝数改变可作为尿路上皮癌患者对免疫治疗反应的潜在生物标志物。