Division of Hematology/Oncology, Department of Medicine, University of California, San Diego, La Jolla.
Moores Center for Personalized Cancer Therapy, University of California, San Diego, La Jolla.
JAMA Oncol. 2018 Sep 1;4(9):1237-1244. doi: 10.1001/jamaoncol.2018.1701.
Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors.
To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective study (October 1, 2012, to October 1, 2017) used a deidentified tumor database from a commercial company and annotated clinical records from a subset of patients treated at a university tertiary referral center. The study analyzed 118 187 tumors from the deidentified database, including a clinically annotated subgroup of 2039 malignant tumors.
Comprehensive genomic profiling was performed on all samples to determine PDL1 amplification, microsatellite instability, and tumor mutational burden (TMB). A subset of patients was treated with PD-1/PD-L1 blockade.
The prevalence of PDL1 amplification was determined among 118 187 patient samples that underwent next-generation sequencing. Solid tumors treated with checkpoint blockade were evaluated for response and progression-free survival (PFS).
Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1-amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1-amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months).
The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1-amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.
程序性细胞死亡配体 1（PDL1 或 CD274）、程序性细胞死亡 1 配体 2（PDCD1LG2 或 PDL2）和 Janus 激酶 2（JAK2）基因（染色体 9p24.1）的拷贝数改变是霍奇金淋巴瘤的特征，导致对程序性细胞死亡 1（PD-1）/程序性细胞死亡配体 1（PD-L1）阻断的高反应率。PD-L1 扩增作为 PD-1/PD-L1 阻断反应生物标志物在其他肿瘤中的普遍性和实用性尚不清楚。
研究程序性细胞死亡配体 1（PDL1 或 CD274）、程序性细胞死亡 1 配体 2（PDCD1LG2 或 PDL2）和 Janus 激酶 2（JAK2）基因（染色体 9p24.1）在霍奇金淋巴瘤中的拷贝数改变，导致对程序性细胞死亡 1（PD-1）/程序性细胞死亡配体 1（PD-L1）阻断的高反应率。PD-L1 扩增作为 PD-1/PD-L1 阻断反应生物标志物在其他肿瘤中的普遍性和实用性尚不清楚。
设计、设置和参与者：这是一项回顾性研究（2012 年 10 月 1 日至 2017 年 10 月 1 日），使用商业公司的匿名肿瘤数据库，并注释了来自大学三级转诊中心治疗的患者的临床记录。该研究分析了来自匿名数据库的 118187 个肿瘤，包括一个由 2039 个恶性肿瘤组成的临床注释亚组。
对所有样本进行全面的基因组分析，以确定 PDL1 扩增、微卫星不稳定性和肿瘤突变负荷（TMB）。对一部分患者进行 PD-1/PD-L1 阻断治疗。
确定了 118187 个接受下一代测序的患者样本中 PDL1 扩增的发生率。评估接受检查点阻断治疗的实体瘤的反应和无进展生存期（PFS）。
在 118187 个匿名肿瘤样本中，鉴定出 843 个（0.7%）PDL1 扩增，包括 100 多种实体肿瘤。大多数 PDL1 扩增肿瘤（84.8%）具有低至中等 TMB。PDL1 扩增并不总是与免疫组织化学分析中高阳性 PD-L1 表达相关。在 1 个中心的 9 名 PDL1 扩增实体瘤患者中，有 6 名（66.7%）在接受检查点阻断治疗后出现客观反应。所有治疗患者的中位 PFS 为 15.2 个月。反应者包括 1 名胶质母细胞瘤患者（PFS，≥5.2 个月）、2 名头颈部鳞状细胞癌患者（PFS，≥9 和 15.2 个月）、2 名转移性基底细胞癌患者（PFS，3.8 和≥24.1 个月）和 1 名尿路上皮癌患者（PFS，≥17.8 个月）。
这项研究的结果表明，PDL1 扩增发生在一小部分恶性肿瘤中。需要进行更大规模的前瞻性研究来确认本文所述的 PDL1 扩增癌症对检查点阻断的反应，即使在没有微卫星不稳定性、高 PD-L1 表达和高 TMB 的情况下也是如此。
