283050 例患者样本中（PD-L1）重排的泛癌分析，及其与 PD-L1 蛋白表达和免疫治疗反应的相关性。
Pan-cancer landscape of (PD-L1) rearrangements in 283,050 patient samples, its correlation with PD-L1 protein expression, and immunotherapy response.
机构信息
Department of Medical Oncology, Foundation Medicine Inc, Cambridge, Massachusetts, USA
Department of Medical Oncology, Foundation Medicine Inc, Cambridge, Massachusetts, USA.
出版信息
J Immunother Cancer. 2021 Nov;9(11). doi: 10.1136/jitc-2021-003550.
BACKGROUND
Immune checkpoint inhibitors (ICIs) benefit patients with multiple cancer types, however, additional predictive biomarkers of response are needed. (programmed cell death ligand-1, PD-L1) gene rearrangements are positively associated with PD-L1 expression and may confer benefit to ICI, thus a pan-cancer characterization of these alterations is needed.
METHODS
We analyzed 283,050 patient samples across multiple tumor types that underwent comprehensive genomic profiling for activating rearrangements and other alterations. The DAKO 22C3 Tumor Proportion Scoring (TPS) method was used for PD-L1 immunohistochemistry (IHC) testing in a small subset with available data (n=55,423). A retrospective deidentified real-world clinico-genomic database (CGDB) was examined for ICI treatment outcomes. We also report a detailed case of rearranged metastatic rectal adenocarcinoma.
RESULTS
We identified 145 samples with functional rearrangements in . There were significant enrichments for , , , , and co-mutations (ORs=2.1, 16.7, 17.8, 3.6, and 3.4, respectively, p<0.01). Genomic human papillomavirus (HPV)-16, Epstein-Barr virus, and mismatch repair genes also co-occurred (OR=6.2, 8.4, and 4.3, respectively, p<0.05). Median tumor mutational burden (TMB) was higher compared with wild-type samples (7.0 vs 3.5 mutations/Mb, p=1.7e-11), with disease-specific TMB enrichment in non-small cell lung, colorectal, unknown primary, and stomach cancers. PD-L1 IHC skewed toward positivity (N=39/43 samples with ≥1% positivity). Of eight patients from the CGDB, three remained on ICI treatment after 6 months. Separately, one patient with metastatic rectal adenocarcinoma experienced a pathologic complete response on chemoimmunotherapy.
CONCLUSIONS
gene rearrangements are associated with increased PD-L1 IHC scores, higher TMB, and potential clinical benefit in ICI-treated patients with cancer.
背景
免疫检查点抑制剂（ICIs）有益于多种癌症类型的患者，但仍需要额外的预测反应的生物标志物。（程序性死亡配体-1，PD-L1）基因重排与 PD-L1 表达呈正相关，并且可能对 ICI 有获益，因此需要对这些改变进行泛癌特征分析。
方法
我们分析了 283050 名接受全面基因组分析的多种肿瘤类型患者的样本，以检测激活重排和其他改变。在有可用数据的一小部分（n=55423）中，使用 DAKO 22C3 肿瘤比例评分（TPS）方法进行 PD-L1 免疫组化（IHC）检测。检查了一个回顾性的匿名真实世界临床基因组数据库（CGDB）以评估 ICI 治疗结果。我们还报告了一个详细的转移性直肠腺癌重排病例。
结果
我们在 中鉴定出 145 个具有功能重排的样本。存在显著富集的 、 、 、 和 共突变（ORs=2.1、16.7、17.8、3.6 和 3.4，分别，p<0.01）。基因组人乳头瘤病毒（HPV）-16、爱泼斯坦-巴尔病毒和错配修复基因也同时发生（OR=6.2、8.4 和 4.3，分别，p<0.05）。与野生型样本相比，中位肿瘤突变负荷（TMB）更高（7.0 对 3.5 突变/Mb，p=1.7e-11），非小细胞肺癌、结直肠癌、未知原发性和胃癌中存在疾病特异性 TMB 富集。PD-L1 IHC 倾向于阳性（N=39/43 个样本中≥1%阳性）。在 CGDB 中的 8 名患者中，有 3 名在 6 个月后仍继续接受 ICI 治疗。另外，一名转移性直肠腺癌患者在化疗免疫治疗后出现病理完全缓解。
结论
基因重排在接受 ICI 治疗的癌症患者中与更高的 PD-L1 IHC 评分、更高的 TMB 和潜在的临床获益相关。
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