PO.CL01.01 · 临床研究
STAT5A启动子高甲基化作为cfDNA液体活检中鳞状细胞癌免疫检查点抑制剂反应的生物标志物
STAT5A promoter hypermethylation as a biomarker of immune checkpoint inhibitor response in squamous cell carcinoma in cfDNA liquid biopsies
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：STAT5A是JAK-STAT通路的下游转录因子，调控免疫相关和肿瘤相关基因的表达。STAT5A启动子的高甲基化与头颈鳞状细胞癌（HNSCC）和肺鳞状细胞癌（LSCC）中免疫细胞耗竭及抗肿瘤免疫活性降低相关（Liang等，2023）。我们假设可在cfDNA中检测到的STAT5A启动子高甲基化（PM）是鳞状细胞癌（SCC）中免疫检查点抑制剂（ICPI）反应的预测性生物标志物。
方法：使用Guardant360 Liquid（Guardant Health，加州帕洛阿尔托）检测高甲基化的STAT5A启动子区域，初步定义为转录起始位点（TSS）上游5kb。使用癌症基因组图谱（TCGA）数据确定PM区域甲基化与表达之间的相关性，以识别PM与转录沉默相关的位点。在一个大型无癌样本队列（n=32k）中评估候选位点，以确保分析特异度。PM状态相对于组成性高甲基化对照区域加以区分，测量相对于总cfDNA的甲基化水平。临床结局分析使用GuardantINFORM真实世界临床基因组学数据库。
结果：Guardant360 Liquid所测得的STAT5A PM患病率在各肿瘤类型间与已发表数据集一致。该检测显示出高分析特异度（阴性一致百分比>98%）。在接受ICPI治疗的SCC患者中，STAT5A PM与更短的下次治疗时间（TTNT）相关（n=815，91% LSCC，9% HNSCC，未校正log-rank p=0.01）。STAT5A PM+患者（n=16）的中位TTNT为8.6个月（95% CI，4.6-10.4），而PM-患者（n=799）为30.7个月（95% CI，25.6-38.1）。在多变量Cox比例风险模型中，校正临床协变量（年龄、性别和治疗线数）后，PM+仍独立地与更短的TTNT相关（HR=2.10；p=0.03）。按癌症类型分析时，STAT5A PM与TTNT之间的关联主要由LSCC驱动（HR=2.33；p=0.01）。PM+ HNSCC病例数量有限（n=3），使该亚组无法达到统计学显著性。
结论：使用Guardant360 Liquid对STAT5A PM进行的非侵入性检测与LSCC患者的真实世界ICPI获益呈负相关，这为已在ICPI中显示出预测意义的日益增多的生物标志物名单增添了一项，并拓宽了基于甲基化的谱分析在精准肿瘤学中的作用。
查看英文原文 English abstract
Background: STAT5A is a downstream transcription factor in the JAK-STAT pathway that regulates immune- and tumor-related gene expression. Hypermethylation of the STAT5A promoter is linked to immune cell depletion and reduced antitumor immune activity in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LSCC) (Liang et al. 2023). We hypothesized that STAT5A promoter hypermethylation (PM) detectable in cfDNA is a predictive biomarker of immune checkpoint inhibitor (ICPI) response in squamous cell carcinomas (SCC).
Methods: Guardant360 Liquid (Guardant Health, Palo Alto, CA) was used to detect hypermethylated STAT5A promoter region, defined initially as 5kb upstream from the transcription start sites (TSS). Correlation between methylation and expression for PM regions was determined using The Cancer Genome Atlas (TCGA) data to identify loci where PM was associated with transcriptional silencing. Candidate loci were evaluated in a large cohort of cancer-free samples (n=32k) to ensure analytical specificity. PM status is distinguished relative to constitutively hypermethylated control regions, measuring methylation level relative to total cfDNA. Clinical outcomes analyses used the GuardantINFORM real-world clinico-genomics database.
Results: STAT5A PM prevalence as measured by Guardant360 Liquid was concordant with published datasets across tumor types. The assay demonstrated high analytical specificity (negative percent agreement > 98%). STAT5A PM was associated with a shorter time to next treatment (TTNT) among ICPI-treated patients with SCC (n=815, 91% LSCC, 9% HNSCC, unadjusted log-rank p=0.01). Median TTNT for STAT5A PM+ patients (n=16) was 8.6 mo (95% CI, 4.6-10.4) versus 30.7 mo (95% CI, 25.6-38.1) for PM- patients (n=799). In a multivariable Cox proportional hazards model, adjusting for clinical covariates (age, gender, and line of therapy), PM+ remained independently associated with shorter TTNT (HR=2.10; p=0.03). When analyzed by cancer type, the association between STAT5A PM and TTNT was primarily driven by LSCC (HR=2.33; p=0.01). The limited number of PM+ HNSCC cases (n=3) precluded statistical significance in that subgroup.
Conclusion: Non-invasive detection of STAT5A PM using Guardant360 Liquid is inversely correlated with real-world ICPI benefit in patients with LSCC, adding to a growing list of biomarkers demonstrated to have predictive significance in ICPI and broadening the role of methylation-based profiling in precision oncology.
利益披露 Disclosure
J. Patterson, None..
B. Overstreet, None..
J. Liao, None.