Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab, but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify a cancer-specific methylation (CSM) and fragment length score (FLS) for each sample. CSM and FLS are strongly correlated with tumor-informed ctDNA levels. Early kinetics of CSM predict overall survival and progression-free survival, independently of tumor type, PD-L1, and tumor mutation burden. Early kinetics of FLS are associated with overall survival independently of CSM. Our tumor-naïve mutation-agnostic ctDNA approach integrating methylomics and fragmentomics could predict outcomes in patients treated with pembrolizumab.

中文翻译：

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肿瘤幼稚无细胞甲基化组和片段组的早期变化可预测帕博利珠单抗治疗实体瘤的结果

血浆中循环肿瘤 DNA (ctDNA) 的早期动力学可预测对派姆单抗的反应，但通常需要对匹配的肿瘤组织或固定基因组进行测序。我们使用无细胞甲基化 DNA 免疫沉淀和测序 (cfMeDIP-seq) 对来自 87 名患者的 204 份血浆样本进行了全基因组甲基化和片段长度分析，这些样本来自一项泛癌症 II 期研究者发起的试验 (INSPIRE)。 ）。我们使用来自癌症基因组图谱的独立甲基化阵列数据训练了泛癌甲基化特征，以量化每个样本的癌症特异性甲基化 (CSM) 和片段长度评分 (FLS)。CSM 和 FLS 与肿瘤相关的 ctDNA 水平密切相关。CSM 的早期动力学可预测总生存期和无进展生存期，与肿瘤类型、PD-L1 和肿瘤突变负荷无关。FLS 的早期动力学与总生存率相关，与 CSM 无关。我们整合甲基组学和片段组学的肿瘤初始突变不可知 ctDNA 方法可以预测接受派姆单抗治疗的患者的结果。