Purpose: Physicians are expected to assess prognosis both for patient counseling and for determining suitability for clinical trials. Increasingly, cell-free circulating tumor DNA (cfDNA) sequencing is being performed for clinical decision making. We sought to determine whether variant allele frequency (VAF) in cfDNA is associated with prognosis. Experimental Design: We performed a retrospective analysis of 298 patients with metastatic disease who underwent clinical comprehensive cfDNA analysis and assessed association between VAF and overall survival. Results: cfDNA mutations were detected in 240 patients (80.5%). Median overall survival (OS) was 11.5 months. cfDNA mutation detection and number of nonsynonymous mutations (NSM) significantly differed between tumor types, being lowest in appendiceal cancer and highest in colon cancer. Having more than one NSM detected was associated with significantly worse OS (HR = 2.3; P < 0.0001). VAF was classified by quartiles, Q1 lowest, Q4 highest VAF. Higher VAF levels were associated with a significantly worse overall survival (VAF Q3 HR 2.3, P = 0.0069; VAF Q4 HR = 3.8, P < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level <3.5 g/dL, number of nonvisceral metastatic sites >0 and number of prior therapies >4 were independent predictors of worse OS. Conclusions: Higher levels of cfDNA VAF and a higher number of NSMs were associated with worse OS in patients with metastatic disease. Further study is needed to determine optimal VAF thresholds for clinical decision making and the utility of cfDNA VAF as a prognostic marker in different tumor types.

中文翻译：

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无细胞循环肿瘤 DNA 变异等位基因频率与转移性癌症的生存相关


目的：医生应评估预后，以便为患者提供咨询并确定是否适合临床试验。无细胞循环肿瘤 DNA (cfDNA) 测序越来越多地用于临床决策。我们试图确定 cfDNA 中的变异等位基因频率 (VAF) 是否与预后相关。实验设计：我们对 298 名转移性疾病患者进行了回顾性分析，这些患者接受了临床综合 cfDNA 分析，并评估了 VAF 与总生存期之间的关联。结果：240 名患者（80.5%）检测到 cfDNA 突变。中位总生存期 (OS) 为 11.5 个月。 cfDNA 突变检测和非同义突变 (NSM) 数量在肿瘤类型之间存在显着差异，阑尾癌中最低，结肠癌中最高。检测到超过一种 NSM 与显着较差的 OS 相关（HR = 2.3；P < 0.0001）。 VAF 按四分位数分类，Q1 最低，Q4 VAF 最高。单变量分析显示，较高的 VAF 水平与显着较差的总生存率相关（VAF Q3 HR 2.3，P = 0.0069；VAF Q4 HR = 3.8，P < 0.0001）。在多变量分析中，VAF Q4、男性、白蛋白水平 <3 id=18>0 和既往治疗次数 >4 是较差 OS 的独立预测因素。结论：较高水平的 cfDNA VAF 和较高数量的 NSM 与转移性疾病患者较差的 OS 相关。需要进一步研究来确定临床决策的最佳 VAF 阈值以及 cfDNA VAF 作为不同肿瘤类型预后标志物的效用。