PURPOSE ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer. EXPERIMENTAL DESIGN A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response. RESULTS A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (P < 0.0001). Four-week change in tumor markers also predicted response (P = 0.0026) and CB (P = 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (P = 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00; P < 0.0001). CONCLUSIONS Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.

中文翻译：

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连续ctDNA监测可预测转移性胃肠道癌对全身治疗的反应。

目的ctDNA提供了一种有前途的，无创的方法来实时监测治疗效果。我们探讨了治疗开始后早期ctDNA的定量变化是否可以预测转移性胃肠道癌患者的治疗反应和无进展生存期（PFS）。实验设计共有138例患有转移性胃肠道癌且通过​​下一代测序对肿瘤进行分析的患者在治疗期间按预定间隔进行了连续抽血。使用个体化液滴数字PCR对ctDNA进行评估，该技术测量了血浆中活检组织中鉴定出的突变体中的突变等位基因分数。ctDNA的变化与肿瘤标志物和影像学反应相关。结果总共招募了138名患者。在第4周时，共有101例患者的ctDNA评估为68例，肿瘤标志物的评估为68例。到4周时ctDNA的变化百分比预示了部分反应（PR，P <0.0001）和临床获益[CB：PR和稳定疾病（SD），P <0.0001]。所有PR患者的ctDNA下降了98％（中位数）和> 30％。ctDNA的变化在8周而不是2周时也可以预测CB（P <0.0001）。肿瘤标志物的四周变化也预测了反应（P = 0.0026）和CB（P = 0.022）。但是，在90％的临床相关特异性阈值下，与肿瘤标志物相比，4周ctDNA变化更有效地预测了CB，敏感性分别为60％对24％（P = 0.0109）。4周ctDNA下降超过此阈值（≥30％下降）的患者的中位PFS为175天，而中位PFS为59.5天（HR，3.29； 95％CI，1.55-7.00； P <0.0001）。