Circulating Tumor DNA-Based Disease Monitoring of Patients with Locally Advanced Esophageal Cancer

SIMPLE SUMMARY: The standard of care for patients diagnosed with locally advanced esophageal cancer is neoadjuvant chemoradiotherapy followed by surgery. There is a high clinical need to monitor response to neoadjuvant treatment and recognize patients at risk for recurrence to enable individual treatment strategies. Ultradeep sequencing-based detection of circulating tumor DNA in preoperative plasma of patients with locally advanced esophageal cancer can predict which patients have a high risk of recurrence after neoadjuvant chemoradiotherapy and surgery. Circulating tumor DNA-based prediction of the presence of distant metastasis might eventually be used to reconsider surgery and its associated morbidity in patients with detected circulating tumor DNA or stratify patients for adjuvant treatment. ABSTRACT: Patients diagnosed with locally advanced esophageal cancer are often treated with neoadjuvant chemoradiotherapy followed by surgery. This study explored whether detection of circulating tumor DNA (ctDNA) in plasma can be used to predict residual disease during treatment. Diagnostic tissue biopsies from patients with esophageal cancer receiving neoadjuvant chemoradiotherapy and surgery were analyzed for tumor-specific mutations. These tumor-informed mutations were used to measure the presence of ctDNA in serially collected plasma samples using hybrid capture-based sequencing. Plasma samples were obtained before chemoradiotherapy, and prior to surgery. The association between ctDNA detection and progression-free and overall survival was measured. Before chemoradiotherapy, ctDNA was detected in 56% (44/78) of patients and detection was associated with tumor stage and volume (p = 0.05, Fisher exact and p = 0.02, Mann-Whitney, respectively). After chemoradiotherapy, ctDNA was detected in 10% (8/78) of patients. This preoperative detection of ctDNA was independently associated with recurrent disease (hazard ratio 2.8, 95% confidence interval 1.1–6.8, p = 0.03, multivariable Cox-regression) and worse overall survival (hazard ratio 2.9, 95% confidence interval 1.2–7.1, p = 0.02, multivariable Cox-regression).Ultradeep sequencing-based detection of ctDNA in preoperative plasma of patients with locally advanced esophageal cancer may help to assess which patients have a high risk of recurrence after neoadjuvant chemoradiotherapy and surgery.