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

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.

Genome‐wide and panel‐based cell‐free DNA characterization of patients with resectable esophageal adenocarcinoma

“…Prediction of CR was not possible by baseline ctDNA profiling due to the fact that responders also shed ctDNA before the start of neoadjuvant treatment. In a tissue informed panel-based EAC sequencing study (n = 78), several complete responders were also positive at baseline, in line with our findings [8]. Several studies have found that ctDNA dynamics of EAC patients predicts pathological response to neoadjuvant therapy [10,11,27].…”

“…By combining these two approaches mentioned above, we were able to classify 50.5% of baseline samples as ctDNA-positive. This is comparable to previously published studies with baseline detection rates of between 36% and 56% with panel-based sequencing and 30% with ichorCNA in an advanced-stage cohort [6,8,11,14]. For the future development of ctDNA assays, combining multiple metrics may thus improve detection.…”

“…Prognostic utility was also observed based on pre-surgery sampling in our EAC cohort with 14% positivity (nonclearance of baseline mutation or ichorCNA > 3%). Previous tumor-informed and tumor-agnostic studies support the strong relationship between ctDNA status posttreatment (10-16% positive) and disease recurrence [6][7][8]26,27]. Our results are thus comparable to the literature, and could indicate that further improvement in post-treatment detection may require, for example, repeated sampling to improve detection rates.…”

“…The detection of circulating tumor DNA (ctDNA) can be leveraged for clinical purposes in gastroesophageal cancer, as previously observed in stage IV patients [5]. In locally advanced EAC, several studies were able to predict recurrence both before and after surgery through next‐generation sequencing (NGS) of plasma samples [6–9]. In a longitudinal sampling study based on a pan‐cancer panel (77 genes), nine out of ten patients who were ctDNA‐positive after surgery experienced disease relapse [6].…”

“…However, ctDNA positivity after accounting for clonal hematopoiesis with indeterminate potential (CHIP) was only 16% (10/63) after surgery, while more than half of all patients experienced relapse. A recent study reported on a tumor‐informed sequencing method where ctDNA was detected in 56% (44/78) of baseline samples, but again a low detection rate of 10% (8/78) was observed in post‐treatment samples [8]. The detection of ctDNA post‐treatment also seems to be specific for incomplete response to nCRT but suffers from poor sensitivity (21%) [10,11].…”