Detection of circulating tumour DNA after neoadjuvant chemoradiotherapy in patients with locally advanced oesophageal cancer

Abstract

Active surveillance instead of standard surgery after neoadjuvant chemoradiotherapy (nCRT) has been proposed for patients with oesophageal cancer. Circulating tumour DNA (ctDNA) may be used to facilitate selection of patients for surgery. We show that detection of ctDNA after nCRT seems highly suggestive of major residual disease. Tumour biopsies and blood samples were taken before, and 6 and 12 weeks after, nCRT. Biopsies were analysed with regular targeted next‐generation sequencing (NGS). Circulating cell‐free DNA (cfDNA) was analysed using targeted NGS with unique molecular identifiers and digital polymerase chain reaction. cfDNA mutations matching pre‐treatment biopsy mutations confirmed the presence of ctDNA. In total, 31 patients were included, of whom 24 had a biopsy mutation that was potentially detectable in cfDNA (77%). Pre‐treatment ctDNA was detected in nine of 24 patients (38%), four of whom had incurable disease progression before surgery. Pre‐treatment ctDNA detection had a sensitivity of 47% (95% CI 24–71) (8/17), specificity of 85% (95% CI 42–99) (6/7), positive predictive value (PPV) of 89% (95% CI 51–99) (8/9), and negative predictive value (NPV) of 40% (95% CI 17–67) (6/15) for detecting major residual disease (>10% residue in the resection specimen or progression before surgery). After nCRT, ctDNA was detected in three patients, two of whom had disease progression. Post‐nCRT ctDNA detection had a sensitivity of 21% (95% CI 6–51) (3/14), specificity of 100% (95% CI 56–100) (7/7), PPV of 100% (95% CI 31–100) (3/3), and NPV of 39% (95% CI 18–64) (7/18) for detecting major residual disease. The addition of ctDNA to the current set of diagnostics did not lead to more patients being clinically identified with residual disease. These results indicate that pre‐treatment and post‐nCRT ctDNA detection may be useful in identifying patients at high risk of disease progression. The addition of ctDNA analysis to the current set of diagnostic modalities may not improve detection of residual disease after nCRT. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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

“…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]. For example, non-clearance of ctDNA pre-surgery is associated with an incomplete response [10,11].…”

“…Several studies have found that ctDNA dynamics of EAC patients predicts pathological response to neoadjuvant therapy [10,11,27]. For example, non‐clearance of ctDNA pre‐surgery is associated with an incomplete response [10,11]. Our results also showed that tracking mutations is specific for an incomplete response but the number of positive classified patients was limited.…”

“…Based on our findings, ctDNA seems to be a useful marker for identifying a small subgroup of patients at high risk of future disease progression irrespective of pathological response status and is therefore suited for the above‐mentioned purposes. At this moment, it is not yet sensitive enough to identify every pathological responder in the locally advanced setting, as recently reported, and therefore can not yet serve as a marker to spare surgery in ctDNA‐negative patients post‐treatment [10]. To adequately evaluate and explore the clinical value of ctDNA in EAC and build upon these results, we need clinical trials to explore standardized assays focused on patients at high risk of progression.…”

“…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]. These results suggest that ctDNA can be used to identify risk of recurrence but it is not yet sensitive enough to identify every patient with residual disease.…”

An update of Clinical value of circulating tumor DNA in esophageal cancer： a systematic review and meta- analysis

“…Nineteen studies reported on the PFS of the ctDNA [14,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44]. As the range of HR between these studies was 1.21 to 18.70, a significant association was observed between ctDNA-positivity in EC patients and the poorer PFS.…”