Molecular residual disease detection by serial tumour-informed circulating tumour DNA analysis in resectable oesophageal & gastroesophageal junctional adenocarcinoma: a prospective UK multi-centre study

Background The value and optimal timing of circulating tumour DNA (ctDNA) analysis in locally advanced oesophageal adenocarcinoma (OAC) is uncertain. We hypothesised that perioperative detection would predict event-free (EFS) and overall (OS) survival, and that 3-6 months post-operative detection would predict recurrence. Methods In this prospective multi-centre cohort study, tumour-informed ctDNA assays were designed for 49 patients using whole-exome sequencing. Bloods were collected for ctDNA detection up to 8 days prior to surgery, and at 3-6 weeks and 3-6 months post-surgery, then correlated with clinicopathological characteristics, EFS and OS. Results Pre- and early post- surgery ctDNA positivity were associated with worse EFS (HRs 7.97 (95% confidence interval, CI 2.64-24.04), p<0.0001; 8.18 (95%CI 3.23-20.69), p<0.0001) and OS (HRs 7.82 (95%CI 2.22-27.54), p=0.00018; 13.69 (95%CI 4.52-41.49), p<0.0001). In pre-surgery positive patients, post-surgery ctDNA clearance associated with improved EFS and OS, and predicted better OS in those with a poor histopathological response to neoadjuvant treatment. 3-6 month ctDNA-positivity preceded standard-of-care recurrence detection by median 53.5 (interquartile range 39.3-200.0) days. Conclusions Perioperative ctDNA positivity associates with worse EFS and OS in OAC, identifying a subgroup with improved outcomes despite adverse pathological features. ctDNA testing at 3-6 months predicts recurrence earlier than standard-of-care surveillance.