ctDNA for Risk of Recurrence Assessment in Patients Treated with Neoadjuvant Treatment: A Systematic Review and Meta-analysis

BackgroundWe wanted to investigate the association between circulating tumor DNA (ctDNA) detection at baseline, during and after neoadjuvant treatment, after surgery, and recurrence, in patients with nonmetastatic cancer.Patients and MethodsIn this systematic review and meta-analysis, we included studies that investigated patients undergoing neoadjuvant treatment for nonmetastatic cancer and provided recurrence indices stratified for ctDNA status at the following timepoints: baseline, during treatment, posttreatment, and postsurgery. Study quality was reported with the Newcastle–Ottawa scale, REMARK checklist, and GRADE approach. PubMed, Embase, Cochrane Library, and Web of Science were our data sources (inception to 3 June 2021). The main outcome was risk of recurrence.ResultsWe identified ten studies including 727 patients with rectal, breast, gastric, and bladder cancer. All studies reported posttreatment ctDNA analysis, while seven, four, and six reported baseline, during treatment, and postsurgery ctDNA analysis, respectively. ctDNA detection was associated to recurrence across all timepoints [baseline: risk ratio (RR) 2.86, 95% confidence interval (CI) 1.33–6.14, during treatment: RR 3.81, 95% CI 2.09–6.92, posttreatment: RR 4.29, 95% CI 2.79–6.60, postsurgery: RR 8.03, 95% CI 3.16–20.43]. Heterogeneity was low to moderate.ConclusionsThis meta-analysis of observational studies found that ctDNA detection in patients undergoing neoadjuvant treatment for nonmetastatic cancer was associated with recurrence. A stronger association was evident in posttreatment and postsurgery timepoints. However, some studies reported low negative predictive value (NPV) of pathological complete response, showing that ctDNA-detection-guided escalation and de-escalation studies following neoadjuvant treatment regimens are needed before its role as a treatment guidance can be affirmed.