Abstract
BackgroundPrecise methods for postoperative risk stratification to guide the administration of adjuvant chemotherapy (ACT) in localized colorectal cancer (CRC) are still lacking. Here, we conducted a prospective, observational, and multicenter study to investigate the utility of circulating tumor DNA (ctDNA) in predicting the recurrence risk.MethodsFrom September 2017 to March 2020, 276 patients with stage II/III CRC were prospectively recruited in this study and 240 evaluable patients were retained for analysis, of which 1290 serial plasma samples were collected. Somatic variants in both the primary tumor and plasma were detected via a targeted sequencing panel of 425 cancer-related genes. Patients were treated and followed up per standard of care.ResultsPreoperatively, ctDNA was detectable in 154 of 240 patients (64.2%). At day 3–7 postoperation, ctDNA positivity was associated with remarkably high recurrence risk (hazard ratio [HR], 10.98; 95%CI, 5.31–22.72; P < 0.001). ctDNA clearance and recurrence-free status was achieved in 5 out of 17 ctDNA-positive patients who were subjected to ACT. Likewise, at the first sampling point after ACT, ctDNA-positive patients were 12 times more likely to experience recurrence (HR, 12.76; 95%CI, 5.39–30.19; P < 0.001). During surveillance after definitive therapy, ctDNA positivity was also associated with extremely high recurrence risk (HR, 32.02; 95%CI, 10.79–95.08; P < 0.001). In all multivariate analyses, ctDNA positivity remained the most significant and independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors. Serial ctDNA analyses identified recurrence with an overall accuracy of 92.0% and could detect disease recurrence ahead of radiological imaging with a mean lead time of 5.01 months.ConclusionsPostoperative serial ctDNA detection predicted high relapse risk and identified disease recurrence ahead of radiological imaging in patients with stage II/III CRC. ctDNA may be used to guide the decision-making in postsurgical management.
Highlights
Precise methods for postoperative risk stratification to guide the administration of adjuvant chemo‐ therapy (ACT) in localized colorectal cancer (CRC) are still lacking
Our work indicates that the detection of circulating tumor DNA (ctDNA) could reflect the existence of minimal residual disease (MRD), and ctDNA evaluation as early as 3–7 days postoperatively may facilitate risk stratification and decision-making in postsurgical management
Clinicopathological characteristics of the study cohort A total of 276 patients diagnosed with clinical stage II/ III CRC were recruited at the study entry, and 240 evaluable patients were retained for analysis (Fig. 1)
Summary
Precise methods for postoperative risk stratification to guide the administration of adjuvant chemo‐ therapy (ACT) in localized colorectal cancer (CRC) are still lacking. A substantial proportion of patients still experience disease recurrence after the curative resection. A standard of care of 3- to 6-month adjuvant chemotherapy (ACT) has been widely adopted to eradicate the MRD in patients with clinicopathological high-risk factors, including stage III, poor differentiation, lymphovascular invasion, nerve invasion, and so on [8, 9]. As not all patients with these high-risk factors have MRD after surgery, a considerable number of patients have to suffer from the adverse effects of ACT without clinical benefit. For patients without high-risk factors, MRD may still exist and some of them could potentially benefit from ACT. 20–30% patients who received ACT still experience disease recurrence [10, 11], but there is no available tool to evaluate the efficacy of ACT and guide the post-ACT management
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