Predictive value of circulating tumor DNA in locally advanced rectal cancer patients receiving neoadjuvant radiochemotherapy

Background: Neoadjuvant radiochemotherapy (RCT) is rapidly becoming the preferred treatment for patients diagnosed with late-stage locally advanced rectal cancer (LARC). Presently, tumor regression grades (TRG) is used to characterize treatment responsiveness; patients with low TRG scores have been shown to receive no benefit from surgery. To-date, however, there exists no reliable method for identifying low TRG-scoring patients without surgery. Here we propose the use of circulating tumor DNA (ctDNA) to identify low TRG-scoring patients to reduce overtreatment and improve quality of life. 

Methods: 30 LARC patients undergoing neoadjuvant RCT were prospectively enrolled in our study. Plasma was collected before treatment, immediately preceding cycle 3 chemotherapy, and 2 weeks following cycle 4 chemotherapy. Tumor tissue was also collected before treatment start. CtDNA and tumor DNA were sequenced using Accu-Act, a 61-gene NGS panel. Tumor response was classified as TRG1-5 according to Mandard classification system. Somatic mutation profiles were correlated with tumor response. The accuracy of ctDNA and tumor DNA in predicting TRG scores was calculated using the change of allele frequency. The predictive value of ctDNA was also compared to that of standard CEA and CA199 assays. Patients with CEA and CA199 scores below threshold were also considered for evaluation. 

Results: 18 of the 30 LARC patients enrolled had complete ctDNA profiling test among whom 13 had already undergone surgery. 17 somatic mutations were identified from the 10 patients with TRG scores of either 1, 2, or 3. Predictive accuracy of pretreatment ctDNA profiling was 70%, compared to that of CEA analysis (66%) and CA199 analysis (50%). TRG prediction using ctDNA successfully evaluated half of patients for whom CEA analysis failed to predict the change in tumor burden. 

Conclusions: Our findings suggest ctDNA mutation profiling may be a powerful tool for predicting TRG in LARC patients undergoing RCT. Further studies are needed to validate the utility of ctDNA in identifying patients who can be spared from unnecessary surgical treatment in LARC. 

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