Circulating tumour DNA and MRI circumferential resection margin are key prognostic indicators for survival in rectal cancer.

Background: Recurrence of colorectal cancer has been linked to the presence of methylated circulating tumour DNA (ctDNA) in patient plasma after surgery. The prognostic significance of ctDNA before treatment remains unclear. This study investigated the correlation between pretreatment ctDNA and current radiological [magnetic resonance imaging (MRI)] prognostic markers in patients with rectal cancer and its association with recurrence-free survival and overall survival (OS). Patients and methods: A total of 42 patients with rectal cancer were enrolled. All patients had staging MRI before treatment. Blood was taken at diagnosis for ctDNA analysis for the presence of either methylated branched chain amino acid transaminase 1 (BCAT1) or IKAROS family zinc finger 1 (IKZF1). The correlation of MRI prognostic indicators and ctDNA test results was assessed with chi-square tests. Univariable and multivariate Cox regression analyses were carried out to determine variables associated with recurrence-free survival and OS. Results: The mean age of patients was 64.4 years (standard deviation 12.5 years), and the majority were male (30/42, 71.4%). A total of 11, 13, 9 and 9 patients were in stages I, II, III and IV, respectively. Patients were followed up for a minimum of 36 months unless disease recurrence or death occurred earlier. A total of 36 (85.7%) patients received neoadjuvant chemoradiotherapy, and 30 (71.4%) underwent surgical resection. The 3-year survival rate was 64%. About 67% (28/42) of patients were positive for the methylated ctDNA at diagnosis. Further, 11 out of 12 patients with a positive circumferential resection margin (CRM+) were ctDNA positive; univariable analysis showed that prognostic indicators for OS were presence of extramural venous invasion [EMVI; hazard ratio (HR) 2.63, 95% confidence interval (CI) 0.95-7.31], CRM+ (HR 10.69, 95% CI 3.51-32.56), metastatic disease (HR 7.7, 95% CI 2.79-21.67) and ctDNA% methylation (HR 1.04, 95% CI 1.02-1.06). The presence of CRM+ and a positive ctDNA had an HR of 19.57 (95% CI 3.47-110.49). In the multivariate analysis, including adjustment for age and EMVI, only the CRM+/ctDNA+ variable was an independent predictor for poor survival (HR 19.57, 95% CI 3.47-110.49). Conclusions: In rectal cancer, almost all patients with CRM involvement have ctDNA, and these patients had the worst prognosis. Future studies with longitudinal ctDNA assessment before and after treatment may potentially inform prognosis and help tailor patients' treatment.