Risk stratification by circulating tumor DNA-based pretreatment genomic profile and post-operative molecular residual disease detection in resectable colorectal oligometastases: PRECISION, a prospective multicenter study

BACKGROUND: The role of a comprehensive genomic profile (CGP) and molecular residual disease (MRD) in circulating tumor DNA (ctDNA) for risk stratification of resectable colorectal oligometastases (CRMs) remains unclear. This study aimed to investigate the feasibility of ctDNA analysis in patients with CRM and to conduct an exploratory assessment of its recurrence risk. PATIENTS AND METHODS: This study assessed ctDNA in patients with previously untreated resectable CRM scheduled for curative resection, before starting treatment and 4 weeks postoperatively. Pretreatment samples were prospectively tested for genomic alteration using a 74-gene CGP assay (Guardant360). The pathogenic mutations in BRAF, KRAS, PIK3CA, SMAD4, or TP53 were defined as poor genomic profiles. Postoperative samples were retrospectively analyzed for MRD using a methylation-based MRD assay (Guardant Reveal). RESULTS: Among 118 eligible patients, pretreatment ctDNA was detected in 114 (96.6%) patients, 75 (63.6%) of whom had poor profiles. MRD was detected in 34 (31.2%) patients out of 109 evaluable patients who underwent surgery. Using multivariable analysis, pretreatment poor profiles and post-operative MRD were significantly associated with shorter recurrence-free survival (RFS) [hazard ratio (HR) 3.28, 95% confidence interval (CI) 1.72-6.25; HR 4.07, 95% CI 2.40-6.90, respectively] and time to surgical failure (TSF) (HR 2.76, 95% CI 1.35-5.64; HR 3.05, 95% CI 1.70-5.45, respectively). Patients with both poor pretreatment profiles and post-operative MRD demonstrated the worst prognosis in RFS (HR 13.28, 95% CI 5.86-30.10), TSF (HR 8.98, 95% CI 3.77-21.40), and overall survival (HR 9.21, 95% CI 2.06-41.18). CONCLUSIONS: Combining pretreatment CGP and post-operative MRD in ctDNA showed potential for improved prognostic stratification after CRM resection.