Comprehensive genomic profiling (CGP)-informed personalized molecular residual disease (MRD) detection: An exploratory analysis from the PREDATOR study of metastatic colorectal cancer (mCRC) patients undergoing surgical resection.

Abstract

187 Background: Detection of MRD following metastatic liver resection in advanced CRC patients is associated with poor prognosis with high rate of relapse. Nevertheless, there is currently no standard of care to guide further therapy after curative intent surgery. MRD detection has the promise to be implemented into standard of care and guide treatment decision making. Here we establish feasibility of MRD detection using Foundation Medicine’s novel tissue-informed personalized monitoring assay, FoundationOne Tracker (F1T), in mCRC patients undergoing surgical resection with curative intent. Methods: Tissue-based CGP was performed retrospectively on a cohort of 72 patients from the PREDATOR trial. Trackable patient-specific single nucleotide variants were selected using a novel computational approach negating the need for buffy coat sequencing to filter germline variants. Personalized multiplex PCR was used to detect and evaluate prognostic value of ctDNA from plasma collected at MRD timepoint post-surgery (median 27 days, range 8-99.5). Median follow-up of patients in the overall population was 10.7 months (range: 0.9-53.8 months). Survival analyses were performed using the Kaplan-Meier Estimator and Cox regression. Results: Post-surgical F1T analysis was successful on 96% of cases (69/72). CGP analysis revealed at least one driver mutation in 57% of samples (41/72) including KRAS/NRAS (46%) and BRAF mutations (3%). MRD was detected in 45% (31/69) of patients, of which 94% (29/31) had progressed at the time of the data cut. Median progression -free survival (PFS) was 3.2 months (2.1-7.1) in ctDNA-positive vs 28 months (20.9-NA) in ctDNA-negative population (HR 5, CI 2.7-9.3, p<0.001). Median overall survival (OS) was 31.6 months in ctDNA-positive vs not reached in ctDNA-negative group (HR 27, CI 3.6-205, p<0.001). Conclusions: CGP-informed post-operative MRD detection is a strong prognostic biomarker and correlates with survival outcomes in patients with resected mCRC. F1T is a novel and convenient technological approach to MRD detection utilizing highly validated FMI testing to reveal potentially targetable mutations and inform personalized ctDNA monitoring. These results demonstrate the ability of F1T to accurately detect MRD in mCRC patients following surgical resection, without the need for germline sequencing.