Plasma clearance of RAS mutation under therapeutic pressure is a rare event in metastatic colorectal cancer

In metastatic colorectal cancer (mCRC), circulating tumor DNA (ctDNA) monitoring can be used to genotype tumors and track clonal evolution. We investigated the clearance ofRASmutated clones under chemotherapy pressure by ctDNA analysis in patients with aRASmutated mCRC. Patients with aRASmutated tumor included in the prospective PLACOL study were monitored for ctDNA. Analyses were based on optimized targeted next-generation sequencing and/or droplet-based digital polymerase chain reaction (ddPCR). For plasma samples without detectable mutations at progression disease, we tested the methylation status ofWIF1andNPYgenes using methylation-ddPCR (met-ddPCR) to validate the presence of ctDNA. Among the 36 patients with positive plasma samples forRASmutations at inclusion, 28 (77.8%) remainedRASpositive at disease progression and 8 (22.2%) became negative. Subsequent met-ddPCR for methylated markers showed that only two out of the eight patients withRASnegative plasma had detectable ctDNA at progression. Therefore, only 2 samples among 36 were confirmed for clearance ofRASmutation in our series. In conclusion, this study suggests that the clearance ofRASmutations in patients treated by chemotherapy for aRASmutated mCRC is a rare event. Monitoring tumor mutations in plasma samples should be combined with a strict control of the presence of ctDNA. The therapeutic impacts ofRASclearance need to be further explored.