Chemotherapy-induced Reversion of Mutant RAS to Wild-type RAS in Metastatic Colorectal Cancer

Secondary mutation of mutated RAS, induced by chemotherapy, is thought to be rare. However, introduction of liquid biopsy (LB) has made it possible to monitor RAS status in patients' plasma throughout the course of chemotherapy for metastatic colorectal cancer (mCRC), and disappearance of the RAS mutation (RAS-mt), i.e., the NeoRAS-wt phenomenon, has been reported and is receiving attention, especially with respect to treatment implications.A prospective study of 129 patients undergoing chemotherapy for mCRC (RAS-wt, n=65; RAS-mt, n=64) was carried out. Plasma RAS status was monitored in these patients by LB. Relations between secondary genetic change, chemotherapy, and 6-month disease outcomes were analyzed. The effect of anti-EGFR mAb therapy on NeoRAS-wt mCRC was also examined.NeoRAS-wt was detected in 27 (43.5%) RAS-mt patients overall and in all patients with a G12S or Q61H mutation. First-line treatment was more effective among NeoRAS-wt patients than non-NeoRAS-wt patients (70.9% vs. 48.6% overall response rate, p=0.087), and the time from treatment to LB was shorter in this group. Six-month outcomes were significantly better in the NeoRAS-wt group (p<0.001), and conversion to NeoRAS-wt was found to be predictive of a good outcome (OR=7.886, 95% CI=2.458-25.30; p<0.001). Anti-EGFR mAb therapy was found to restrict disease progression in NeoRAS-wt patients.Conversion to NeoRAS-wt is relatively frequent, and it may predict good responses to treatment. Anti-EGFR mAb therapy was effective for our NeoRAS-wt patients. Detection of NeoRAS-wt by LB may significantly change the indication for anti-EGFR mAb therapy and the mCRC treatment strategy.