Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies

SIMPLE SUMMARY: Increasing evidence suggests that circulating cell-free DNA (cfDNA) testing might allow for monitoring the response to anti-EGFR monoclonal antibodies in patients with metastatic colorectal carcinoma (mCRC). However, few data are available in treatment-naïve patients. We tested cfDNA samples obtained from mCRC patients enrolled in a phase III trial of the anti-EGFR monoclonal antibody cetuximab plus chemotherapy as first-line treatment. Analysis of serial plasma samples revealed a complex dynamic of RAS/BRAF mutations in response to treatment, with transitory peaks of these mutations that were not associated with resistance to therapy. Overall, our findings suggest that early appearance of RAS/BRAF mutations in the plasma of patients receiving first-line anti-EGFR agents in combination with chemotherapy should not be considered as marker of resistance. ABSTRACT: Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.