To evaluate RAS and BRAF mutation testing in circulating tumor (ct) DNA for prediction of chemotherapy plus anti-EGFR benefit and acquisition of resistance in metastatic colorectal cancer (mCRC) patients (pts).
RAS and BRAF mutational status, were assessed by Idylla™ system (Biocartis) ctDNA methodology in a baseline plasma sample and a serum sample collected at the time of the last available determination from KRAS exon 2 wild-type (WT) mCRC patients treated with first-line antiEGFR therapy within two first-line prospective biomarker-designed clinical trials (PULSE; NCT01288339 and POSIBA; NCT01276379).
Analysis of extended RAS and BRAF in tissue and plasma from 178 KRAS exon 2 wild-type mCRC pts showed a sensitivity of 59% and a specificity of 90%. Patients with baseline RAS and BRAF (n = 36) mutant ctDNA had a median Progression Free Survival (mPFS) of 8.2 months (CI 95% 6.3-10 months) and 6.7 months (CI 95% 4.3-9.1 months) respectively, whereas double wild-type (2WT) pts had a mPFS of 13.6 months (CI 95% 11.7-15.4 months; p < 0.0001). Analogously the median overall survival (mOS) of baseline RAS and BRAF ctDNA mutant pts was 22.3 months (CI 95% 15.6-29 months) and 8.9 months (CI 95% 6.3-11.4 months) respectively, which were significantly inferior to the mOS of 40.4 months (CI 95% 35.9-44.9 months) in 2WT pts (p < 0.0001). Acquisition of RAS/BRAF mutations was 9/63 (14%) in pts with progressive disease (PD) (i.e, blood draw within 1 month before PD or after PD) (median 24.8 days (-29 to 484 days)) compared to 6/73 (8%) in pts with no PD or blood extraction for ctDNA analysis before 1 month of PD (median -265.6 days (-31 to -1126 days) (p = 0.47). Median OS in patients with RAS/BRAF acquisition was 23.9 months (CI 95% 19.7-27.9 months) compared to 40.6 months (CI 95% NR-NR months) in pts who remained free of mutations (p = 0.016).
Our results confirm that baseline RAS and BRAF testing in ctDNA discriminates PFS and OS. The emergence of RAS/BRAF mutations has limited impact on the time to progression to antiEGFR therapy and confers poor prognosis.
Clinical trial identification
Legal entity responsible for the study
Grupo Español Multidisciplinar de Cáncer Digestivo.
All authors have declared no conflicts of interest.