cfDNA for accurate determination of RAS and BRAF mutations using OncoBEAM liquid biopsy in metastatic colorectal cancer patients: Results of the real-world multicentric ColoBEAM study.

Abstract

3542 Background: Determination of KRAS, NRAS ( RAS) and BRAF mutations is a standard of care for the management of patients with metastatic colorectal cancer (mCRC). RAS mutations are well characterized resistance biomarkers to anti-EGFR antibodies and BRAF V600 mutations indicate poor prognosis. Tissue biopsy has traditionally been used to determine RAS and BRAF status, but liquid biopsy analysis of circulating tumor DNA (ctDNA) has demonstrated utility as a less invasive tool to expedite molecular testing results to the clinic. The ColoBEAM study reports the performance of plasma mutation testing in a real-life prospective series of 278 patients across 8 centers. Methods: Plasma derived ctDNA was prepared from 20mL blood samples prospectively collected from mCRC patients who had not received chemotherapy in the prior 15 days. ctDNA was centrally assessed using OncoBEAM and results compared to those obtained by routine analysis of tissue. Both tissue and blood samples with discrepant RAS results were blindly reassessed with OncoBEAM. Results: Of 278 patients enrolled, 202 blood samples were available for OncoBEAM testing. RAS and BRAF V600E mutations were detected in tissue in 132/202 (65.4%) and 4/198 (2.0%) patients, respectively. Analysis of the first ctDNA sample as compared to tissue DNA resulted in a kappa coefficient (κ) of 0.52 [0.41 – 0.63] and accuracy of 75.2% (65.1% sensitivity; 94.3% specificity). OncoBEAM testing of a second sample resulted (κ) of 0.66 [0.56 - 0.76] and accuracy of 83.2% (77.3% sensitivity; 94.3% specificity). Of the 4 samples with a BRAF V600E mutation in tumor tissue 2 were detected in blood. In the subgroup of patients with liver metastasis (n=136), accuracy was 88.2% (87.4% sensitivity; 90.2% specificity) for RAS and BRAF status with (κ) of 0.73 [0.61 – 0.86]. In a subgroup of chemotherapy naïve patients with liver metastasis (n=49), accuracy was 91.8% (93.3% sensitivity; 89.5% specificity) for RAS and BRAF status with (κ) of 0.83 [0.67 – 0.99]. Conclusions: The results of the ColoBEAM study confirm plasma ctDNA as a credible surrogate marker to tissue DNA for RAS and BRAF status assessment and may be incorporated as a first-line theragnostic assessment. New testing on a second sample for wild-type status demonstrated 91.8% concordance between blood and tissue. Clinical trial information: NCT02751177.

Personalized Medicine—Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer

“…In a prospective-multicenter study, Thierry and colleagues show that cfDNA analysis could advantageously replace tumor-section analysis for KRAS and BRAF mutations [168]. These findings are in line with results from the ColoBEAM study, where BEAMing assay technology confirmed high overall tissue and blood concordance for RAS/BRAF of 89.3% (Se = 87.5%; Sp = 92.0%) in chemotherapy-naïve patients [171]. These studies highlight that cfDNA extracted from plasma is an attractive surrogate marker to tissue DNA biopsy for KRAS, NRAS and BRAF mutation assessment ( Table 2).…”

“…There are a large number of studies that have correlated cfDNA with BRAF and KRAS tissue mutations [168,[171][172][173]. In a prospective-multicenter study, Thierry and colleagues show that cfDNA analysis could advantageously replace tumor-section analysis for KRAS and BRAF mutations [168].…”

Liquid Biopsy and Artificial Intelligence as Tools to Detect Signatures of Colorectal Malignancies: A Modern Approach in Patient’s Stratification

“…Various commercial platforms are available for identifying actionable mutations in CRC such as Idylla or OncoBEAM, Idylla platform being used also for MSI detection (201)(202)(203). Vidal and colleagues (204) revealed a 93% overall agreement between the mutational status of RAS when comparing tissue and plasma samples.…”

The current state of molecular profiling in gastrointestinal malignancies

“…Taking anti-EGFR therapy as an example [ 125 – 127 , 131 ], ctDNA studies demonstrate that RAS/EGFR mutant clones emerge during treatment, which might regress upon the withdrawal of anti-EGFR therapy, thereby allowing for rechallenge with the targeted therapy [ 128 ]. This regression could not be reasonably assessed using tumor tissue because it would mean the risk of repeated biopsying.…”