Analysis of RAS/BRAF mutations in cell-free circulating tumour DNA as a diagnostic strategy to determine eligibility for anti-EGFR therapy
2Department of Epidemiology and Biostatistics, Amsterdam University Medical Centers, Amsterdam, Netherlands
3Department of Medical Oncology, Amsterdam University Medical Centers, Amsterdam, Netherlands
4Department of Laboratory Medicine, The Netherlands Cancer Institute, Amsterdam, Netherlands
5Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
6Department of Medical Oncology, University Medical Center Utrecht, Utrecht, Netherlands
7Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, Netherlands
Introduction: RAS/BRAF mutations predict poor responsiveness of metastatic colorectal cancer patients to treatment with anti-EGFR therapeutic antibodies. Therefore, eligibility for anti-EGFR therapy is currently based on RAS/BRAF mutation analyses using tissue biopsies. Liquid biopsies are minimally invasive and easy to obtain, rendering RAS/BRAF mutation analyses of cell-free circulating tumour DNA (ctDNA) as an attractive complementary or alternative approach.
Aim: This study aimed to examine the optimal diagnostic strategy incorporating liquid biopsy RAS/BRAF ctDNA mutation analyses to determine eligibility for anti-EGFR therapy.
Method: Tissue biopsies and liquid biopsies were collected prior to treatment from 100 colorectal cancer patients with liver-only metastases, accrued in 30 hospitals. Tissue biopsy RAS/BRAF mutation status was determined using various standard-of-care assays. Liquid biopsies were collected in Streck BCT® tubes and shipped to a central lab for isolation of cell-free DNA. RAS/BRAF ctDNA mutation status was determined by droplet digital PCR. Three diagnostic strategies were evaluated: two combination strategies of liquid biopsy followed by tissue biopsy in liquid biopsy-negative cases and one liquid biopsy only strategy. These were compared to the current practice in terms of costs and percentage of patients eligible for anti-EGFR therapy using decision tree analyses.
Results: Tissue mutations in KRAS, NRAS and BRAF were detected in 54%, 0% and 3%, respectively. Overall, a 93% concordance was observed between tissue- and liquid-biopsy mutation analyses. Compared to the current practice, the proportion of patients detected with RAS/BRAF alterations increased from 57% to 60% for the combination strategies. All three evaluated strategies were favourable in terms of assay costs compared to current practice.
Conclusion: A combination of liquid biopsy analyses followed by tissue biopsy analyses in case of a liquid biopsy-negative result was the most favourable strategy to comprehensively determine eligibility for anti-EGFR therapy and has added value to current standard-of-care in terms of assay costs.
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