Abstract
BackgroundCirculating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy.Patients and methodsA prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue.ResultsctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71 − 0.90) and BEAMing in tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74 − 0.92). Fifteen cases (10.3%) showed discordant tissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possibly due to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explained by low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second- or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allele fractions in plasma below 1%.ConclusionsPlasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection.
Highlights
In metastatic colorectal cancer, treatment with antiepidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab or panitumumab has demonstrated efficacy in wildtype (WT) RAS mutations and it is considered imperative this determination at the time of diagnosis [1, 2]
The feasibility and practicality of circulating tumor DNA (ctDNA) analysis may translate into an alternative tool for anti-EGFR treatment selection
We investigated the value of this determination in terms of progression-free survival (PFS) in patients who had received anti-EGFR as well as overall survival (OS) and mutant allele fraction (MAF) analysis
Summary
In metastatic colorectal cancer (mCRC), treatment with antiepidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab or panitumumab has demonstrated efficacy in wildtype (WT) RAS mutations and it is considered imperative this determination at the time of diagnosis [1, 2]. In mCRC, ctDNA is detected in almost all patients but the low abundance requires highly sensitive techniques to study mutations present at low frequencies. This approach represents a liquid non-invasive biopsy with a potential for determining RAS status. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy
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