Search

Background: Circulating 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 methods: A 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. Results: ctDNA 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%. Conclusions: Plasma 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., This work was supported by Merck, S.L., Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany and partially by the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad) and 'Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa' grants [FIS PI12-01589 to RS] and RETICC Cancer: Grupo Cancer Digestivo - Instituto de Salud Carlos III. TTD ULTRA study (EC11-050) was supported by the Ministerio de Sanidad y Politica Social [SPI/2885/2011]. To CM grants [PI15/00457 and DTS15/00048].

The original version of this Article contained an error in the spelling of the author P. Garcia-Alfonso, which was incorrectly given as P. Garcia. This error has now been corrected in the PDF and HTML versions of this Article.