Analysis of Circulating Tumor DNA to Confirm Somatic KRAS Mutations

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KRAS mutations have clearly emerged as a pharmacogenomic marker that can predict which metastatic colorectal cancers will be resistant to treatment with antibodies that inhibit the epidermal growth factor receptor (EGFR) ( 1 , 2 ). The evaluation of patients for mutations in KRAS is rapidly becoming part of routine practice in clinical oncology and so far has relied mostly on formalin-fixed paraffin-embedded (FFPE) tumor tissue. Accurate KRAS testing is critical because it determines which patients may benefit from anti-EGFR therapy. However, the selection of specimens with a sufficient number of tumor cells, possible genetic heterogeneity between different tumor sites (eg, between primary tumor and metastases), the quality of extracted DNA, and different detection methods for KRAS mutations can interfere with accurate analysis. In addition, formalin fixation often indiscriminately and irreversibly damages DNA, increasing sample-to-sample variability and decreasing the amount of DNA available for molecular analysis. A recent article by Tol et al. ( 3 ), on the effects of KRAS mutations on first-line therapy of colorectal cancer patients with anti-EGFR therapies, highlights this issue. Eight patients had to be excluded from the study because of the discordance in the mutation status of KRAS as assessed by two independent sequencing methods, both performed on FFPE sections of tumor tissue.