Accuracy of plasma RAS mutation testing for therapy selection and monitoring of colorectal cancer patients

Abstract

Background: Tumor tissue is currently used for RAS testing in metastatic colorectal cancer (mCRC) patients, but detection of circulating tumor DNA in plasma is being actively investigated as an alternative for detection and monitoring of RAS mutations during therapy. Method(s): Concordance of plasma and tissue RAS mutation was evaluated in 102 mCRC patients. RAS mutation status was also monitored in serial plasma samples from 18 patients. The OncoBEAMTMRAS CRC assay was used to detect RAS mutations in plasma and results were compared to those obtained by standard-of-care RAS testing of tissue. For discordant cases, tissue samples were re-examined with BEAMing. Result(s): The overall percent agreement of the two methods was 93.1% (95/102 patients), with positive agreement of 95.6% (43/45) and negative agreement of 91.2% (52/57). Of the 5 plasma+/tissue- cases, 3 patients were treated with anti-EGFR therapy; 2 showed responses with loss of RAS mutations in plasma and 1 patient did not respond to therapy. In another plasma+/tissue- case, tissue BEAMing revealed a RAS mutation. This patient was treated with anti-VEGF therapy with a partial response. Longitudinal monitoring of plasma RAS status showed that of 13 patients initially treated with cetuximab, 4 showed emergence of RAS mutations at progression. In 4 other patients with basal RAS mutations treated with QT + anti-VEGF, 3 showed a significant decrease in the fraction of RAS mutant alleles. This decline mirrored responses to treatment. Interestingly, all 4 of these patients were determined to have stable disease by RECIST criteria upon CT scan. (Table presented) Conclusion(s): The high overall agreement between plasma and tissue RAS mutation status indicates that blood-based testing with OncoBEAMTMRAS CRC is a viable alternative to tissue testing for mCRC patients. Moreover, this study shows that BEAMing will be useful to monitor RAS mutation status in patients undergoing systemic therapy to monitor resistance and evaluate the efficacy of particular treatments.