Clinical applications of extended ctDNA RAS mutation determination in metastatic colorectal cancer.

Abstract

607 Background: Tumor tissue is currently used for RAS testing in metastatic colorectal cancer (mCRC) patients, but detection of circulating tumor (ct) DNA in plasma is being actively investigated as an alternative for detection and monitoring RAS mutations during therapy. Methods: Concordance of RAS testing in plasma using the OncoBEAM RAS CRC test and RAS testing in tissue using standard-of-care RAS detection techniques was evaluated in 114 mCRC antiEGFR-naïve patients. In discordant cases, tissue samples were re-examined by BEAMing. OncoBEAM RAS CRC assay was also used to monitor RAS mutation status in serial plasma samples from 34 patients treated with anti-VEGF +/- chemotherapy or anti-EGFR based therapy. Results: The overall agreement of the two methods was 93% (106/114 patients), with positive agreement of 96.2% (51/53) and negative agreement of 90.2% (55/61). Longitudinal monitoring of plasma samples from 13 patients with RAS mutated tumors treated with chemotherapy +/- anti-VEGF, showed a significant decrease (or disappearance) of RAS mutant allele fraction (MAF) in all cases at the time of CT-scan (8-12 weeks after onset of treatment). In 3 patients, plasma was also analyzed at week 4 showing the same dramatic decrease in MAF. RAS decline mirrored clinical and radiological response to treatment. Interestingly, RAS decline was also observed in patients with stable disease in CT-scan by RECIST1.1. In 7 of 9 patients that subsequently progressed, RAS ctDNA fraction increased accordingly. On the other hand, among 22 patients RAS wt treated with cetuximab, 6 showed emergence of RAS mutations at progression. In two cases, multiple RAS mutations were concomitantly present. Conclusions: The high overall agreement between basal plasma and tissue RAS mutation status indicates that blood-based testing with OncoBEAM RAS CRC is a viable alternative to tissue RAS testing in mCRC patients. Moreover, this study highlights the utility of OncoBEAM RAS CRC to monitor treatment of mCRC patients in two setting: (a) evaluation of response to anti-VEGF +/- chemotherapy in RAS mutant patients, as a complement to RECIST radiological criteria and (b) to monitor emergence of resistant clones during anti-EGFR treatment in RAS wt patients.