Abstract
An increasingly large body of evidence supports the assertion that the analysis of circulating tumor DNA (ctDNA) in metastatic colorectal cancer (mCRC) patients allows the temporal heterogeneity of cancer during the course of targeted therapies to be monitored. From liquid biopsy-guided genomic studies in mCRC, we have learned that there may be a rise in RAS mutant clones in the plasma of patients before the onset of secondary resistance to anti-EGFR therapy, generating new hypotheses for blood-guided adaptive therapeutic strategies (1). Similarly, the clearance of RAS mutant clones in plasma has been more recently suggested, supporting, for the first time, an unexpected negative selection of RAS mutant clones during the clonal evolution of mCRC (2–4). This phenomenon had previously been described in leukemia patients, with some showing a loss of RAS mutations during disease progression, supporting the hypothesis that the evolutionary pressure of therapies can result in positive but also negative selection of RAS mutant clones at relapse (5). The temporary prevalence of wt RAS clones at relapse in mCRC raises the question of whether liquid biopsy testing might expand the population of anti-EGFR-eligible patients by including those with primary RAS-mutant mCRC that “convert” to wild type in plasma at the time of disease progression (PD). Whether undetectable RAS mutations in plasma might really reflect wt RAS status or might simply mirror a low analytic sensitivity in the adopted assays is still a matter of debate (6).
Highlights
An increasingly large body of evidence supports the assertion that the analysis of circulating tumor DNA in metastatic colorectal cancer patients allows the temporal heterogeneity of cancer during the course of targeted therapies to be monitored
A recent comparison between the OncoBEAM RAS CRC mutation test and Idylla ctKRAS assay from paired plasma samples of metastatic colorectal cancer (mCRC) patients identified a “gray zone” below a 1% mutant allele fraction (MAF) where Idylla shows reduced RAS mutation detection accuracy vs. OncoBEAM [16]
An increased sensitivity of RAS testing under 1%, which is undoubtedly useful for monitoring the early onset of mutations, in this specific case might risk excluding from treatment patients with low MAF, who might benefit from anti-EGFR [17]
Summary
An increasingly large body of evidence supports the assertion that the analysis of circulating tumor DNA (ctDNA) in metastatic colorectal cancer (mCRC) patients allows the temporal heterogeneity of cancer during the course of targeted therapies to be monitored. It is undeniable that correct interpretation of the clearance of RAS mutations in plasma must be supported by the demonstration of detectable ctDNA; the crux of the matter is the urgent need for appropriate methods to confirm (or to exclude) the presence of ctDNA in plasma samples For this purpose, plausible options would be [1] to monitor a somatic mutation other than RAS that was previously detected in the primary tissue, [2] to provide evidence of wt RAS status in metastatic sites at the time of PD. All samples with no mutation and no WIF1/NPY methylation were considered as “inconclusive.” In their study, Moati et al described 8/36 (22%) patients who converted to a wt-RAS status in blood at the time of disease progression, but only in two patients was the presence of ctDNA in the sample confirmed by methylation test, while for the other six cases, the results were inconclusive.
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