LAUSR

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).