True conversions from RAS mutant to RAS wild-type in circulating tumor DNA from metastatic colorectal cancer patients as assessed by methylation and mutational signature

The paucity of targeted treatments available in patients with RAS mutant colorectal cancers contributes to the poor prognosis of this patient group compared to those with RAS wild-type disease. Recent liquid biopsy-driven studies have demonstrated that RAS mutant clones might disappear in plasma during the clonal evolution of the disease, opening new unforeseen perspectives for EGFR blockade in these patients. Nevertheless, the lack of detection of RAS mutations in plasma might depend on the low amount of released circulating tumor DNA (ctDNA), making it necessary a more accurate selection of patients with true RAS mutation conversions. In this liquid biopsy-based study, we assessed RAS mutational status in initially RAS-mutant patients at the time of progressive disease from any line of therapy and investigated the incidence of true conversions to plasma RAS wild-type, comparing a colon cancer specific methylation profile with a mutational signature of ctDNA. Globally, considering either mutational panel or methylation profile as reliable tests to confirm or exclude the presence of ctDNA, the percentage of true RAS converters was 37.5%. In our series we observed a trend toward a better PFS in patients who received anti-EGFR as second or subsequent treatment lines compared to those who did not.

Automated summary

The lack of targeted treatments in RAS mutant colorectal cancers leads to poorer prognosis compared to RAS wild-type disease. Liquid biopsy studies have shown that RAS mutant clones may disappear in plasma during clonal evolution, potentially enabling new possibilities for EGFR blockade. However, the detection of RAS mutations in plasma may be hindered by the low levels of circulating ctDNA, necessitating a more precise selection of true RAS mutation converters. In this study, evaluating RAS mutational status at the time of disease progression in initially RAS-mutant patients revealed a 37.5% incidence of true RAS converters, with a trend towards improved PFS in patients receiving anti-EGFR treatment as second or subsequent lines.