| Summary: | The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA <i>RAS</i> (<i>KRAS</i>/<i>NRAS</i>) mutational status evolution in first-line, metastatic CRC, <i>RAS</i> wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment—panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA <i>RAS</i> mutations (<i>n</i> = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA <i>RAS</i> mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (<i>n</i> = 9; panitumumab subpopulation) presented emergent mutations (<i>RAS</i> conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA <i>RAS</i> mutations were <i>RAS</i> wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA <i>RAS</i> mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA <i>RAS</i> wild-type patients compared to those presenting cfDNA <i>RAS</i> mutations at any time. Continuous evaluation of <i>RAS</i> mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.
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