Evolution of RAS Mutations in Cell-Free DNA of Patients with Tissue RAS Wild-Type Metastatic Colorectal Cancer Receiving First-Line Treatment: The PERSEIDA Study

Simple Summary Cell-free DNA RAS mutation is being increasingly monitored in metastatic colorectal cancer (mCRC) for disease molecular characterization and selecting eligible patients for anti-EGFR initiation and rechallenge. Here, we monitored a homogeneous mCRC RAS wild-type (as per baseline solid biopsy) population starting first-line treatment using a BEAMing technique at three different mutant allele fraction (MAF) sensitivity cut-offs and we characterized the role of each MAF threshold and its correlation with clinical variables. 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 RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS 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 RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction >= 0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.

Automated summary

Monitoring cell-free DNA RAS mutations is important for selecting eligible patients for anti-EGFR treatment and disease molecular characterization in metastatic colorectal cancer (mCRC). This study evaluated the role of different mutant allele fraction thresholds in monitoring RAS mutations and found that continuous evaluation of RAS mutations can provide valuable insights into tumor molecular dynamics.