Plasma clearance of RAS mutation under therapeutic pressure is a rare event in metastatic colorectal cancer

• Published in: International journal of cancer Vol. 147; no. 4; pp. 1185 - 1189
• Main Authors: Moati, Emilie, Blons, Hélène, Taly, Valerie, Garlan, Fanny, Wang‐Renault, Shu‐Fang, Pietrasz, Daniel, Didelot, Audrey, Garrigou, Sonia, Saint, Angélique, Pernot, Simon, Taieb, Julien, Laurent‐Puig, Pierre, Zaanan, Aziz
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15.08.2020; Wiley Subscription Services, Inc
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; Cancer; Chemotherapy; circulating tumor DNA; Circulating Tumor DNA - analysis; Circulating Tumor DNA - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - blood; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; DNA Methylation; droplet‐based digital PCR; Genotypes; High-Throughput Nucleotide Sequencing; Humans; Male; Medical research; Metastases; Metastasis; metastatic colorectal cancer; Middle Aged; Mutation; Neoplasm Metastasis; Neuropeptide Y; next‐generation sequencing; Plasma; Polymerase Chain Reaction; Prospective Studies; Proto-Oncogene Proteins p21(ras) - genetics; RAS mutations; Tumors; droplet-based digital PCR; metastatic colorectal cancer; next-generation sequencing; RAS mutations; circulating tumor DNA
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32657

In metastatic colorectal cancer (mCRC), circulating tumor DNA (ctDNA) monitoring can be used to genotype tumors and track clonal evolution. We investigated the clearance of RAS mutated clones under chemotherapy pressure by ctDNA analysis in patients with a RAS mutated mCRC. Patients with a RAS mutated tumor included in the prospective PLACOL study were monitored for ctDNA. Analyses were based on optimized targeted next‐generation sequencing and/or droplet‐based digital polymerase chain reaction (ddPCR). For plasma samples without detectable mutations at progression disease, we tested the methylation status of WIF1 and NPY genes using methylation‐ddPCR (met‐ddPCR) to validate the presence of ctDNA. Among the 36 patients with positive plasma samples for RAS mutations at inclusion, 28 (77.8%) remained RAS positive at disease progression and 8 (22.2%) became negative. Subsequent met‐ddPCR for methylated markers showed that only two out of the eight patients with RAS negative plasma had detectable ctDNA at progression. Therefore, only 2 samples among 36 were confirmed for clearance of RAS mutation in our series. In conclusion, this study suggests that the clearance of RAS mutations in patients treated by chemotherapy for a RAS mutated mCRC is a rare event. Monitoring tumor mutations in plasma samples should be combined with a strict control of the presence of ctDNA. The therapeutic impacts of RAS clearance need to be further explored. What's new? Evidence indicates that in about half of chemotherapy‐treated metastatic colorectal (mCRC) patients, RAS status switches from mutant to wild‐type, with possible therapeutic implications. Here, analyses of circulating tumor DNA (ctDNA) were used to monitor RAS mutation in mCRC patients treated with chemotherapy. More than three‐quarters of patients were found to be positive for RAS mutation at the time of disease progression, while remaining patients were RAS mutation‐negative. However, assessment of methylation status of WIF1 and NPY genes to validate ctDNA presence in RAS‐negative patients revealed that overall, out of 36 patients, just two experienced complete RAS mutation clearance by chemotherapy.