Detection of RAS mutations in circulating tumor DNA: a new weapon in an old war against colorectal cancer. A systematic review of literature and meta-analysis

Abstract

Background: Tissue evaluation for RAS (KRAS or NRAS) gene status in metastatic colorectal cancer (mCRC) patients represent the standard of care to establish the optimal therapeutic strategy. Unfortunately, tissue biopsy is hampered by several critical limitations due to its invasiveness, difficulty to access to disease site, patient’s compliance and, more recently, neoplastic tissue spatial and temporal heterogeneity. Methods: The authors performed a systematic literature review to identify available trials with paired matched tissue and ctDNA RAS gene status evaluation. The authors searched EMBASE, MEDLINE, Cochrane, www.ClinicalTrials.gov , and abstracts from international meetings. In total, 19 trials comparing standard tissue RAS mutational status matched paired ctDNA evaluated through polymerase chain reaction (PCR), next generation sequencing (NGS) or beads, emulsions, amplification and magnetics (BEAMing) were identified. Results: The pooled sensitivity and specificity of ctDNA were 0.83 (95% CI: 0.80–0.85) and 0.91 (95% CI: 0.89–0.93) respectively. The pooled positive predictive value (PPV) and negative predictive value (NPV) of the ctDNA were 0.87 (95% CI: 0.81–0.92) and 0.87 (95% CI: 0.82–0.92), respectively. Positive likelihood ratio (PLR) was 8.20 (95% CI: 5.16–13.02) and the negative likelihood ratio (NLR) was 0.22 (95% CI: 0.16–0.30). The pooled diagnostic odds ratio (DOR) was 50.86 (95% CI: 26.15–98.76), and the area under the curve (AUC) of the summary receiver operational characteristics (sROC) curve was 0.94. Conclusion: The authors’ meta-analysis produced a complete and updated overview of ctDNA diagnostic accuracy to test RAS mutation in mCRC. Results provide a strong rationale to include the RAS ctDNA test into randomized clinical trials to validate it prospectively.

Combined Analysis of Concordance between Liquid and Tumor Tissue Biopsies for RAS Mutations in Colorectal Cancer with a Single Metastasis Site: The METABEAM Study

“…This is the first combined analysis of individual patient data from Europe and Asia on the concordance of RAS mutational status by metastatic site between plasma ctDNA and tumor tissue DNA testing (14). There were no differences between the European and Asian data.…”

Clinical Utility of Plasma KRAS, NRAS and BRAF Mutational Analysis with Real Time PCR in Metastatic Colorectal Cancer Patients—The Importance of Tissue/Plasma Discordant Cases

“…They are classified into PCR-based or sequencing-based technologies (NGS). NGS allows deep sequencing of amplicons and, while the PCR-based methods can detect specific, already-known mutations, NGS has the advantage of detecting novel mutations in addition to the known ones [ 25 , 26 ].…”

The molecular profiling of solid tumors by liquid biopsy: a position paper of the AIOM–SIAPEC-IAP–SIBioC–SIC–SIF Italian Scientific Societies

“…By contrast, a variety of studies has demonstrated the feasibility of carrying out the RAS test on LB as a potential substitute for analysis on tumor tissue in stage IV metastatic CRC (mRCR). 65 The concordance between tissue versus LB varies from 60% to 80% 5 : we underline that tumor and peripheral blood are two distinct tissues and discrepancies observed in terms of specificity—taking tumor tissue as a reference—are justified by the fact that LB is able to overcome the spatial and temporal heterogeneity that limits tissue analysis. Undoubtedly, LB offers the advantages of a relatively noninvasive and more flexible approach, both for the possibility of making the determination of the mutational status more easily (based on the exact time of therapeutic intervention with anti-EGFR) and for the reduced TAT.…”