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Concordance between RAS and BRAF mutational status determination in ctDNA and tissue in patients with mCRC
Background
Liquid biopsy is a tool that enables identification of diagnostic, prognostic and predictive biomarkers of response to treatment in circulating tumour DNA (ctDNA). Previous studies have demonstrated a high degree of concordance between RAS mutations detected in tumour tissue and plasma. Clinical practice guidelines urge the determination of RAS and BRAF mutational status in patients with mCRC prior to initiation of treatment, since the absence of RAS mutations is predictive of response to anti-EGFR drugs and BRAF mutations to combination therapy with BRAF and EGFR inhibitors. Around 50% of CRC cases have mutations in KRAS/NRAS, and, in 9% of CRC the specific mutation V600E of BRAF gene has been found. The aim of our study is to analyse the concordance between baseline RAS and BRAF status determination in plasma (ctDNA) and tissue in mCRC patients. Also, examine clinical characteristics of patients with RAS and BRAF mutations found in tissue and ctDNA and evaluate clinicopathological characteristics and response to anti-EGFR drugs in patients with discordances.
Methods
Retrospective and descriptive analysis of RAS and BRAF mutational status in tumour tissue and plasma (ctDNA) in patients with mCRC from March-2017 to February-2022 in the University Healthcare Complex of Salamanca. Determination of these biomarkers was performed using the IdyllaTM platform (Biocartis). Subsequently, a statistical correlation between two diagnostic methods and a comprehensive analysis of clinical characteristics in carrier mutation patients and those with tissue-plasma mismatches were carried out.
Results
Ninety patients (p) with mCRC were included. Median age: 64 years [41–85]. Stage IV at diagnosis: 78.9%. Location of primary tumour: left colon; 60 p (66.7%). Most frequently metastatic location: liver involvement (74.4%) followed by lymph node involvement (38.9%). Regarding mutational status at tissue level, 37 mutations (41.1%); 32 KRAS, 2 NRAS and 3 BRAF. In plasma, 40 pathogenic variants (44.4%), 34 KRAS, 3 NRAS and 3 BRAF. Most prevalent mutations in carrier patients: G12V (c.35G>T) and G12D (c.35G>A), in KRAS gene. In 5 patients, discordant results were obtained between two diagnostic methods. Four patients with KRAS/NRAS mutations not detected in tissue. Three of them in treatment with Chemotherapy (CT) plus anti-EGFR; progression-free survival (PFS): 6.4, 12.4 and 59 months, respectively. In the other patient, tissue biopsy (peritoneal implant) was discordant with the result obtained in primary tumour and plasma. He received treatment with capecitabine; PFS of 6 months. One patient with KRAS mutation not detected in plasma, in treatment with CT; PFS: 13.3 months. Overall agreement: 88.9%. Kappa index(k): 0.881.
Conclusions
IdyllaTM platform is an efficient and accurate tool useful in clinical practice in the baseline determination of RAS and BRAF at diagnosis and prior to the choice of anti-EGFR therapy. It is a minimally invasive method with a high degree of sensitivity and is representative of tumour heterogeneity. Future work is needed to evaluate cases with tissue-plasma discordance and the emerging monitoring of acquired mutations in RAS and BRAF as mechanisms of resistance.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
