Abstract
Tumor heterogeneity represents a possible cause of error in detecting predictive genetic alterations on tumor tissue and can be overcome by testing alterations in circulating tumor DNA (ctDNA) using liquid biopsy. We assessed 72 consecutive patients with a diagnosis of metastatic colorectal cancer (mCRC) using Idylla™ Biocartis, a fully automated platform that evaluates the most frequent mutations of KRAS, NRAS and BRAF genes. We correlated the results of liquid biopsy and standard tissue-based next generation sequencing (NGS) analyses to patient clinical features. The overall agreement was 81.94%. Concordance was 85.71% and 96.15% in treatment-naïve patients and in the patient subgroup with liver metastases, respectively. In liver metastases positive, treatment-naïve patients, sensitivity, specificity and positive predictive value (PPV) were 92.31%, 100% and 100%, respectively. Circulating mutational fraction (CMF) was significantly higher in patients with liver metastases and high carcinoembryonic antigen (CEA) levels. In a subgroup of patients pre-treated with anti-Epidermal Growth Factor Receptor (EGFR) agents, emerging KRAS mutations were evidenced in 33% of cases. Testing RAS/BRAF mutations on plasma using the Idylla™ Biocartis platform is feasible and reliable in mCRC patients in clinical practice.
Highlights
Metastatic colorectal cancer is one of the main causes of cancer death worldwide, with881,000 deaths in 2018 alone [1]
Concordance was calculated according to different patient subgroups: patients without liver metastases (NON-LIVER) and patients with at least one liver metastasis (LIVER POSITIVE), further divided into patients with metastases limited to the liver (LIVER ONLY) and patients with metastases in the liver and other organs (LIVER and OTHER) (Table 1A)
Considering only the liquid biopsies performed on the 42 metastatic colorectal cancer (mCRC) patients that were evaluated before starting first line therapy (BASAL COHORT), the concordance raised to 85.71% (36/42; kappa 0.714; 95% CI: 0.507–0.922) with a maximum concordance of 96.15% (25/26; kappa 0.923; 95% CI: 0.776–1) in patients with at least one liver metastasis (LIVER POSITIVE) and 100% in patients with metastases not limited to the liver (LIVER and OTHER) (Table 1B)
Summary
Metastatic colorectal cancer (mCRC) is one of the main causes of cancer death worldwide, with881,000 deaths in 2018 alone [1]. Anti-Epidermal Growth Factor Receptor (EGFR) MoAbs, cetuximab and panitumumab, are currently administered in all-RAS (KRAS and NRAS) wild type (WT) mCRC patients as first or subsequent lines of treatment either in monotherapy or in association with chemotherapy, KRAS and NRAS tumor mutations being negative predictive biomarkers for their use. Analysis of ctDNA has been evaluated in mCRC patients for different purposes: correlation between its levels and survival, monitoring of response to therapy, detection of RAS/BRAF mutations at different time points [5]. Recent reports show how the highest sensitivity of the technique does not reflect a better prediction of the response to anti-EGFR agents, as it may include rare KRAS mutant subclones that do not have clinical significance [14,15,16]. The main purpose of these studies has generally been the evaluation of the degree of agreement between PCR on formalin-fixed paraffin-embedded (FFPE)
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