RAS testing practices and RAS mutation prevalence among patients with metastatic colorectal cancer: results from a Europe-wide survey of pathology centres

Abstract

BackgroundTreatment options for patients with metastatic colorectal cancer (mCRC) include anti-epithelial growth factor therapies, which, in Europe, are indicated in patients with RAS wild-type tumours only and require prior mutation testing of “hot-spot” codons in exons 2, 3 and 4 of KRAS and NRAS. The aim of this study was to evaluate the implementation of RAS testing methods and estimate the RAS mutation prevalence in mCRC patients.MethodsOverall, 194 pathology laboratories were invited to complete an online survey. Participating laboratories were asked to provide information on their testing practices and aggregated RAS mutation data from 20 to 30 recently tested patients with mCRC.ResultsA total of 96 (49.5 %) laboratories across 24 European countries completed the survey. All participants tested KRAS exon 2, codons 12 and 13. Seventy (72.9 %) laboratories reported complete testing of all RAS hot-spot codons, and three (3.1 %) reported only testing KRAS exon 2. Sixty-nine (71.9 %) laboratories reported testing >80 patients yearly for RAS mutation status. Testing was typically performed within the reporting institution (93.8 %, n = 90), at the request of a treating oncologist (89.5 %, n = 85); testing methodology varied by laboratory and by individual codon tested. For laboratory RAS testing, turnaround times were ≤10 working days for the majority of institutions (90.6 %, n = 87). The overall crude RAS mutation prevalence was 48.5 % (95 % confidence interval: 46.4–50.6) for laboratories testing all RAS hot-spot codons. Prevalence estimates varied significantly by primary tumour location, approximate number of patients tested yearly and indication given for RAS testing.ConclusionOur findings indicate a rapid uptake of RAS testing in the majority of European pathology laboratories.

RAS testing for colorectal cancer patients is reliable in European laboratories that pass external quality assessment

“…The frequency of the variants in the mCRC samples used in this study (Table 4 and Supplemental Table 1) is in accordance with previously reported results [4,12,[18][19][20]. KRAS exon 2 variants were most commonly identified (41%) and no NRAS exon 4 variants occurred.…”

“…Despite the label given by EMA to EGFR-targeted agents for patients with mCRC, one laboratory did not test all relevant codons (12,13,59,61,117,146) and did not mention this limitation in the reports. This is an improvement compared to studies performed right after the labels changed [7,12,20].…”

Evaluation of the correlation betweenKRASmutated allele frequency and pathologist tumorous nuclei percentage assessment in colorectal cancer suggests a role for zygosity status

“…Mutations affecting exon 2 codons 12 and 13 accounted for 66% and 16%, respectively, of all KRAS mutations found, in line with published positivity rates of different types of KRAS mutations in European patients with colorectal cancer 5. As shown in Figure 1, there is a significant correlation between KRAS MAF and TNP, with a Pearson correlation coefficient of 0.3881 and a p value of 0.000072.…”

Prevalence of RAS and BRAF mutations in metastatic colorectal cancer patients by tumor sidedness: A systematic review and meta‐analysis

“…Risk factors for colon cancer have been shown to vary by side as well with right‐sided colon cancer being associated with female sex, increasing age, history of cancer, and insulin resistance, while left‐sided tumors have been associated with heavy smoking, alcohol abuse, and a low fiber diet . A survey of pathology centers across Europe observed that the prevalence of RAS mutations was higher in right‐sided tumors than left‐sided tumors in these centers (54.6% vs 46.4%, respectively) . Patients with right‐sided colon tumors have been shown to have worse prognosis and it has been hypothesized that genetic differences in the tumor may account for these findings .…”