External Quality Assessment for KRAS Testing Is Needed: Setup of a European Program and Report of the First Joined Regional Quality Assessment Rounds

Abstract

Learning Objectives After completing this course, the reader will be able to: Identify the most frequent errors made in KRAS testing in this study and the possible consequences for a patient. Describe factors that could increase the chance of an error during KRAS testing. This article is available for continuing medical education credit at http://CME.TheOncologist.com The use of epidermal growth factor receptor–targeting antibodies in metastatic colorectal cancer has been restricted to patients with wild‐type KRAS tumors by the European Medicines Agency since 2008, based on data showing a lack of efficacy and potential harm in patients with mutant KRAS tumors. In an effort to ensure optimal, uniform, and reliable community‐based KRAS testing throughout Europe, a KRAS external quality assessment (EQA) scheme was set up. The first large assessment round included 59 laboratories from eight different European countries. For each country, one regional scheme organizer prepared and distributed the samples for the participants of their own country. The samples included unstained sections of 10 invasive colorectal carcinomas with known KRAS mutation status. The samples were centrally validated by one of two reference laboratories. The laboratories were allowed to use their own preferred method for histological evaluation, DNA isolation, and mutation analysis. In this study, we analyze the setup of the KRAS scheme. We analyzed the advantages and disadvantages of the regional scheme organization by analyzing the outcome of genotyping results, analysis of tumor percentage, and written reports. We conclude that only 70% of laboratories correctly identified the KRAS mutational status in all samples. Both the false‐positive and false‐negative results observed negatively affect patient care. Reports of the KRAS test results often lacked essential information. We aim to further expand this program to more laboratories to provide a robust estimate of the quality of KRAS testing in Europe, and provide the basis for remedial measures and harmonization.

KRAS genotyping in rectal adenocarcinoma specimens with low tumor cellularity after neoadjuvant treatment

“…[8][9][10][11] Various laboratory-based or commercial KRAS mutation assays are used in the routine practice and the majority of them have been optimized to be compatible with DNA extracted from formalin-fixed paraffin-embedded samples, which represent the most available source of tumor tissue. However, they are characterized by different sensitivity, turnaround time, and cost.…”

Quality control materials for pharmacogenomic testing in the clinic

“…For single gene-based mutation assays, QC materials can be prepared from residual patient samples or bought from commercial sources. The materials derived from surplus patient tumors are ideal for QC and widely used in EQA schemes for cancer therapy-associated gene mutational analysis [16][17][18][19][20][21][22][23][24]. However, there are several apparent shortcomings of this material: (1) the amount of tissue that can be obtained is limited; (2) samples with rare mutations are difficult to get; (3) the heterogeneity within a single tumor; (4) the precise amount of wild-type alleles versus mutated alleles is hard to determine.…”

Biomarkers in Gastrointestinal Cancer: Focus on Colon, Pancreatic and Gastric Cancer

“…Incomplete or inaccurate exams lead to incorrect diagnoses and can have important consequences for a patient. Therefore, further development of the KRAS EQA scheme aims to provide a baseline picture of the accuracy and reliability of the analysis of the KRAS test, to identify areas of particular difficulty in testing procedures and to provide a mechanism for improvement for the participating laboratories (Bellon et al, 2011).…”

“…In Europe, the EMEA changed the approval of these drugs for use in wild-type KRAS populations only. This has important implications because the exact mutations to be tested are not specified nor is the methodology (see further below) (Bellon et al, 2011).…”