VEEVA APPROVED EQA webinar EGFR Tissue Results Review Webinar video recordings

This webinar, presented by Dr. Simon Patton, CEO of EMQN CIC, provides a comprehensive overview of the lessons learned from the 2024 External Quality Assessment (EQA) scheme for molecular testing in lung cancer tissue samples. The session delves into the principles of EQA, its role in ensuring quality and regulatory compliance in clinical laboratories, and detailed performance data from 342 participating laboratories worldwide. The primary objective is to foster continuous education and improvement in molecular diagnostics within the pharmaceutical and life sciences sectors, particularly concerning the accurate detection, interpretation, and reporting of key cancer biomarkers.

The presentation systematically breaks down the EQA scheme into two sub-schemes: one for common biomarkers (EGFR, KRAS, BRAF) and another for new and emerging biomarkers (ERBB2, MET, with mandatory EGFR and KRAS). For each sub-scheme, Dr. Patton discusses the testing strategies employed by laboratories (e.g., targeted Next-Generation Sequencing, real-time PCR), the specific clinical scenarios and variants provided in the EQA samples, and the analytical (genotyping) and interpretive performance. He highlights common challenges such as inconsistent sample quality, the need for appropriate methodologies to differentiate variants (e.g., KRAS codon 12), and the complexities of interpreting challenging variants like MET exon 14 skipping.

A significant portion of the webinar focuses on aggregate performance data, including critical error rates for both genotyping and interpretation across different cases and participating regions. Dr. Patton introduces novel analysis demonstrating a statistically significant correlation between repeated EQA participation and improved laboratory performance, underscoring the educational value of these schemes. The session concludes with key learning points for laboratories, emphasizing the importance of comprehensive reporting, appropriate methodology selection, standardized nomenclature (like the MAIN initiative), tailored clinical interpretation, and clear, concise report generation to enhance patient care.

Key Takeaways:

• EQA as a Pillar of Quality Assurance: External Quality Assessment (EQA) schemes are crucial for independently auditing the quality of molecular testing laboratories, ensuring adherence to standards like ISO 15189, and providing continuous education to improve patient care.
• Performance Trends in Lung Cancer Testing: The 2024 EQA for lung cancer tissue testing showed high overall genotyping accuracy (less than 2.5% critical errors) with over 75% of laboratories scoring full marks in either sub-scheme, reflecting good quality testing practices.
• Impact of Repeated Participation: Longitudinal data analysis revealed that laboratories participating multiple times (up to 10 years) in EQA schemes demonstrated statistically significant improvements in both genotyping and interpretation scores, as well as a reduction in poor performance, highlighting the long-term educational benefits.
• Challenges with Sample Quality and Reporting Failures: One challenging EQA sample led to 82% of laboratories correctly reporting test failure due to poor sample quality. It's emphasized that laboratories should provide a clinical report for failed tests, clearly stating the failure and suggesting repeat samples or alternative methodologies (e.g., liquid biopsy).
• Comprehensive Gene Reporting is Essential: Laboratories often only report variants found, omitting genes tested where no variants were detected. Best practice dictates reporting all genes tested, or including a statement that "no other clinically actionable variants were detected," to provide a complete picture to the clinician.
• Appropriate Methodology Selection: With the increasing number and complexity of biomarkers in lung cancer, laboratories should consider using methodologies with higher sensitivity and broader scope, such as Next-Generation Sequencing (NGS), rather than highly targeted tests or less sensitive methods like Sanger sequencing, to avoid missing clinically actionable variants.
• Standardized Nomenclature: Consistent and internationally accepted nomenclature for describing variants (e.g., following the MAIN initiative) is critical for clarity and standardization across laboratories and clinical reports.
• Tailored Clinical Interpretation: While many laboratories provide interpretation, it is often generic. Interpretations should be specifically tailored to the patient's clinical scenario and the specific variant detected, avoiding confusion and ensuring the end-user receives relevant, actionable information.
• Clear and Concise Reporting: Reports should be clear, concise, and of an appropriate length, avoiding overly long documents (e.g., 20-30 pages) that can obscure key messages. Page pagination on multi-page reports is also recommended for usability.
• Challenging Variants and Copy Number Assessment: EGFR exon 20 insertions/deletions, ERBB2, and MET variants (especially MET exon 14 skipping) remain technically challenging for detection and interpretation. Copy number variant testing, particularly in somatic mutation analysis, is highlighted as extremely challenging with high error rates in other EQA schemes.
• No Correlation Between Technology and Failure Rates: The EQA data showed no strong evidence of technical failures correlating with specific technologies used (e.g., NGS vs. qPCR), suggesting that issues are more related to laboratory practice rather than the inherent limitations of a particular platform for standard variants.
• Turnaround Time Considerations: While not assessed in EQA due to logistical challenges, turnaround time is a critical aspect of real-world clinical practice, emphasizing the need for efficient laboratory processes beyond analytical accuracy.

Key Concepts:

• External Quality Assessment (EQA): An independent, external assessment of the quality of testing laboratories, providing standardized materials and benchmarking performance.
• Genotyping/Analytical Component: The process of accurately identifying genetic variants in a sample.
• Interpretation Component: The process of translating analytical results into clinically meaningful information for patient management.
• Variant Allele Frequency (VAF): The percentage of DNA reads at a specific locus that contain a variant allele.
• Critical Errors: Errors in genotyping or interpretation that could potentially lead to patient harm.
• MAIN Initiative: A proposed standard for molecular analysis for improved nomenclature in genetic reporting.
• FFPE Samples: Formalin-Fixed Paraffin-Embedded tissue samples, commonly used in pathology; artificial versions are manufactured for EQA.
• Targeted NGS (Next-Generation Sequencing): A high-throughput sequencing method focusing on specific genes or regions, increasingly preferred for its broad variant detection capabilities.
• Real-time PCR/Fluorescent PCR: Polymerase Chain Reaction methods used for rapid detection of specific DNA sequences.
• VUS (Variant of Unknown Significance): A genetic variant whose clinical significance is not yet established.
• Codon 12 (KRAS): A specific position in the KRAS gene where mutations are common and have therapeutic implications (e.g., G12C).
• Exon 14 Skipping (MET): A specific type of MET gene alteration that can be targeted by therapies.
• Copy Number Variants (CNVs): Alterations in the number of copies of a particular gene or DNA segment.

Examples/Case Studies:

• Common Biomarkers Sub-scheme - Case 1: A mock clinical scenario involving a long-time smoker diagnosed with lung adenocarcinoma, where laboratories were expected to identify an L858R variant in the EGFR gene. This case was challenging due to inconsistent sample performance, leading to an educational-only marking for analytical components.
• New and Emerging Biomarkers Sub-scheme - Case 1: A mock clinical scenario of a never-smoking lady with lung adenocarcinoma, requiring detection of a KRAS G12A variant. This case highlighted the importance of understanding future therapeutic options and differentiating KRAS codon 12 variants.
• MET Variant (Case 3 in New/Emerging Sub-scheme): This variant was identified as the most challenging, with many laboratories incorrectly reporting an intronic variant as a frameshift instead of a splice site variant, underscoring the need for precise nomenclature and, if possible, RNA testing to confirm exon 14 skipping.