Access and quality of biomarker testing for precision oncology in Europe.

BACKGROUND: Predictive biomarkers are essential for selecting the best therapeutic strategy in patients with cancer. The International Quality Network for Pathology, the European Cancer Patient Coalition and the European Federation of Pharmaceuticals Industries and Associations evaluated the access to and quality of biomarker testing across Europe. METHODS: Data sources included surveys of 141 laboratory managers and 1.665 patients, and 58 in-depth interviews with laboratory managers, physicians and payers. Four access metrics (laboratory access, test availability, test reimbursement, test order rate) and three quality metrics (quality scheme participation, laboratory accreditation, test turnaround time) were applied to rank the results. RESULTS: The access to precision medicines is higher in countries with public national reimbursement processes in place. Lack of diagnostic laboratory infrastructure, inefficient organization and/or insufficient public reimbursement narrow the access to single biomarker tests in many European countries. In countries with limited public reimbursement, pharma and patients' out of pocket were the primary funding sources for testing. Uptake of multi-biomarker next generation sequencing (NGS) is highly varied, ranging from 0% to >50%. Financial constraints, a lack of NGS testing capabilities and the failure to include NGS testing in the guidelines represent the main barriers to NGS implementation. The quality of biomarker testing is highest in Western and Northern Europe, with more than 90% of laboratories participating in quality assurance schemes. CONCLUSIONS: Our data clearly indicate the need for a call to action to ensure the clinical implementation of precision medicine in Europe.

Harmonization and Standardization of Panel-Based Tumor Mutational Burden Measurement: Real-World Results and Recommendations of the Quality in Pathology Study.

INTRODUCTION: Tumor mutational burden (TMB) is a quantitative assessment of the number of somatic mutations within a tumor genome. Immunotherapy benefit has been associated with TMB assessed by whole-exome sequencing (wesTMB) and gene panel sequencing (psTMB). The initiatives of Quality in Pathology (QuIP) and Friends of Cancer Research have jointly addressed the need for harmonization among TMB testing options in tissues. This QuIP study identifies critical sources of variation in psTMB assessment. METHODS: A total of 20 samples from three tumor types (lung adenocarcinoma, head and neck squamous cell carcinoma, and colon adenocarcinoma) with available WES data were analyzed for psTMB using six panels across 15 testing centers. Interlaboratory and interplatform variation, including agreement on variant calling and TMB classification, were investigated. Bridging factors to transform psTMB to wesTMB values were empirically derived. The impact of germline filtering was evaluated. RESULTS: Sixteen samples had low interlaboratory and interpanel psTMB variation, with 87.7% of pairwise comparisons revealing a Spearman's ρ greater than 0.6. A wesTMB cut point of 199 missense mutations projected to psTMB cut points between 7.8 and 12.6 mutations per megabase pair; the corresponding psTMB and wesTMB classifications agreed in 74.9% of cases. For three-tier classification with cut points of 100 and 300 mutations, agreement was observed in 76.7%, weak misclassification in 21.8%, and strong misclassification in 1.5% of cases. Confounders of psTMB estimation included fixation artifacts, DNA input, sequencing depth, genome coverage, and variant allele frequency cut points. CONCLUSIONS: This study provides real-world evidence that all evaluated panels can be used to estimate TMB in a routine diagnostic setting and identifies important parameters for reliable tissue TMB assessment that require careful control. As complex or composite biomarkers beyond TMB are likely playing an increasing role in therapy prediction, the efforts by QuIP and Friends of Cancer Research also delineate a general framework and blueprint for the evaluation of such assays.

Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions.

Characterization of tumors utilizing next-generation sequencing methods, including assessment of the number of somatic mutations (tumor mutational burden [TMB]), is currently at the forefront of the field of personalized medicine. Recent clinical studies have associated high TMB with improved patient response rates and survival benefit from immune checkpoint inhibitors; hence, TMB is emerging as a biomarker of response for these immunotherapy agents. However, variability in current methods for TMB estimation and reporting is evident, demonstrating a need for standardization and harmonization of TMB assessment methodology across assays and centers. Two uniquely placed organizations, Friends of Cancer Research (Friends) and the Quality Assurance Initiative Pathology (QuIP), have collaborated to coordinate efforts for international multistakeholder initiatives to address this need. Friends and QuIP, who have partnered with several academic centers, pharmaceutical organizations, and diagnostic companies, have adopted complementary, multidisciplinary approaches toward the goal of proposing evidence-based recommendations for achieving consistent TMB estimation and reporting in clinical samples across assays and centers. Many factors influence TMB assessment, including preanalytical factors, choice of assay, and methods of reporting. Preliminary analyses highlight the importance of targeted gene panel size and composition, and bioinformatic parameters for reliable TMB estimation. Herein, Friends and QuIP propose recommendations toward consistent TMB estimation and reporting methods in clinical samples across assays and centers. These recommendations should be followed to minimize variability in TMB estimation and reporting, which will ensure reliable and reproducible identification of patients who are likely to benefit from immune checkpoint inhibitors.