Assay Harmonization
The goal of assay harmonization is to ensure that clinical laboratory test results are comparable, even if test conditions differ. As molecular profiling becomes a widely adopted diagnostic tool in clinical studies and patient care, quality control measures are important to ensure robustness and inter-assay comparability. External reference standards and laboratory sample exchanges can ensure that assay results are understood in the same context, independent of where or by whom a test is performed. This has direct applications to patient care, where clinical guidelines for diagnosis or disease management may be based on assay results.
The Cancer Diagnosis Program (CDP) promotes assay harmonization efforts within the cancer research community by providing resources including funding, and by participating in multi-stakeholder efforts to develop recommendations on harmonization requirements and approaches.
CIMAC-CIDC Harmonized Assays
CDP and the Cancer Therapy Evaluation Program (CTEP) jointly launched the CIMAC-CIDC Network as a Cancer Moonshot℠ initiative, funded through NCI Cooperative Agreements (U24) awarded in September 2017. The Network was established to address the critical importance of improving management of cancer patients receiving immunotherapy by identifying biomarkers for optimizing immunotherapeutic strategies. Four academic laboratories at leading cancer research institutions perform multi-modal assay analysis in specimens from immunotherapy clinical trials. The CIMAC laboratories perform comprehensive profiling of specimens using standardized, validated assays. The network has harmonized a core set of these assays to reduce data variability among assay sites, thereby facilitating cross-trial analysis of correlative data.
- Genomics Harmonization:
Zeng Z, Fu J, Cibulskis C, et al. Cross-Site Concordance Evaluation of Tumor DNA and RNA Sequencing Platforms for the CIMAC-CIDC Network. Clin Cancer Res. 2021;27(18):5049-5061. doi:10.1158/1078-0432.CCR-20-3251 - CyTOF harmonization:
Sahaf B, Pichavant M, Lee BH, et al. Immune Profiling Mass Cytometry Assay Harmonization: Multicenter Experience from CIMAC-CIDC. Clin Cancer Res. 2021;27(18):5062-5071. doi:10.1158/1078-0432.CCR-21-2052 - IHC/IF harmonization:
Akturk G, Parra ER, Gjini E, et al. Multiplex Tissue Imaging Harmonization: A Multicenter Experience from CIMAC-CIDC Immuno-Oncology Biomarkers Network. Clin Cancer Res. 2021;27(18):5072-5083. doi:10.1158/1078-0432.CCR-21-2051
Designated Laboratory (DL) Network
The Designated Laboratory (DL) Network is a network of over 27 academic and commercial laboratories which performs standard-of-care NGS tumor testing to identify and refer potentially eligible patients to the ComboMATCH (Combination Therapy Platform Trial with Molecular Analysis of Therapy Choice) precision medicine trial. The DL Network was originally established to support NCI MATCH.
Since the launch of NCI MATCH, the network of laboratories has expanded through a series of Federal Register Notices inviting applications from CLIA (Clinical Laboratory Improvements Program) certified/accredited laboratories with Next-Generation Sequencing (NGS) assays to participate in the NCI MATCH and ComboMATCH trials. All participating labs underwent a rigorous evaluation before being admitted to the DL network to ensure assay performance benchmarks were met and the uniformity of results between labs. Labs were required to perform concordance testing with the study central assay where an 80% concordance threshold is required to be included in the network. Labs will be monitored through periodic reporting of proficiency testing results and CLIA certificate renewals as well as report on UADEs and changes to their approved assay through regular reporting requirements and quarterly calls. Non-FDA approved Lab Developed Tests (LDTs) approved for use for ComboMATCH will participate in periodic concordance testing. FDA approved assays are waived from this requirement. Future expansion of the DL Network will include labs that perform ctDNA testing.
SPOT/Dx Working Group
The Cancer Diagnosis Program participated in the Sustainable Predictive Oncology Therapeutics and Diagnostics (SPOT/Dx) Working Group which designed the Diagnostic Quality Assurance Pilot to focus on achieving inter-laboratory standardization in NGS assays across different platforms by using reference standards. Participating clinical laboratories were provided with reference samples and in silico files and were evaluated on the analytical performance of their own validated platforms compared to an FDA-approved companion diagnostic. Read about the outcome here.
EBV DNA in Plasma/Serum/Blood
CDP convened a Workshop on Harmonization of EBV Testing for Nasopharyngeal Cancer, where experts in head and neck oncology and laboratory medicine addressed the limitations and appropriate clinical use of polymerase chain reaction-based EBV DNA quantitation assays.
The workshop resulted in two publications:
- This article presents the key recommendations to direct future efforts in assay harmonization and validation.
- This article discusses the clinical utility of EBV DNA testing and issues that need to be considered for future studies aimed at informing clinical practice guidelines for EBV DNA.