A Primer on Gene Editing: What Does It Mean for Pathologists?

CONTEXT.­: Gene editing-based therapies are currently in development in the areas of oncology, inherited disease, and infectious disease. These potentially life-altering therapies are derived from decades of research in both academic and industry settings that developed technologies rooted in principles and products of nature. However, with such technologic developments come many important considerations, including adverse risks, high cost, and ethical questions. OBJECTIVE.­: To educate pathologists about gene editing technologies, inform them of potential indications and risks, outline regulatory and practical issues that could affect hospital-based practice and laboratory testing, and advocate that pathologists need to be present at discussions among industry and regulators pertaining to gene editing-based therapies. DESIGN.­: A Gene Editing Workgroup, facilitated by the College of American Pathologists Personalized Health Care Committee and consisting of pathologists of various backgrounds, was convened to develop an educational paper to serve as a stimulus to increase pathologist involvement and inquiry in gene editing therapeutic and diagnostic implementation. RESULTS.­: Through multiple discussions and literature review, the workgroup identified potential gaps in pathologists' knowledge of gene editing. Additional topics that could impact pathology and laboratory medicine were also identified and summarized in order to facilitate pathologists as stakeholders in gene editing therapy administration and monitoring and potential use in diagnostics. CONCLUSIONS.­: Gene editing therapy is a complex but potentially transformative area of medicine. This article serves as an introduction to pathologists to assist them in future discussions with colleagues and potentially identify and alter pathology practices that relate to gene editing.

A Primer on Gene Editing.

CONTEXT­: Gene editing-based therapies are currently in development in the areas of oncology, inherited disease, and infectious disease. These potentially life-altering therapies are derived from decades of research in both academic and industry settings that developed technologies rooted in principles and products of nature. However, with such technologic developments come many important considerations, including adverse risks, high cost, and ethical questions. OBJECTIVE­: To educate pathologists about gene editing technologies, inform them of potential indications and risks, outline regulatory and practical issues that could affect hospital-based practice and laboratory testing, and advocate that pathologists need to be present at discussions among industry and regulators pertaining to gene editing-based therapies. DESIGN­: A Gene Editing Workgroup, facilitated by the College of American Pathologists Personalized Health Care Committee and consisting of pathologists of various backgrounds, was convened to develop an educational paper to serve as a stimulus to increase pathologist involvement and inquiry in gene editing therapeutic and diagnostic implementation. RESULTS­: Through multiple discussions and literature review, the workgroup identified potential gaps in pathologists' knowledge of gene editing. Additional topics that could impact pathology and laboratory medicine were also identified and summarized in order to facilitate pathologists as stakeholders in gene editing therapy administration and monitoring and potential use in diagnostics. CONCLUSIONS­: Gene editing therapy is a complex but potentially transformative area of medicine. This article serves as an introduction to pathologists to assist them in future discussions with colleagues and potentially identify and alter pathology practices that relate to gene editing.

Getting Your Laboratory on Track With Neurotrophic Receptor Tyrosine Kinase.

CONTEXT.­: Neurotrophic receptor tyrosine kinase (NTRK) fusion testing has both diagnostic and therapeutic implications for patient care. With 2 tumor-agnostic US Food and Drug Administration-approved tropomyosin receptor kinase (TRK) inhibitors, testing is increasingly used for therapeutic decision making. However, the testing landscape for NTRK fusions is complex, and optimal testing depends on the clinicopathologic scenario. OBJECTIVE.­: To compare different NTRK testing methods to help pathologists understand test features and performance characteristics and make appropriate selections for NTRK fusion detection for their laboratory and individual patient specimens. DATA SOURCES.­: A literature search for NTRK gene fusions and TRK protein was performed, including papers that discussed treatment, testing methodology, and detection or prevalence of fusion-positive cases. CONCLUSIONS.­: As standard of care in some tumor types, next-generation sequencing (NGS) panel testing is a cost effective and reliable way to detect a broad range of NTRK fusions. The design of the panel and use of DNA or RNA will affect performance characteristics. Pan-TRK immunohistochemistry may be used as a rapid, less expensive screen in cases that will not undergo routine NGS testing, or on specimens unsuitable for NGS testing. Fluorescence in situ hybridization may be appropriate for low-tumor-content specimens that are unsuitable for NGS testing. Quantitative reverse transcription polymerase chain reaction is best suited for monitoring low-level disease of a specific, previously identified target. This information should help laboratories develop a laboratory-specific NTRK testing algorithm that best suits their practice setting and patients' needs.

Companion Diagnostics: Lessons Learned and the Path Forward From the Programmed Death Ligand-1 Rollout.

CONTEXT.­: Programmed death ligand-1 (PD-L1) immunohistochemistry companion diagnostic assays play a crucial role as predictive markers in patients being considered for immune checkpoint inhibitor therapy. However, because of a convergence of several factors, including recognition of increased types of cancers susceptible to immunotherapy, increasing numbers of immune checkpoint inhibitors, and release of multiple PD-L1 immunohistochemistry antibodies with differing reporting systems, this complex testing environment has led to significant levels of confusion for pathologists and medical oncologists. OBJECTIVE.­: To identify which processes and procedures have contributed to the current challenges surrounding programmed death receptor-1 (PD-1)/PD-L1 companion diagnostics and to propose potential remedies to this issue. This is based upon input from key industrial stakeholders in conjunction with the College of American Pathologists Personalized Health Care Committee. DESIGN.­: A meeting of representatives of pharmaceutical and in vitro diagnostic companies along with the Personalized Health Care Committee reviewed the process of release of the PD-L1 companion diagnostic assays using a modified root cause analysis format. The modified root cause analysis envisioned an ideal circumstance of development and implementation of a companion diagnostic to identify shortcomings in the rollout of the PD-L1 assay and to suggest actions to improve future companion diagnostic assay releases. RESULTS.­: The group recommended improvements to key principles in companion diagnostics implementation related to multi-stakeholder communication, increased regulatory flexibility to incorporate postapproval medical knowledge, improved cross-disciplinary information exchange between medical oncology and pathology societies, and enhanced postmarket training programs. CONCLUSIONS.­: The rapidly changing nature of and increasing complexity associated with companion diagnostics require a fundamental review of processes related to their design, implementation, and oversight.

Proceedings From the ASCO/College of American Pathologists Immune Checkpoint Inhibitor Predictive Biomarker Summit.

PURPOSE: Immune checkpoint inhibition (ICI) therapy represents one of the great advances in the field of oncology, highlighted by the Nobel Prize in 2018. Multiple predictive biomarkers for ICI benefit have been proposed. These include assessment of programmed death ligand-1 expression by immunohistochemistry, and determination of mutational genotype (microsatellite instability or mismatch repair deficiency or tumor mutational burden) as a reflection of neoantigen expression. However, deployment of these assays has been challenging for oncologists and pathologists alike. METHODS: To address these issues, ASCO and the College of American Pathologists convened a virtual Predictive Factor Summit from September 14 to 15, 2021. Representatives from the academic community, US Food and Drug Administration, Centers for Medicare and Medicaid Services, National Institutes of Health, health insurance organizations, pharmaceutical companies, in vitro diagnostics manufacturers, and patient advocate organizations presented state-of-the-art predictive factors for ICI, associated problems, and possible solutions. RESULTS: The Summit provided an overview of the challenges and opportunities for improvement in assay execution, interpretation, and clinical applications of programmed death ligand-1, microsatellite instability-high or mismatch repair deficient, and tumor mutational burden-high for ICI therapies, as well as issues related to regulation, reimbursement, and next-generation ICI biomarker development. CONCLUSION: The Summit concluded with a plan to generate a joint ASCO/College of American Pathologists strategy for consideration of future research in each of these areas to improve tumor biomarker tests for ICI therapy.