Cancer immunotherapy provides unprecedented rates of durable clinical benefit to late-stage cancer patients across many tumor types, but there remains a critical need for biomarkers to accurately ...predict clinical response. Although some cancer immunotherapy tests are associated with approved therapies and considered validated, other biomarkers are still emerging and at various states of clinical and translational exploration.
To provide pathologists with a current and practical update on the evolving field of cancer immunotherapy testing. The scientific background, clinical data, and testing methodology for the following cancer immunotherapy biomarkers are reviewed: programmed death ligand-1 (PD-L1), mismatch repair, microsatellite instability, tumor mutational burden, polymerase δ and ε mutations, cancer neoantigens, tumor-infiltrating lymphocytes, transcriptional signatures of immune responsiveness, cancer immunotherapy resistance biomarkers, and the microbiome.
Selected scientific publications and clinical trial data representing the current field of cancer immunotherapy.
The cancer immunotherapy field, including the use of biomarker testing to predict patient response, is still in evolution. PD-L1, mismatch repair, and microsatellite instability testing are helping to guide the use of US Food and Drug Administration-approved therapies, but there remains a need for better predictors of response and resistance. Several categories of tumor and patient characteristics underlying immune responsiveness are emerging and may represent the next generation of cancer immunotherapy predictive biomarkers. Pathologists have important roles and responsibilities as the field of cancer immunotherapy continues to develop, including leadership of translational studies, exploration of novel biomarkers, and the accurate and timely implementation of newly approved and validated companion diagnostics.
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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.
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.
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.
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.
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.
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Biospecimens acquired during routine medical practice are the primary sources of molecular information about patients and their diseases that underlies precision medicine and translational research. ...In cancer care, molecular analysis of biospecimens is especially common because it often determines treatment choices and may be used to monitor therapy in real time. However, patient specimens are collected, handled, and processed according to routine clinical procedures during which they are subjected to factors that may alter their molecular quality and composition. Such artefactual alteration may skew data from molecular analyses, render analysis data uninterpretable, or even preclude analysis altogether if the integrity of a specimen is severely compromised. As a result, patient care and safety may be affected, and medical research dependent on patient samples may be compromised. Despite these issues, there is currently no requirement to control or record preanalytical variables in clinical practice with the single exception of breast cancer tissue handled according to the guideline jointly developed by the American Society of Clinical Oncology and College of American Pathologists (CAP) and enforced through the CAP Laboratory Accreditation Program. Recognizing the importance of molecular data derived from patient specimens, the CAP Personalized Healthcare Committee established the Preanalytics for Precision Medicine Project Team to develop a basic set of evidence-based recommendations for key preanalytics for tissue and blood specimens. If used for biospecimens from patients, these preanalytical recommendations would ensure the fitness of those specimens for molecular analysis and help to assure the quality and reliability of the analysis data.
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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.
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.
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.
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.
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Laboratories worldwide find it challenging to identify enough tissues and cases for verification and validation studies of low-incidence, rare antigens. These antigens have a low frequency of ...occurrence in the population, or have little or no expression in normal tissues. Validation studies are essential to assure testing standardization before introducing a new instrument, product, or test into the clinical laboratory. The College of American Pathologists has published comprehensive guidelines for the verification and validation of new immunohistochemical tests introduced into the laboratory menu. Within the guidelines, varied numbers of cases are required for nonpredictive versus predictive markers. However, regarding low-incidence antigens, the laboratory medical director determines the extent of validation required. Recommended practical solutions available to clinical laboratories for low-incidence validation include developing internal resources using the laboratory information system with retrospective and prospective search(s) of archival material and purchase of tissue microarray blocks, slides, or cell lines from external resources. Utilization of homemade multitissue blocks has proved to be extremely valuable in biomarker research and demonstrated great utility in clinical immunohistochemistry laboratories. Participation in External Quality Assessment program(s) may provide insufficient numbers or the ability to calculate concordance rates. However, supplementation with in-house tissues can allow a laboratory to reach the optimal number of cases needed for verification and/or validation schemes. An alternative approach is conducting a thorough literature search and correlating staining patterns of the new test to the expected results. These solutions may be used uniquely or together to assure consistent standardized testing.
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8.
Preanalytics and Precision Pathology Compton, Carolyn C; Robb, James A; Anderson, Matthew W ...
Archives of pathology & laboratory medicine (1976),
11/2019, Volume:
143, Issue:
11
Journal Article
Peer reviewed
According to the Personalized Medicine Coalition, there are currently more than 60,000 molecular genetic tests on the market, with 8 to 10 new products entering the market every day.38 Multiplex ...technologies such as next-generation sequencing for nucleic acids and mass spectrometry for proteins, once residing solely in the research domain, have swiftly moved into the clinical care arena. ...biospecimens of poor or unknown quality continue to contribute to the overall inefficiency, excessive cost, poor reproducibility, and high rate of failure of translational research, in general, and of biomarker development, in particular.2,54,55 Recent efforts by biobanking experts to address this problem after the fact include the development of batteries of assays for measurands in specimens that are affected by preanalytical factors. Lithium heparin tubes are not suitable for nucleic acid analysis by PCR because lithium heparin is a PCR inhibitor.172,187-189 Volume of Tube Fill: The Optimal Tube-Fill Volume per the Tube Manufacturer's Recommendation Is Advised.- Tube additives are calibrated to provide optimal ratios of blood to additive. ...in tubes with additives, the tube fill level is an essential quality indicator for the test sample and should be documented at the time of the blood draw.190 Draw Order: The Recommended Draw Order Is as Shown Below (With Consideration to Alterations as Indicated Clinically) and Is Only Applicable if Multiple Specimens Are Being Collected at 1 Draw.-Prioritized Draw Order, First to Last 1. Furthermore, at the time of acquisition, it may not be known whether or not a biospecimen will be undergoing molecular testing, either as part of immediate patient care or in the future. ...it is prudent and reasonable to treat all patient specimens in a uniform manner that safeguards molecular integrity and ensures their fitness for molecular analysis as a routine part of patient care.
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The field of diagnostics has unprecedented opportunities to contribute to the practice of medicine in the era of targeted therapy and personalized healthcare. Rather than simply providing information ...regarding the presence and classification of disease, innovative molecular diagnostic tests will directly inform patient-management decisions, such as which targeted therapies to prescribe or whether a patient should be treated more aggressively. However, in order for diagnostics to deliver this high level of medical value, several challenges ranging from technical, pre-analytical, developmental, regulatory, reimbursement and quality perspectives need to be overcome. This review focuses on recent developments in each of these areas that are expected to improve the power and impact of diagnostics.
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