Investigating the Current Harmonization Status of Tumor Markers Using Global External Quality Assessment Programs: A Feasibility Study.

BACKGROUND: The harmonization status of most tumor markers (TMs) is unknown. We report a feasibility study performed to determine whether external quality assessment (EQA) programs can be used to obtain insights into the current harmonization status of the tumor markers α-fetoprotein (AFP), prostate specific antigen (PSA), carcinoembryonic antigen (CEA), cancer antigen (CA)125, CA15-3 and CA19-9. METHODS: EQA sample results provided by 6 EQA providers (INSTAND [Germany], Korean Association of External Quality Assessment Service [KEQAS, South Korea], National Center for Clinical Laboratories [NCCL, China], United Kingdom National External Quality Assessment Service [UK NEQAS, United Kingdom], Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek [SKML, the Netherlands], and the Royal College of Pathologists of Australasia Quality Assurance Programs [RCPAQAP, Australia]) between 2020 and 2021 were used. The consensus means, calculated from the measurement procedures present in all EQA programs (Abbott Alinity, Beckman Coulter DxI, Roche Cobas, and Siemens Atellica), was used as reference values. Per measurement procedure, the relative difference between consensus mean for each EQA sample and the mean of all patient-pool-based EQA samples were calculated and compared to minimum, desirable, and optimal allowable bias criteria based on biological variation. RESULTS: Between 19040 (CA15-3) and 25398 (PSA) individual results and 56 (PSA) to 76 (AFP) unique EQA samples were included in the final analysis. The mean differences with the consensus mean of patient-pool-based EQA samples for all measurement procedures were within the optimum bias criterion for AFP, the desirable bias for PSA, and the minimum bias criterion for CEA. However, CEA results <8 µg/L exceeded the minimum bias criterion. For CA125, CA15-3, and CA19-9, the harmonization status was outside the minimum bias criterion, with systematic differences identified. CONCLUSIONS: This study provides relevant information about the current harmonization status of 6 tumor markers. A pilot harmonization investigation for CEA, CA125, CA15-3, and CA19-9 would be desirable.

Standardization of tumor markers - priorities identified through external quality assessment.

Tumor markers are often heterogeneous substances that may be present in elevated concentrations in the serum of cancer patients. Typically measured by immunoassay, they contribute to clinical management, particularly in screening, case-finding, prognostic assessment, and post-treatment monitoring. Data both from external quality assessment (EQA) schemes and clinical studies demonstrate significant variation in tumor marker results obtained for the same specimen using different methods. Between-method between-laboratory coefficients of variation (CV) reported by EQA schemes generally reflect the complexity of the measurand, ranging from <5% for the structurally relatively simple α-fetoprotein (AFP) to >25% for the complex mucinous cancer antigen 19-9 (CA19-9). Improving the standardization of tumor marker measurements is particularly important for three reasons. The primary use of tumor markers is in monitoring cancer patients over long periods of time. Clinical interpretation of trends may consequently be affected if results are obtained in different laboratories using different methods or if a laboratory has to change method. Differences in results may have major implications for adoption of area-wide decision cut-offs and make implementation of these difficult. Method-related differences also make it difficult to compare clinical studies. Improving comparability of tumor marker results requires broad international agreement about which molecular forms of the measurand have clinical utility, identifying and adopting pure molecular forms as calibrants, and defining antibody specificities for their optimal detection. These aims have been achieved to varying extents for the most frequently measured serum tumor markers as described in this paper.

Validation of new cancer biomarkers: a position statement from the European group on tumor markers.

BACKGROUND: Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use. CONTENT: In this review, we discuss the key steps in advancing a newly discovered cancer candidate biomarker from pilot studies to clinical application. Four main steps are necessary for a biomarker to reach the clinic: analytical validation of the biomarker assay, clinical validation of the biomarker test, demonstration of clinical value from performance of the biomarker test, and regulatory approval. In addition to these 4 steps, all biomarker studies should be reported in a detailed and transparent manner, using previously published checklists and guidelines. Finally, all biomarker studies relating to demonstration of clinical value should be registered before initiation of the study. SUMMARY: Application of the methodology outlined above should result in a more efficient and effective approach to the development of cancer biomarkers as well as the reporting of cancer biomarker studies. With rigorous application, all stakeholders, and especially patients, would be expected to benefit.

External quality assessment of hormone determinations.

Hormone determinations are of central importance to the practice of Clinical Endocrinology, and ensuring their correct use and performance is a multidisciplinary responsibility involving clinicians, laboratory staff, manufacturers of diagnostic systems and healthcare regulatory agencies. All these professional groups have, therefore, an interest in external quality assessment (EQA) as an audit tool that can identify areas where use of tests in routine practice requires improvement to reduce risks to patients. This chapter reviews the principles of EQA, and outlines its strengths and limitations, illustrated with example data from the UK National External Quality Assessment Service (UK NEQAS). The immunological nature of many hormone assays, often further complicated by heterogeneity of analyte structure and lack of suitable calibrators, presents special problems for the designers of EQA schemes in ensuring that specimens are appropriate and that target values are accurate. Laboratory users of EQA should have sufficient knowledge of the characteristics of the EQA schemes in which they participate to make informed interpretation of their data. The trend since the 1980s for in-house assays designed in individual laboratories to be superseded by automated assays provided by a small number of diagnostics manufacturers places a special responsibility on manufacturers to ensure reliable assay design and calibration. In collaboration with other parties EQA can help identify priorities for improved assay design and calibration. Although traditionally the focus of EQA has been on assessing the analytical phase it can also make some assessment of other important aspects of performance, e.g. the consistency of reference ranges and how results are interpreted. Overall, EQA has a valuable role both in laboratory accreditation and as an educational resource, thereby helping to ensure and improve the quality of laboratory services that support patient care.

External quality assessment schemes for immunoassays.

External quality assessment schemes (EQAS) provide an important means of monitoring the quality of the performance of immunoassays in the field. Set up by external bodies and complementing internal quality control procedures, they enable ongoing comparison of individual laboratory results, both with independently established target values and with results of other participating laboratories. Well-designed EQAS assess analytical performance particularly with respect to bias and precision, but also give some indication of the type of errors that most frequently occur in routine practice. EQAS must themselves meet nationally and/or internationally agreed standards so that participants can have confidence in the data generated. Some of the standards currently applied in the UK are described in this chapter, with examples of how these standards can be met also provided.

Analytical error and interference in immunoassay: minimizing risk.

Although generally robust, immunoassays remain vulnerable to occasional analytical errors that may have serious implications for patient care. Sporadic errors that occur as a result of properties of the specimen are particularly difficult to detect. They may be due to the presence of cross-reacting substances, antianalyte antibodies or antireagent antibodies, all of which may lead to erroneously high or low results. Low results may be observed for tumour markers due to high-dose hooking in the presence of very high analyte concentrations. Erroneous results can occur unexpectedly with any specimen and there is no practical means of identifying specimens likely to cause problems in immunoassays. The possibility of interference should always be considered when results do not appear to be in accord with the clinical picture. Errors can occur in even the best-managed laboratories and their early investigation is always desirable. If there is any doubt whatsoever about a result, clinical staff should be encouraged to contact the laboratory. Investigations for possible interference that can be undertaken in most laboratories include testing for linearity on dilution, recovery experiments, treatment with heterophilic blocking tubes and confirmation using a different method. It may be desirable to consult specialist laboratories if more complex studies are necessary. Informing clinical and laboratory staff of the ever-present possibility of unexpected interference, ensuring brief clinical details are available to laboratory staff, and above all facilitating excellent communication between laboratory and clinical staff are key to minimizing the risk of clinical mismanagement due to unsuspected interference.

Taking a new biomarker into routine use--a perspective from the routine clinical biochemistry laboratory.

There is increasing pressure to provide cost-effective healthcare based on "best practice." Consequently, new biomarkers are only likely to be introduced into routine clinical biochemistry departments if they are supported by a strong evidence base and if the results will improve patient management and outcome. This requires convincing evidence of the benefits of introducing the new test, ideally reflected in fewer hospital admissions, fewer additional investigations and/or fewer clinic visits. Carefully designed audit and cost-benefit studies in relevant patient groups must demonstrate that introducing the biomarker delivers an improved and more effective clinical pathway. From the laboratory perspective, pre-analytical requirements must be thoroughly investigated at an early stage. Good stability of the biomarker in relevant physiological matrices is essential to avoid the need for special processing. Absence of specific timing requirements for sampling and knowledge of the effect of medications that might be used to treat the patients in whom the biomarker will be measured is also highly desirable. Analytically, automation is essential in modern high-throughput clinical laboratories. Assays must therefore be robust, fulfilling standard requirements for linearity on dilution, precision and reproducibility, both within- and between-run. Provision of measurements by a limited number of specialized reference laboratories may be most appropriate, especially when a new biomarker is first introduced into routine practice.