The 2019 Lasker–DeBakey Clinical Medical Research Award goes to scientists whose work on the human epidermal growth factor receptor 2 in breast cancer launched a new era in clinical research and the ...practice of oncology.
Tumor biomarker tests (TBTs) are used to guide therapeutic strategies for patients with cancer. However, the regulatory environment for TBTs in the United States is inconsistent and, in general, TBTs ...are poorly valued. The National Academy of Medicine has recommended that TBTs should not be used in general practice until they are shown to have analytical validity and clinical utility. The latter term, first coined by the Evaluation of Genomic Applications in Practice and Prevention Initiative, has been widely stated but is indeterminately defined. In considering whether a TBT has clinical utility, several factors need to be considered: (1) What is the intended use of the TBT? (2) What are the end points that are used to determine clinical utility? (3) How substantial does the difference in end points between groups defined by the TBT need to be to determine therapeutic strategies? (4) What is the risk tolerance of the stakeholders? and (5) Who are the stakeholders that make the decision? For all these factors, the data used to consider clinical utility must be derived from level I evidence studies. In conclusion, there is no strict definition of clinical utility for a TBT. However, consideration of these factors will lead to more objective conclusions. Doing so will facilitate value-based decisions regarding whether a TBT should be used to guide patient care.
A tumor biomarker is a molecular or process-based change that reflects the status of an underlying malignancy. A tumor biomarker may be identified and measured by one or more assays, or tests, for ...the biomarker. Increasingly, tumor biomarker tests are being used to drive patient management, either by identifying patients who do not require any, or any further, treatment, or by identifying patients whose tumors are so unlikely to respond to a given type of treatment that it will cause more harm than good. A tumor biomarker assay should only be used to guide management if it has analytical validity, meaning that it is accurate, reproducible, and reliable, and if it has been shown to have clinical utility. The latter implies that high levels of evidence are available that demonstrate that application of the tumor biomarker test for a given use context results in better outcomes, or similar outcomes with less cost, than if the assay were not applied. Use contexts include risk categorization, screening, differential diagnosis, prognosis, prediction of therapeutic activity or monitoring disease course. Very few tumor biomarker tests have passed these high bars for routine clinical application. However, if tumor biomarker tests are going to be used to drive patient care, than an understanding, and careful assessment, of these concepts are essential, since “A Bad Tumor Biomarker Test Is as Bad as a Bad Drug.”
In a meta-analysis of 88 trials involving nearly 63,000 women with breast cancer who were disease-free after 5 years of endocrine therapy, the risk of recurrence ranged from 10 to 41% between years 5 ...and 20, depending on nodal status and tumor grade.
Cancer biomarkers Henry, N. Lynn; Hayes, Daniel F.
Molecular oncology,
April 2012, Volume:
6, Issue:
2
Journal Article
Peer reviewed
Open access
Biomarkers have many potential applications in oncology, including risk assessment, screening, differential diagnosis, determination of prognosis, prediction of response to treatment, and monitoring ...of progression of disease. Because of the critical role that biomarkers play at all stages of disease, it is important that they undergo rigorous evaluation, including analytical validation, clinical validation, and assessment of clinical utility, prior to incorporation into routine clinical care. In this review we address key steps in the development of biomarkers, including ways to avoid introducing bias and guidelines to follow when reporting results of biomarker studies.
► Cancer biomarkers must undergo rigorous analytic and clinical validation. ► Clinical validity must be established before a biomarker is used in the clinic. ► Guidelines have been established for reporting results of tumor marker studies.
Abstract
Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The ...International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor–positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.
To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer guideline.
A ...multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature.
The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines.
Clinical management decisions for patients with cancer are increasingly being guided by prognostic and predictive markers. Use of these markers should be based on a sufficiently comprehensive body of ...unbiased evidence to establish that benefits to patients outweigh harms and to justify expenditure of health care dollars. Careful assessments of the clinical utility of markers by using comparative effectiveness research methods are urgently needed to more rigorously summarize and evaluate the evidence, but multiple factors have made such assessments difficult. The literature on tumor markers is plagued by nonpublication bias, selective reporting, and incomplete reporting. Several measures to address these problems are discussed, including development of a tumor marker study registry, greater attention to assay analytic performance and specimen quality, use of more rigorous study designs and analysis plans to establish clinical utility, and adherence to higher standards for reporting tumor marker studies. More complete and transparent reporting by adhering to criteria such as BRISQ Biospecimen Reporting for Improved Study Quality criteria for reporting details about specimens and REMARK Reporting Recommendations for Tumor Marker Prognostic Studies criteria for reporting a multitude of aspects relating to study design, analysis, and results, is essential for reliable assessment of study quality, detection of potential biases, and proper interpretation of study findings. Adopting these measures will improve the quality of the body of evidence available for comparative effectiveness research and enhance the ability to establish the clinical utility of prognostic and predictive tumor markers.
TAILORx established the role of the 21-gene predictor of genetic risk in ascertaining treatment for women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative breast ...cancer. Clinical risk factors provided additional prognostic information for women with intermediate genetic risk.
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