American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.
ABSTRACT To develop a guideline to improve the accuracy of human epidermal growth factor receptor 2(HER2) testing in invasive breast cancer and its utility as a predictive marker.
The American Society of Clinical Oncology and the College of American Pathologists convened an expert panel, which conducted a systematic review of the literature and developed recommendations for optimal HER2 testing performance. The guideline was reviewed by selected experts and approved by the board of directors for both organizations.
Approximately 20% of current HER2 testing may be inaccurate. When carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry(IHC) or in situ hybridization (ISH) as a predictor of benefit from anti-HER2 therapy.
The panel recommends that HER2 status should be determined for all invasive breast cancer. A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of brightfield ISH, is proposed. Elements to reliably reduce assay variation (for example, specimen handling, assay exclusion, and reporting criteria) are specified. An algorithm defining positive, equivocal, and negative values for both HER2 protein expression and gene amplification is recommended: a positive HER2 result is IHC staining of 3 + (uniform, intense membrane staining of 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2; a negative result is an IHC staining of 0 or 1 +, a FISH result of less than 4.0 HER2 gene copies per nucleus, or FISH ratio of less than 1.8. Equivocal results require additional action for final determination. It is recommended that to perform HER2 testing, laboratories show 95% concordance with another validated test for positive and negative assay values. The panel strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment. The panel recommends that HER2 testing be done in a CAP-accredited laboratory or in a laboratory that meets the accreditation and proficiency testing requirements set out by this document.
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ABSTRACT: Ten years after completion of the Human Genome Project, progress towards making "personalized medicine" a reality has been slower than expected. The reason is twofold. Firstly, the science is more difficult than expected. Secondly, limited progress has been made in aligning economic incentives to invest in diagnostics. This paper develops nine case studies of "success" where diagnostic tests are bringing personalized medicine into clinical practice with health and economic impact for patients, healthcare systems, and manufacturers. We focus on the availability of evidence for clinical utility, which is important not only for clinicians but also for payers and budget holders. We find that demonstrating diagnostic clinical utility and the development of economic evidence is currently feasible (i) through drug-diagnostic co-development, and (ii) when the research is sponsored by payers and public bodies. It is less clear whether the diagnostic industry can routinely undertake the work necessary to provide evidence as to the clinical utility and economic value of its products. It would be good public policy to increase the economic incentives to produce evidence of clinical utility: otherwise, opportunities to generate value from personalized medicine-in terms of both cost savings and health gains-may be lost.Journal of personalized medicine. 01/2013; 3(4):288-305.
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ABSTRACT: Background: The human epidermal growth factor receptor-2 (HER-2) expression level is a critical element for determining the prognosis and management of breast cancer. HER-2 targeted therapy in breast cancer depends on the reliable assessment of HER-2 expression status but current standard methods are lacking a rigorous quantitative assay. To address this challenge, we developed an assessment of HER-2 expression method by well-based reverse phase protein array (RPPA). Results: Well-based RPPA is based on a robust protein isolation methodology paired with a novel electrochemiluminescence detection system. HER-2 value of well-based RPPA significantly correlated with dot blotting results (R2 = 0.939). By well-based RPPA, we successfully detected HER-2 expression in 76 human breast formalin-fixed paraffin-embedded tissue samples. We observed 93.4% (71/76) concordance between well-based RPPA and current HER-2 immunohistochemical assessment guideline. When the cutoff level of HER-2 value was set to 0.689 (HER-2/GAPDH) on the basis of receiver-operating characteristic curve, the area under the curve was 0.975 (95% CI, 0.941-1.000). Sensitivity and specificity of well-based RPPA was 92.1% and 94.7%, respectively. Conclusions: HER-2 value by well-based RPPA was correlated with the current HER-2 status guideline, suggesting that this normalized HER-2 assessment may offer advantages over unnormalized current immunohistochemical assessment methods. Keywords: Breast cancer, Formalin-fixed paraffin-embedded, Human epidermal growth factor receptor- 2, Immunohistochemistry, Reverse-phase protein arrayClinical Proteomics 11/2014;
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ABSTRACT: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have revolutionized the treatment of HER2-positive breast cancer, both in the metastatic and early stage settings. While trastuzumab and lapatinib had been the mainstays of treatment in combination with chemotherapy, innate and acquired resistance to these therapies occur. More recently, two additional HER2-directed therapies have been approved for HER2-positive breast cancer. Pertuzumab is a humanized monoclonal antibody that binds to the extracellular portion of the receptor on a domain distinct from the binding site of trastuzumab. The addition of pertuzumab to trastuzumab results in synergistic tumor cell inhibition and has been shown to significantly improve clinical outcomes for patients with HER2-positive metastatic breast cancer (MBC) compared to trastuzumab plus chemotherapy alone. In addition, ado-trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate linking trastuzumab with the cytotoxic maytansinoid, DM1, is an effective treatment for HER2-positive breast cancer that has progressed on other HER2-directed therapies. Both pertuzumab and T-DM1 are relatively well tolerated. This review presents the mechanisms of action as well as phase I, II and III clinical data describing the safety and efficacy of pertuzumab and T-DM1 for HER2-positive breast cancer.Annals of translational medicine. 12/2014; 2(12):122.