Angela N. Bartley

HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology

Context ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. Objectives To establish an evidence-based guideline for HER2 testing in patients with GEA, formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. Design The College of American Pathologists (CAP), American Society for Clinical Pathology (ASCP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. Results The Panel is proposing 11 recommendations with strong agreement from the open comment participants. Recommendations The Panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and an HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. Conclusion This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.

Validation of p53 immunohistochemistry as a prognostic factor in breast cancer in clinical practice

CONTEXT Abnormal p53 tumor suppressor gene expression as detected by immunohistochemistry is a possible prognostic factor in breast cancer. The difference in techniques used to evaluate the expression of mutated p53 protein is under intense scrutiny, as well as its uses either independently or in conjunction with other prognostic factors in breast cancer. OBJECTIVE To determine whether p53 immunohistochemistry can be used as a reliable indicator of the presence of mutated nuclear p53 protein, and whether this method can be performed reliably in a community hospitals clinical practice. DESIGN ne hundred twenty-two cases of breast carcinoma were stained and analyzed for the presence of p53 protein using DO-7 (Dako Corporation, Carpinteria, Calif) p53 antibody. RESULTS Of the 122 cases of invasive carcinoma studied, 23 (18.7%) were positive for p53, and 16 (16.3%) of 98 cases with coexisting ductal carcinoma in situ were positive for p53. This finding is in agreement with comparable published studies. CONCLUSIONS Based on the results of this study, we conclude that p53 immunohistochemistry qualifies as a diagnostic technique suitable for clinical practice in a community hospital. Its detection may be particularly promising in clinical trials of new molecular therapies directed at the p53 tumor suppressor gene.

Template for reporting results of biomarker testing of specimens from patients with carcinoma of the colon and rectum.

The College of American Pathologists offers these templates to assist pathologists in providing clinically useful and relevant information when reporting results of biomarker testing. The College regards the reporting elements in the templates as important elements of the biomarker test report, but the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice.

Template for Reporting Results of HER2 (ERBB2) Biomarker Testing of Specimens From Patients With Adenocarcinoma of the Stomach or Esophagogastric Junction.

The College of American Pathologists offers these templates to assist pathologists in providing clinically useful and relevant information when reporting results of biomarker testing. The College regards the reporting elements in the templates as important elements of the biomarker test report, but the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice. The College developed these templates as educational tools to assist pathologists in the useful reporting of relevant information. It did not issue them for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the templates might be used by hospitals, attorneys, payers, and others. The College cautions that use of the templates other than for their intended educational purpose may involve additional considerations that are beyond the scope of this document.

Select Biomarkers for Tumors of the Gastrointestinal Tract: Present and Future

CONTEXT Advances in molecular biomarkers of the gastrointestinal tract have contributed to a decline in the incidence of and mortality from diseases of the gastrointestinal tract. The discovery and clinical validation of new biomarkers are important to personalized cancer therapy, and numerous clinical trials are currently ongoing to help identify individualized therapy affecting these biomarkers and molecular mechanisms they represent. Distinct molecular pathways leading to cancers of the colorectum, esophagus, stomach, small bowel, and pancreas have been identified. Using biomarkers in these pathways to direct patient care, including selection of proper molecular testing for identification of actionable mutations and reporting the results of these biomarkers to guide clinicians and genetic counselors, is paramount. OBJECTIVE To examine and review select clinically actionable biomarkers of the colon, esophagus, stomach, small bowel, and pancreas, including present and future biomarkers with relevant clinical trials. DATA SOURCES Extensive literature review and practical and consultation experience of the authors. CONCLUSIONS Although numerous biomarkers have been identified and are currently guiding patient therapy, few have shown evidence of clinical utility in the management of patients with gastrointestinal cancers. Inconsistent results and discordant proposed algorithms for testing were identified throughout the literature; however, the potential for biomarkers to improve outcomes for patients with gastrointestinal cancer remains high. Continued advances through high-quality studies are needed.

Comparison of laboratory-developed tests and fda-approved assays for braf, EGFR, and kras testing

Importance The debate about the role of the Food and Drug Administration (FDA) in the regulation of laboratory-developed tests (LDTs) has focused attention on the analytical performance of all clinical laboratory testing. This study provides data comparing the performance of LDTs and FDA-approved companion diagnostics (FDA-CDs) in proficiency testing (PT) provided by the College of American Pathologists Molecular Oncology Committee. Objective To compare the analytical performance of LDTs and FDA-CDs on well-characterized PT samples and to compare the practice characteristics of laboratories using these assays. Design, Setting, and Participants This comparison of PT responses examines the performance of laboratories participating in the College of American Pathologists PT for 3 oncology analytes for which both FDA-CDs and LDTs are used: BRAF, EGFR, and KRAS. A total of 6897 PT responses were included: BRAF (n = 2524; 14 PT samples), EGFR (n = 2216; 11 PT samples), and KRAS (n = 2157, 10 PT samples). US Food and Drug Administration companion diagnostics and LDTs are compared for both accuracy and preanalytic practices of the laboratories. Main Outcomes and Measures As per the College of American Pathologists PT standards, results were scored and the percentages of acceptable responses for each analyte were compared. These were also broken down by the specific variants tested, by kit manufacturer for laboratories using commercial reagents, and by preanalytic practices. Results From analysis of 6897 PT responses, this study demonstrates that both LDTs and FDA-CDs have excellent performance overall, with both test types exceeding 97% accuracy for all 3 genes (BRAF, EGFR, and KRAS) combined. Rare variant-specific differences did not consistently favor LDTs or FDA-CDs. Additionally, more than 60% of participants using an FDA-CD reported adapting their assay from the approved procedure to allow for a greater breadth of sample types, minimum tumor content, and instrumentation, changing the classification of their assay from FDA-CD to LDT. Conclusions This study demonstrates the high degree of accuracy and comparable performance of both LDTs and FDA-CDs for 3 oncology analytes. More significantly, the majority of laboratories using FDA-CDs have modified the scope of their assay to allow for more clinical practice variety, rendering them LDTs. These findings support both the excellent and equivalent performance of both LDTs and FDA-CDs in clinical diagnostic testing.

Screening for Cancer Genetic Syndromes With a Simple Risk-Assessment Tool in a Community-Based Open-Access Colonoscopy Practice

Screening for Cancer Genetic Syndromes With a Simple Risk-Assessment Tool in a Community-Based Open-Access Colonoscopy Practice

HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma

CONTEXT ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.

Reporting results of molecular tests: A retrospective examination of BRAF mutation reporting

CONTEXT - With enormous growth in the field of molecular pathology, the reporting of results gleaned from this testing is essential to guide patient care. OBJECTIVE - To examine molecular reports from laboratories participating in proficiency testing for required elements to convey molecular laboratory test results to clinicians and patients. DESIGN - Molecular laboratories participating in the College of American Pathologists (CAP) proficiency testing program for BRAF mutation analysis were solicited to submit examples of final reports from 2 separate proficiency testing reporting cycles. Reports were reviewed for the presence or absence of relevant components. RESULTS - A total of 107 evaluable reports were received (57 demonstrating a positive result for the BRAF V600E mutation and 50 negative). Methods for BRAF testing varied, with 95% (102 of 107) of reports adequately describing their assay methods and 87% (93 of 107) of reports adequately describing the target(s) of their assays. Information on the analytic sensitivity of the assay was present in 74% (79 of 107) of reports and 83% (89 of 107) reported at least 1 assay limitation, though only 34% (36 of 107) reported on variants not detected by their assays. Analytic and clinical interpretive comments were included in 99% (106 of 107) and 90% (96 of 107) of reports, respectively. Of participants that perform a laboratory-developed test, 88% (88 of 100) included language addressing the development of the assay. CONCLUSIONS - Laboratories participating in BRAF proficiency testing through the CAP are including most of the required reporting elements to unambiguously convey molecular results. Laboratories should continue to strive to report these results in a concise and comprehensive manner.

A Window Into Clinical Next-Generation Sequencing–Based Oncology Testing Practices

CONTEXT - Detection of acquired variants in cancer is a paradigm of precision medicine, yet little has been reported about clinical laboratory practices across a broad range of laboratories. OBJECTIVE - To use College of American Pathologists proficiency testing survey results to report on the results from surveys on next-generation sequencing-based oncology testing practices. DESIGN - College of American Pathologists proficiency testing survey results from more than 250 laboratories currently performing molecular oncology testing were used to determine laboratory trends in next-generation sequencing-based oncology testing. RESULTS - These presented data provide key information about the number of laboratories that currently offer or are planning to offer next-generation sequencing-based oncology testing. Furthermore, we present data from 60 laboratories performing next-generation sequencing-based oncology testing regarding specimen requirements and assay characteristics. The findings indicate that most laboratories are performing tumor-only targeted sequencing to detect single-nucleotide variants and small insertions and deletions, using desktop sequencers and predesigned commercial kits. Despite these trends, a diversity of approaches to testing exists. CONCLUSIONS - This information should be useful to further inform a variety of topics, including national discussions involving clinical laboratory quality systems, regulation and oversight of next-generation sequencing-based oncology testing, and precision oncology efforts in a data-driven manner.