Purpose
To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer.

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Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.

Purpose.—To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in b...

/pdf/recommendations-for-human-epidermal-growth-factor-receptor-2-2ccp79orqo.pdf

Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update

The human epidermal growth factor receptor (HER-2) oncogene encodes a transmembrane tyrosine kinase receptor that has evolved as a major classifier of invasive breast cancer and target of therapy for the disease. The validation of the general prognostic significance of HER-2 gene amplification and protein overexpression in the absence of anti-HER-2 targeted therapy is discussed in a study of 107 published studies involving 39,730 patients, which produced an overall HER-2-positive rate of 22.2% and a mean relative risk for overall survival (OS) of 2.74. The issue of HER-2 status in primary versus metastatic breast cancer is considered along with a section on the features of metastatic HER-2-positive disease. The major marketed slide-based HER-2 testing approaches, immunohistochemistry, fluorescence in situ hybridization, and chromogenic in situ hybridization, are presented and contrasted in detail against the background of the published American Society of Clinical Oncology-College of American Pathologists guidelines for HER-2 testing. Testing issues, such as the impact of chromosome 17 polysomy and local versus central HER-2 testing, are also discussed. Emerging novel HER-2 testing techniques, including mRNA-based testing by real-time polymerase chain reaction and DNA microarray methods, HER-2 receptor dimerization, phosphorylated HER-2 receptors, and HER-2 status in circulating tumor cells, are also considered. A series of biomarkers potentially associated with resistance to trastuzumab is discussed with emphasis on the phosphatase and tensin homologue deleted on chromosome ten/Akt and insulin-like growth factor receptor pathways. The efficacy results for the more recently approved small molecule HER-1/HER-2 kinase inhibitor lapatinib are also presented along with a more limited review of markers of resistance for this agent. Additional topics in this section include combinations of both anti-HER-2 targeted therapies together as well as with novel agents including bevacizumab, everolimus, and tenespimycin. A series of novel HER-2-targeting agents is also presented, including pertuzumab, ertumaxomab, HER-2 vaccines, and recently discovered tyrosine kinase inhibitors. Biomarkers predictive of HER-2 targeted therapy toxicity are included, and the review concludes with a consideration of HER-2 status in the prediction of response to non-HER-2 targeted treatments including hormonal therapy, anthracyclines, and taxanes.

The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine

Recent therapeutic advances in oncology have been driven by the identification of tumour genotype variations between patients, called interpatient heterogeneity, that predict the response of patients to targeted treatments. Subpopulations of cancer cells with unique genomes in the same patient may exist across different geographical regions of a tumour or evolve over time, called intratumour heterogeneity. Sequencing technologies can be used to characterize intratumour heterogeneity at diagnosis, monitor clonal dynamics during treatment and identify the emergence of clinical resistance during disease progression. Genetic interpatient and intratumour heterogeneity can pose challenges for the design of clinical trials that use these data.

Tumour heterogeneity in the clinic

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. HER-2/neu has been widely studied in breast cancer. In this review, the association of HER-2/neu gene and protein abnormalities studied by Southern and slot blotting, immunohistochemistry, enzyme immunoassays, and fluorescence in situ hybridization with prognosis in breast cancer is studied in depth by review of a series of 47 published studies encompassing more than 15,000 patients. The relative advantages of gene amplification assays and frozen/fresh tissue immunohistochemistry over paraffin section immunohistochemistry are discussed. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The potential value of HER-2/neu status for the prediction of response to therapy in breast cancer is presented in the light of a series of recently published studies showing a range of impact on the outcome of patients treated with hormonal, cytotoxic, and radiation therapies. The evidence that HER-2/neu gene and protein abnormalities in breast cancer predict resistance to tamoxifen therapy and relative sensitivity to chemotherapy regimens including adriamycin is presented. The review will also evaluate the status of serum-based testing for circulating the HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. In the final section, the review will briefly present preliminary data concerning the use of antibody-based therapies directed against the HER-2/neu protein and their potential to become a new modality for breast cancer treatment. The recently presented phase III clinical trial evidence that systemic administration of anti-HER2 antibodies (Herceptin®), alone and in combination with cytotoxic chemotherapy in patients with HER-2/neu overexpressing primary tumors, can increase the time to recurrence and overall response rates in metastatic breast cancer is reviewed.

The HER-2/neu Oncogene in Breast Cancer: Prognostic Factor, Predictive Factor, and Target for Therapy

Introduction
The status of the gene encoding human EGF-like receptor 2 (HER2) is an important prognostic and predictive marker in breast cancer. Only breast cancers with HER2 amplification respond to the targeted therapy with trastuzumab. It is controversial to what degree the primary tumour is representative of distant metastases in terms of HER2 status. Discrepancies in HER2 status between primary tumours and distant metastases have been described, but their reasons remain unclear. Here, we compared HER2 status on cytological specimens of distant metastases with the result from the primary carcinomas, and explored the prevalence of and the reasons for discrepant results.

https://link.springer.com/content/pdf/10.1186%2Fbcr1676.pdf

HER2 gene status in primary breast cancers and matched distant metastases

Introduction The status of the gene encoding human EGF-like receptor 2 (HER2) is an important prognostic and predictive marker in breast cancer. Only breast cancers with HER2 amplification respond to the targeted therapy with trastuzumab. It is controversial to what degree the primary tumour is representative of distant metastases in terms of HER2 status. Discrepancies in HER2 status between primary tumours and distant metastases have been described, but their reasons remain unclear. Here, we compared HER2 status on cytological specimens of distant metastases with the result from the primary carcinomas, and explored the prevalence of and the reasons for discrepant results. Methods HER2 status was determined by fluorescence in situ hybridisation. HER2 gene amplification was defined as a HER2/ chromosome 17 signal ratio of 2 or more. HER2 results from cytological specimens of matched distant metastases were compared with the results from the corresponding primary tumours (n = 105 patients). In addition, lymph node metastases were analysed in 31 of these patients.

HER2 gene status in primary breast cancers and matched distant

Angiogenesis in Cervical Neoplasia: Microvessel Quantitation in Precancerous Lesions and Invasive Carcinomas with Clinicopathological Correlations☆

Urinary cytology is limited by high interobserver variability in the evaluation of cells with little atypia. We set up an online quiz on urinary cytology and tested the performance of 246 international participants. The quiz consisted of still images of 42 urinary specimens with equivocal morphologic features and 10 control cases with an unequivocal cytologic diagnosis. The nature of the cells on the 292 quiz images had been verified by multitarget fluorescence in situ hybridization in addition to the information obtained by cystoscopy, clinical follow-up, and/or histologic examination. The original quiz cases and the percentage of answers given by the participants can be viewed at: http://kathrin.unibas.ch/urinzyto/. High-grade cancers were diagnosed correctly in 76.0% and low-grade cancers in only 33.9%. Remarkably, 54.5% of all participants misclassified decoy cells as malignant. This study shows that large-scale international online quizzes may be used to find educational deficits in cytopathology. Urinary cytology is used routinely for the diagnosis and management of patients with urothelial carcinoma and its precursors. The diagnostic yield of urinary cytology in daily practice depends on the grade of the primary lesion and the type of

/pdf/an-international-telecytologic-quiz-on-urinary-cytology-tlrrui5388.pdf

An international telecytologic quiz on urinary cytology reveals educational deficits and absence of a commonly used classification system.

OBJECTIVE: To analyze the sensitivity, specificity, positive and negative predictive values and the efficacy of fine needle aspiration (FNA) in our material, to investigate the influence of the histologic type and stage of carcinoma on the quality of the aspirates and on the detection rates of mammary carcinoma, and to investigate diagnosis in the rate of inadequate samples and the accuracy of cytologic diagnoses, with an emphasis on the rate offalse positive diagnoses in benign mammary lesions. STUDY DESIGN: The results of 1,472 FNAs of the breast obtained over three years were subjected to a retrospective analysis. RESULTS: The cytologic diagnoses were benign in 1,003 cases (68.1%), suspicious in 49 (3.3%) and malignant in 181 (12.3%); 239 (16.2%) of the aspirates were inadequate. In 393 (26.6%) of the cases and in 85% of cytologically malignant smears, the aspirate was compared with histologic examination. The rate of false negative FNAs was 9.0%. The proportion of inadequate cases was clearly related to stage (pT): it was 9.5% in pT1, 5.0% in pT2 and 0% in pT3. Among invasive carcinomas the sensitivity was 89.9%, specificity 99.3 % and overall accuracy 88.5%. Among the cases diagnosed cytologically as benign, 182 were compared with biopsies. Of these, 79.9% were true negative, 0.5% (1 case) was false positive, and 15.4% had insufficient cells for evaluation. CONCLUSION: FNA cytology has improved decision making and the selection of patients for biopsy of mammary lesions and has contributed to saving time in the clinical management of breast lumps. In no case did FNA lead to inadequate clinical measures or other disadvantages to patients. Thus, FNA cytology is an indispensible diagnostic tool in the management of breast lesions.

Georg Feichter

Papers

HER2 gene status in primary breast cancers and matched distant metastases

HER2 gene status in primary breast cancers and matched distant

Angiogenesis in Cervical Neoplasia: Microvessel Quantitation in Precancerous Lesions and Invasive Carcinomas with Clinicopathological Correlations☆

An international telecytologic quiz on urinary cytology reveals educational deficits and absence of a commonly used classification system.

Breast cytology. Statistical analysis and cytohistologic correlations.