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.

/pdf/recommendations-for-human-epidermal-growth-factor-receptor-2-g57f9qz7g7.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.

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

Recently, Nusing et al. (1) defined a monoclonal antibody Tue 300 (mAB Tue 300) which recognizes thromboxane synthase (T×S) in unfixed tissue sections. Studies on normal human organs revealed that this antibody labels not only thrombocytes from which the immunizing antigen was derived but also all members of the mononuclear phagocytic system, including specialized cells such as starry sky macrophages, dendritic cells of T cell areas, epithelioid cells, multinucleated giant cells, Langerhans cells and Kupffer cells. In addition, a focal labeling of epithelial cells was observed in tonsils, female breast, pancreas, salivary glands and bile ductules (2). In view of controversial findings concerning the role of thromboxane (T×A2) in tumors (for review see ref. 3), an immunohistochemical study on the cellular distribution of T×S was performed on carcinomas of breast, lung and colon.

Immunohistochemical Localization of Thromboxane Synthase in Normal and Neoplastic Tissues by the Monoclonal Antibody Tü 300

The diagnosis of lung cancer is often based on cytologyalone. The relative paucity of tumor cells in these speci-mens is a challenge for the analysis of epidermal growthfactor receptor (EGFR) gene mutation and EGFR genecopy number to select for treatment with EGFR-tyrosinekinase inhibitors. Here, we tested whether such EGFRgene analyses are feasible on cytological specimens ofnon-small-cell lung cancers (NSCLC).

/pdf/egfr-gene-analysis-on-cytological-specimens-of-non-small-4f49o4amoh.pdf

EGFR-gene analysis on cytological specimens of non-small-cell lung cancers

Cell scrapings from 552 consecutive women attending the colposcopy outpatient unit were examined by radioactive isotopic DNA hybridisation using the Dot-Blot technique, and by conventional Papanicolaou-smear cytology. In 315 out of these patients, punch biopsies were submitted for histological examination. HPV DNA-sequences were detected in 72% (n = 167) of 232 cytologically diagnosed CIN cases and in 77% (n = 97) out of 126 histological diagnoses of CIN. The proportion of HPV positive cases increased proportionally to the grade of CIN. The frequency of HPV type 6/11 decreased proportionally to the grade of the CIN, and HPV type 16/18 increased at the same time. The most frequent HPV type was 16/18 (26.3%), followed by the HPV types 31/33/35 (16.3%) and 6/11 (4.2%). Furthermore, HPV positivity was detected in 16.5% of patients with negative cytologic smears, in 21.7% of those with negative histology and in 8.9% of women with both negative histology and cytology. Histological and moreover cytological criteria of HPV infection decreased dramatically and proportionally inverse to the grade of the CIN. These changes were not followed entirely by HPV positivity. The discrepancy between HPV positivity (66.1%/67.6%) and morphological evidence of HPV infection (cytology 4.9%, histology 21.6%) was higher in CIN III than in lower grade CIN. Neither cytology nor histology is able to detect all HPV-related cervical lesions. Hybridisation techniques are helpful in the detection of latent HPV infections as well as of CIN lesions have been missed either by cytology or by histology or both. Thus both morphological methods are supplemented by HPV hybridisation.(ABSTRACT TRUNCATED AT 250 WORDS)

Vergleichende DNS-Hybridisierung, Zytologie und Histologie an kondylomatösen und präkanzerösen Läsionen der Cervix uteri

Chromosomal abnormalities are frequent in most cervical cancers. Amplifications of both the 3q26 (TERC) and 8q24 (MYC) loci have been shown to be prevalent in both high-grade lesions and invasive cervical carcinoma. Most of these studies have looked at either the histological sample or at the entire cytological population of cells. We have developed a Papanicolaou (Pap) destaining method that allows for the accurate analysis of individual cells that were previously identified by cytopathology as dysplastic. The application of fluorescence in situ hybridization (FISH) was then implemented to determine the chromosomal status of the dysplastic cells in the samples and correlate the two events. Chromosomal abnormality is over a thousand times more frequent in dysplastic cells compared with their morphologically normal counterparts.

Dysplastic cells in cytological cervical samples show a high incidence of chromosomal abnormalities.

Die Leber nimmt eine zentrale Stellung im Stoffwechsel des Gesamtorganismus ein. Sie verfugt uber einen doppelten Blutzufluss: Einerseits wird sie direkt uber die Arteria hepatica aus der Aorta mit sauerstoffreichem Blut, andererseits uber die Vena portae mit dem venosen Blut aus Magen-Darm-Trakt und Milz versorgt. Daher ist sie die erste Metastasenstation fur Tumoren des Magen- Darm-Trakts (portaler Typ der Metastasierung) und die zweite Metastasenstation fur Tumoren im venosen Abflussgebiet von grosem und kleinem Kreislauf. Auserdem entsteht in der Leber selbst eine Reihe von gut- und bosartigen Tumoren.

Georg Feichter

Papers

Immunohistochemical Localization of Thromboxane Synthase in Normal and Neoplastic Tissues by the Monoclonal Antibody Tü 300

EGFR-gene analysis on cytological specimens of non-small-cell lung cancers

Vergleichende DNS-Hybridisierung, Zytologie und Histologie an kondylomatösen und präkanzerösen Läsionen der Cervix uteri

Dysplastic cells in cytological cervical samples show a high incidence of chromosomal abnormalities.

Leber und Gallenwege