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

In allen westlichen Landern sind Inzidenz und Mortalitat des Zervixkarzinoms im Wesentlichen dank regelmasiger zytologischer Krebsfruherkennungsuntersuchungen massiv zuruckgegangen. Doch selbst in Schweden mit seinem seit 40 Jahren funktionierenden flachendeckenden Fruherkennungsprogramm ist es bislang nicht gelungen, das Zervixkarzinom vollig auszurotten. Auch wenn Nichtteilnahme an Fruherkennungsuntersuchungen der Hauptgrund sein durfte, ist ein weiterer moglicher Grund die unbefriedigende Sensitivitat von bestenfalls 80% des zytologischen Portioabstrichs. Tatsachlich konnte in mehreren Studien gezeigt werden, dass die Fruherkennungsuntersuchungen in bis zu 30% der Frauen mit invasivem Zervixkarzinom unauffallig oder falsch-negativ beurteilt oder unterdiagnostiziert worden waren [17, 136]. Selbst durch wiederholte Untersuchungen in regelmasigen Zeitabstanden lassen sich offenbar nicht samtliche neoplastische Fruhveranderungen erfassen [135]. Das spricht fur die Notwendigkeit, die Fruherkennungsmasnahmen zu verbessern.

Cervix uteri und Vagina

Die Zytopathologie versucht im Unterschied zur Histopathologie nicht an Gewebsfragmenten, sondern an isolierten Zellen Krankheiten, insbesondere Tumoren zu diagnostizieren. Die zytologischen Krankheitskriterien ergeben sich aus Abweichungen von der „normalen“ Zellstruktur.

Funktionelle Anatomie der Zelle

Karzinome des Magen-Darm-Trakts (MDT) sind haufig Auch wenn die Inzidenz von Kolonkarzinomen und Magenkarzinomen in der Schweiz sinkt, gehoren beide doch zu den haufigsten bosartigen Tumoren In der Schweiz betragt die Mortalitat fur Kolonkarzinome pro Jahr fur Manner 13,8/100000 und 8,26/100000 fur Frauen Die Inzidenz der Magenkarzinome nimmt schon seit langem deutlich ab; die Zahl der Osophaguskarzinome und Dunndarmkarzinome ist in der Schweiz, ahnlich wie in anderen Industriestaaten, relativ gering

Magen-Darm-Trakt

In weitestem Sinne kann jede Gewebsschwellung als Tumor (Geschwulst) bezeichnet werden, so z. B. eine Schwellung, die durch vermehrte Flussigkeitseinlagerung in das Gewebe entsteht. Das klassische Beispiel hierfur ist eine durch einen Insektenstich verursachte Schwellung. Im engeren Sinne wird der Begriff Tumor fur die Neubildung von Gewebe (Neoplasie) verwendet, wobei es sich sowohl um gutartige als auch um bosartige Neubildungen handeln kann. Der Begriff Tumor wird im Folgenden in dieser engeren Bedeutung einer Neubildung verwendet. Wichtig ist zu wissen, dass nicht jeder neoplastische Prozess wie z. B. ein Carcinoma in situ der Cervix uteri unmittelbar als Gewebsschwellung (also Tumor im weiteren Sinne) imponieren muss.

Grundlagen der Tumorbiologie

Im Folgenden werden zusammenfassend diejenigen Zellen und Zellprodukte besprochen, die in allen oder mehreren Organen vorkommen. Am weitesten verbreitet sind die mit dem Blut transportierten Zellen und die Zellen des Stutzgewebes. Daruber hinaus kommen einige Deckzellen wie Plattenepithelien, Zylinderzellen und Flimmerepithelien in mehreren Organsystemen vor und sind deshalb in fast jeder Art von zytologischem Material einmal anzutreffen. Die diagnostische Bedeutung aller dieser fast ubiquitaren Zellen ist meist gering. Sie sind aber in vielen zytologischen Proben ein wichtiger Vergleichsmasstab fur die Beurteilung des Kernchromatins und fur die ungefahre Grosenbestimmung pathologischer Zellen.

Georg Feichter

Papers

Cervix uteri und Vagina

Funktionelle Anatomie der Zelle

Magen-Darm-Trakt

Grundlagen der Tumorbiologie

Häufig vorkommende Zellen und Zellprodukte