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

Participants: Ana-Cristina Anton, Dr.med., Iasi, Romania; Donatella Beccati, Dott.ssa, Ferrara, Italy; Prabodh Kumar Gupta, M.D., F.I.A.C., Philadelphia, Pennsylvania, U.S.A.; Bjorn M. Hagmar, M.D., Prof. Ph.D., M.I.A.C., Oslo, Norway; Lucrecia T. Illescas, M.D., F.I.A.C., Buenos Aires, Argentina; Julisar Lestadi, M.D., M.I.A.C., Jakarta, Indonesia; Maya K. Lulla, M.D., M.I.A.C., Mumbai, Maharashtra, India; Mehdi A. Manji, Dr., M.I.A.C., Karachi, Pakistan; Rodrigo Prado-Buzeta, M.D., F.I.A.C., Santiago, Chile; Robert G. Pretorius, M.D., Fontana, California, U.S.A.; Guglielmo Ronco, M.D., Turin, Italy; Ulrich G. Schenck, Prof. Dr. med., F.I.A.C., Munich, Germany; Naum A. Shapiro, Prof., M.D., Sc.D., M.I.A.C., Moscow, Republic of Russia; and Alain P. Verhest, M.D., F.I.A.C., Brussels, Belgium.

Task force consensus report on HPV-related changes of the lower female genital tract.

Summary Quantitation in diagnostic pathology serves to improve both diagnostic reliability and the prognosis of various malignant tumors. Unfortunately, flexible, user-friendly, reasonably priced and compatible morphometric systems are hardly available on the market. A modular Apple II PC-based system was therefore developed in-house10. It records stereologic, planimetric and digital image analysis data and calculates secondary parameters. Detailed statistical analyses can be performed, after data transfer, on larger computers. A typical application of diagnostic morphometry is to determine whether, and with which probability a patient with an unclear histopathologic finding can be assigned to one or more groups of patients with known diseases and prognoses. To this end morphometric data of the patient under investigation are compared with other patient data stored in an expert system. This paper describes the concept of an expert system carried out on the Apple II PC system mentioned above and outlines the evaluation procedures. Invariant moments were used to describe nucleus textures. Results obtained from the cytological analysis of pleural effusions demonstrate that with this approach it is possible to differentiate between normal mesothelium, mesothelioma and metastases of adenocarcinomas.

A Simple “Expert System” for Morphometric Evaluation of Cells in Pleural Effusions

Only 0.2-1% of all mammary malignancies are sarcomas of the breast. This study includes 4 cases: 2 osteosarcomas, 1 fibrosarcoma, and 1 malignant undifferentiated stromal sarcoma. The therapy was mastectomy in 3 cases with dissection of axillary lymph nodes and simple mastectomy in one case. One patient demonstrated local recurrence and died. The remaining 3 patients developed neither metastases nor local recurrence. They are still alive after a follow-up period of between 18 months and 17 years. As first-line treatment, wide local excision or simple mastectomy is recommended. Dissection of the axillary lymphatics, adjuvant radiotherapy, or chemotherapy have no established value in the treatment of breast sarcoma. In our 4 cases, flow-cytometric analysis does not always agree with the biological properties of the tumour and the clinical behaviour, in contrast to the results obtained in respect of carcinomas.

[Sarcoma of the breast: what is the contribution of immunohistochemistry and flow cytometry?].

The cystosarcoma phylloides, like the sarcoma, represents 0.3 to 0.9% of all tumors of the breast. The clinical features include two different developments, one phase with increase and the other without. After removal of tumors, there are frequent recurrences. The unique therapy is for that reason to remove the lump with a margin in healthy tissue. The sarcoma of the breast represents only 0.2 to 1% of all mammary malignancies. This study reports four cases, including two osteosarcomas, one fibro- and one malignant fibrous sarcoma. The treatment of choice was mastectomy in three cases with dissection of axillary lymph nodes. The remaining patient was treated by simple mastectomy only. One patient demonstrated local recurrence and died. The remaining three patients developed neither metastases nor local recurrence. They are still alive with periods of observation between 18 months and 17 years. As first-line treatment wide local excision or simple mastectomy is recommended. Dissection of the axillary lymphatics, adjuvant radiotherapy or chemotherapy have no proven value in the treatment of breast sarcoma.

Rare breast tumors

Angiogenic properties have been shown in preinvasive cervical lesions. Our goal was to determine the angiogenesis in cervical intraepithelial neoplasms (CIN), the relationship between microvessel counts, histopathological parameters and the clinical outcome in invasive cervical carcinoma. Comparison of microvessel counts from normal epithelium with that from CIN and invasive carcinoma showed significant increases in pre-cancerous lesions and invasive cancer (p < 0.0001). Microvessel density, assessed by CD31 immunostaining, was found to be associated with the overall survival in women with clinical stage IB cervical carcinoma (p < 0.03). There was a significant association of microvessel density (p < 0.05) with relapse-free survival in patients with regional lymph node metastasis.

Georg Feichter

Papers

Task force consensus report on HPV-related changes of the lower female genital tract.

A Simple “Expert System” for Morphometric Evaluation of Cells in Pleural Effusions

[Sarcoma of the breast: what is the contribution of immunohistochemistry and flow cytometry?].

Rare breast tumors

Association of tumor induced vascularization with clinicopathological parameters in cervical neoplasm.