THE HER-2 NEU ONCOGENE IN BREAST-CANCER - PROGNOSTIC FACTOR, PREDICTIVE FACTOR, AND TARGET FOR THERAPY/

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase recepto r with extensive homology to the epidermal growth factor receptor. HER -2/neu has been widely studied in breast cancer. In this review, the a ssociation of HER-2/neu gene and protein abnormalities studied by Sout hern 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 encomp assing more than 15,000 patients. The relative advantages of gene ampl ification assays and frozen/fresh tissue immunohistochemistry over par affin 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 ar e also considered. The potential value of HER-2/neu status for the pre diction of response to therapy in breast cancer is presented in the li ght of a series of recently published studies showing a range of impac t on the outcome of patients treated,vith hormonal, cytotoxic, and rad iation therapies. The evidence that HER-2/neu gene and protein abnorma lities in breast cancer predict resistance to tamoxifen therapy and re lative sensitivity to chemotherapy regimens including adriamycin is pr esented. The review will also evaluate the status of serum-based testi ng for circulating the HER-2/neu receptor protein and its ability to p redict disease outcome and therapy response. In the final section, the review will briefly present preliminary data concerning the use of an tibody-based therapies directed against the HER-2/neu protein and thei r potential to become a new modality for breast cancer treatment. The recently presented phase III clinical trial evidence that systemic adm inistration of anti-HER2 antibodies (Herceptin(R)), alone and in combi nation with cytotoxic chemotherapy in patients with HER-2/neu overexpr essing primary tumors, can increase the time to recurrence and overall response rates in metastatic breast cancer is reviewed.