Comparison of HER-2/neu oncogene amplification detected by fluorescence in situ hybridization in lobular and ductal breast cancer

Background: Abnormal expression of the HER-2/neu oncogene, a tyrosine kinase-type transmembrane growth factor receptor localized to chromosome 17q, has been associated with poor prognosis and the prediction of therapy response in invasive breast cancer. The comparative incidence and significance of HER-2/neu gene amplification for lobular and ductal breast cancer have not been previously characterized. Design: Formalin-fixed, paraffin-embedded primary breast cancer tissue sections from 71 women diagnosed with invasive lobular carcinoma were tested for HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) method using the Ventana unique sequence probe (Ventana Medical Systems, Tucson, AZ). A series of 106 cases of invasive ductal carcinoma was similarly processed and tested. Lymph node status was available for 155 (88%) of the 177 cases and 82 (46%) were lymph node-negative (LN-) and 73 (41 %) were lymph node-positive (LN+). Patients were treated for a mean of 65 months (range 1-169 months). Results: 9 of 71 (13%) cases of lobular cancer featured HER-2/neu gene amplification, whereas 51(48%) of 106 cases of ductal cancer showed amplification (P < 0.0001). On univariate analysis of combined lobular and ductal cases. HER-2/neu gene amplification detected by FISH predicted disease-related death (P < 0.0001). HER-2/neu gene amplification also predicted disease-related death in lobular cases alone (P = 0.003) LN+ lobular cases separately (P = 0.019). and LN- and LN+ ductal cases separately and alone (P < 0.0001). Multivariate analysis of the lobular group alone revealed that LN+ status (P = 0.015) and stage (P = 0.01) were independent predictors of disease-related death, and HER-2/neu gene amplification reached near significance (P = 0.086). In the ductal carcinoma group alone. HER-2/neu gene amplification (P = 0.03), lymph node status (P 0.0001), tumor stage (P = 0.0001). and tumor grade (P = 0.044) were independent predictors of overall disease survival. Conclusions: HER-2/neu gene amplification detected by FISH was identified at a significantly lower rate in lobular compared with ductal breast cancer. HER-21neu gene amplification when present in lobular breast cancer is a significant adverse prognostic factor.