Genetic alterations in early-onset invasive breast carcinomas: correlation of c-erbB-2 amplification detected by fluorescence in situ hybridization with p53 accumulation and tumor phenotype.

p53 tumor-suppressor gene mutation and p53 protein over-expression have been reported with higher frequency in early-onset breast carcinomas (EOBC). Given the role attributed to normal p53 protein in DNA-repair mechanisms, other somatic genomic alterations would be expected to be associated with this abnormality. Amplification of the c-erbB-2 (HER-2/neu) oncogene and over-expression of the corresponding p185erbB-2 protein have been linked to prognosis and response to therapy in breast cancer. In a retrospective study of 62 formalin-fixed paraffin-embedded invasive EOBC (diagnosed at 35 years or less), the amplification status of the c-erbB-2 gene detected by fluorescence in situ hybridization (FISH) using a unique sequence probe was compared with p53 protein accumulation measured by immunohistochemistry (IHC) and phenotypic features. p185erbB2-protein expression was also detected by immunohistochemistry, together with estrogen-receptor (ER) and progesterone-receptor (PR) expression. The data for a sub-set of 33 node-negative EOBC cases were compared with 70 node-negative tumors diagnosed in women above 36 years of age. Compared with node-negative BC in older women, node-negative EOBC was significantly more likely to feature high grade, high proliferation rate, negative ER and/or PR and p53 over-expression (p < 0.05). A trend toward a higher incidence of c-erbB-2 amplification in EOBC (21% vs. 9%) reached near-significance (p = 0.07). In EOBC, c-erbB-2 amplification and p53 over-expression were not associated with high tumor grade or high cell-proliferation rate, in contrast to the significant associations of these markers in tumors in older women. Abnormalities in tumor markers, including c-erbB-2 gene amplification and p53-protein over-expression, occur at different rates in women with EOBC as compared with BC developing in older women. This finding may reflect a different pathogenesis for EOBC, and warrants further investigation.