FISH detection of HER-2/neu oncogene amplification in early onset breast cancer

HER-2/neu (c-erbB-2) gene amplification based on Southern blotting or immunohistochemistry has been shown to be predictive of poor outcome in breast cancer occurring in women over 40, but there is little data on the role of HER-2/neu in young women with breast cancer, many of whom may have inherited BRCA1 or other predisposing genes. The present study used fluorescent in situ hybridization (FISH) on archival specimens of breast cancer from 37 women under the age of 40 to evaluate the role of HER-2/neu amplification in this cohort, and to also evaluate the efficacy of FISH for quantifying amplification. The frequency of primary tumors with a greater than fourfold increase in gene copy number was found to be 38%, which is similar to the frequency of amplification reported in Southern blot studies in older women. However, the greater sensitivity of FISH enabled detection of low level amplification (more than 2 but less than 8 gene copies), which was found in an additional 30% of the tumors. Patients with low level amplification demonstrated a 54% recurrence rate, compared to 86% in those with high amplification and 17% in those with no amplification. HER-2/neu amplification appeared to be more prognostic of recurrence than nodal status, with 45% of node negative tumors recurring compared to 62% of those which were node positive, nor was tumor size predictive of recurrence in this cohort since tumors of 2 cm or less recurred in 44% of cases compared to 57% of those larger than 2 cm. Thus, this study demonstrates that FISH is a reproducible and sensitive technique for detecting HER-2/neu amplification, and that amplification of the oncogene is the strongest independent indicator of recurrence of breast cancer in young women.