Outcome and Human Epithelial Growth Factor Receptor (HER) 1-4 status in invasive breast carcinomas with proliferation indices evaluated using bromodeoxyuridine (BrdU) labelling

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Abstract
We have shown previously that whilst overexpression of HER1, 2 and 3 is associated with poor prognosis in breast cancer, HER4 is associated with a good prognosis. Cell proliferation is a key component of aggressive cancers and is driven by growth factors. In this study bromodeoxyuridine-derived proliferation indices are correlated with clinical outcome and HER1-4 status to further clarify the differing roles for the HER family at a biological level. 78 invasive breast cancers had BrdU in vivo labelling to determine the labelling index (BLI) and the potential tumour doubling time (T pot ). Long term clinical follow up was available for these patients. Using immunohistochemistry we established the HER1-4 status in 55 patients from the BrdU cohort. We demonstrate a significant correlation between high BLI values and breast cancer specific death (p = 0.0174). Low T pot times were also significantly correlated with breast cancer specific death (p = 0.0258). However BLI did not independently predict survival in Cox's multiple regression analysis when combined with other prognostic factors such as size, grade and nodal status. Tumours found to be positive for HER 1, 2 or 3 had significantly (p = 0.041) higher labelling indices, with HER1 also showing significantly higher indices when considered independently (p = 0.024). Conversely HER4 positivity significantly correlated (p = 0.013) with low BLI values in line with previous data associating this receptor with good prognosis tumours. These results support the hypothesis that HER1-3 are associated with driving tumour proliferation whilst HER4 is involved in a non-proliferative or even protective role.

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