Cyclin a is a novel modulator of tamoxifen treatment in early stage breast cancer

Deregulation of G1-S transition has frequently been observed in various tumours, including human breast cancer, and might well affect outcome of therapy. First choice of treatment of estrogen-receptor positive breast cancer is the anti-estrogen tamoxifen. However, in approximately 30% of these cases. tumour recurs despite treatment. Overexpression of G1-S regulators cyclin D1 or cyclin A has been reported to result in ligand-independent activation of estrogen receptor in vitro, and might therefore, provide a mechanism for failure of tamoxifen treatment. We examined by immunohistochemical staining the effect of deregulation of these, and other cell cycle regulators (cyclin E, p53, p21, p27, Neu, epidermal growth factor receptor, Ki67, estrogen receptor (ER), progesterone receptor (PR), on tamoxifen treatment in a group of 394 patients with early stage breast cancer. In univariate analysis, expression of cyclin A, Neu, high Ki-67 index, and lack of ER expression were significantly associated with worse prognosis. When adjusted by the clinical model (for lymph node status, age, performance status, T-classification, grade, prior surgery, estrogen receptor status and tamoxifen use), only Overexpression of cyclin A and Neu were significantly associated with worse prognosis with hazard ratios of. respectively, 1.709 (p=0.0195) and 1.884 (p= 0.0151). In tamoxifen treated ER-positive tumours, overexpression of cyclin A was the only independent marker associated with a worse prognosis (Hazard Ratio 2.024, p= 0.0462). In conclusion, cyclin A is a novel independent predictor of response to tamoxifen treatment in early stage breast cancer.