PREDICTIVE VALUE OF TOPOISOMERASE II-ALPHA AND OTHER PROGNOSTIC FACTORS FOR EPIRUBICIN CHEMOTHERAPY IN ADVANCED BREAST-CANCER

Although cytotoxic chemotherapy is widely used in advanced breast canc er, there are no powerful predictors for the therapy response. Because topoisomerase II alpha (Topo II alpha) is the molecular target for th e anthracycline class of anti-cancer drugs, we compared the immunocyto chemical assay of Topo II alpha. with other biomarkers in the predicti on of clinical response to Topo II inhibitor chemotherapy Fifty-five p atients with advanced breast cancer were treated with a single cytotox ic drug, Topo Ii-inhibitor, epirubicin (30 mg m(-2) weekly up to 1000 mg m(-2)), as first line cytotoxic chemotherapy. Objective response to treatment was analysed according to UICC criteria. The predictive val ue of Topo II alpha. expression, c-erbB2 oncoprotein, p53 tumour-suppr essor protein, oestrogen (ER) and progesterone receptor (PR), S-phase fraction and DNA ploidy were analysed from representative formalin-fix ed paraffin-embedded primary tumour samples. The proportion of Topo II alpha-positive cells (Topo II alpha index) failed to predict response to epirubicin therapy. Mean Topo II alpha scores in 29 responding pat ients were similar when compared with those with no change in disease progression (n = 13) and those with progressive disease (n=13) (14.9% +/- 11.4% vs 15.5% +/- 7.6% vs 17.3% +/- 13.2%, not significant), Amon g the other biomarkers tested, overexpression of c-erbB2 oncoprotein a nd hormone receptor negativity were significantly associated with poor response. Response rate in patients with c-erbB2-overexpressing tumou rs was 32% compared with 65% in patients with no c-erbB2 overexpressio n (P= 0.0058). Accordingly, the response rate for ER-positive patients was 67% compared with 26% in ER-negative patients (P = 0.0021), Altho ugh both negative ER status and c-erbB2 overexpression are associated with high Topo II alpha expression in breast cancer, step-wise logisti c regression analysis showed that ER and c-erbB2 were associated with therapy response independent of Topo II alpha expression, Histological grade, p53, DNA-ploidy, tumour proliferation rate (S-phase fraction), stage of the disease at diagnosis, age of the patient, previous anti- oestrogen therapy or site of metastasis did not predict the response t o epirubicin therapy, In conclusion, despite extensive in vitro eviden ce, expression of Topo II alpha is unlikely to predict the response to Topo II inhibitor chemotherapy in advanced breast cancer. Among the p rognostic biomarkers, overexpression of c-erbB2 oncogene and negative ER may have predictive value in epirubicin therapy in patients with ad vanced breast cancer.