Topoisomerase-IIalpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel

• Published in: Molecular cancer therapeutics 2004-10, Vol.3 (10), p.1207-1214
• Main Authors: Durbecq, Virginie, Paesmans, Marianne, Cardoso, Fatima, Desmedt, Christine, Di Leo, Angelo, Chan, Stephen, Friedrichs, Kay, Pinter, Tamas, Van Belle, Simon, Murray, Elizabeth, Bodrogi, Istvan, Walpole, Euan, Lesperance, Bernard, Korec, Stefan, Crown, John, Simmonds, Peter, Perren, Thimothy J, Leroy, Jean-Yves, Rouas, Ghizlane, Sotiriou, Christos, Piccart, Martine, Larsimont, Denis
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514

Purpose: The predictive value of topoisomerase-IIalpha (topo-II) has been evaluated in advanced breast cancer patients randomly treated with single-agent doxorubicin or docetaxel. Experimental design: Primary tumor samples from patients enrolled in a randomized, phase III clinical trial comparing single- agent doxorubicin (75 mg/m super(2) q3wks) with docetaxel (100 mg/m super(2) q3wks) were collected and topo-II status was evaluated by immunohistochemistry (clone KiS1). Results: Topo-II status was evaluated in 108 samples, 55 (51%) in the doxorubicin arm and 53 (49%) in the docetaxel arm. An increment of 10% in cells expressing topo-II is associated with a statistically significant odds ratio (OR; 95% confidence interval) of 1.09 (1.03-1.15; P = 0.002) for overall response to doxorubicin versus 1.002 (0.94-1.07; P = 0.95) in the docetaxel arm. With increasing topo-II, the favorable OR for overall response to docetaxel compared with doxorubicin decreases to become not significant in patients with topo-II tumor content >10%. In a multivariate analysis, (a) HER-2 status seems positively correlated with overall response to chemotherapy (OR, 2.34; 95% confidence interval, 0.87-6.27; P = 0.09). (b) Overall response to doxorubicin is significantly lower than overall response to docetaxel (OR, 0.17; 95% confidence interval, 0.04-0.64; P = 0.009) but with a significant interaction term for doxorubicin-treated patients with topo-II tumor content >10% (OR, 8.31; 95% confidence interval, 1.86-37.03; P = 0.05). Conclusions: (a) Topo-II overexpression confers a higher probability of response in the doxorubicin arm only. (b) Despite being a small retrospective study, this study is in line with previously reported studies and the hypotheses raised are now being tested in a prospective neoadjuvant trial.