Comparative value of tumour grade, hormonal receptors, Ki-67, HER-2 and topoisomerase II alpha status as predictive markers in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy T. Petit a, *,M.Wilt b , M. Velten c , R. Millon d , J.-F. Rodier e , C. Borel a , R. Mors a ,P.Haegele´ a ,M.Eber d , J.-P. Ghnassia b a Department of Medical Oncology, Centre de Lutte Contre le Cancer Paul Strauss, 3 rue de la Porte de l’Ho ˆpital, 67065 Strasbourg Cedex, France b Department of Pathology, Centre de Lutte Contre le Cancer Paul Strauss, Strasbourg, France c Department of Biostatistics, Centre de Lutte Contre le Cancer Paul Strauss, Strasbourg, France d Department of Molecular Biology, Centre de Lutte Contre le Cancer Paul Strauss, Strasbourg, France e Department of Surgical Oncology, Centre de Lutte Contre le Cancer Paul Strauss, Strasbourg, France Received 19 May 2003; received in revised form 24 June 2003; accepted 31 July 2003 Abstract The aim of this study was to evaluate the predictive value of five different biological factors in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy: (1) tumour grade scored according to the Elston–Ellis classification, (2) hormonal receptor (HR) status; (3) tumour cell proliferation evaluated by Ki-67 staining, (4) HER-2 and topoisomerase II alpha (TopoIIa) expression evaluated by immunohistochemistry (IHC), (5) HER-2 and TopoII amplification evaluated by real-time polymerase chain reaction (PCR). 119 patients with operable breast cancer were treated with six cycles of FEC (100 5-fluorouracil (5-FU) 500 mg/m 2 , Epirubicin 100 mg/m 2 , Cyclophosphamide 500 mg/m 2 ). Tumour response was assessed clinically and by computed tomo- graphy (CT) scan, then by pathological assessment. The clinical overall response (OR) was 80%, with 19% of complete responders (CR). The radiological OR was 71%, with 16% of CR. A pathological CR was demonstrated in 13% of the patients according to the Sataloff classification. In the multivariate analysis, the absence of HR expression and Ki-67520% were predictive for a clinical CR. A high tumour grade was predictive for a pathological CR. Overexpression or amplification of HER2 or Topollc were not predictive of response. # 2003 Elsevier Ltd. All rights reserved. Keywords: Breast cancer; Neoadjuvant chemotherapy; Predictive factors 1. Introduction As the clinical and pathological responses of breast cancer to neoadjuvant chemotherapy are short-term markersforalong-termoutcome [1,2],itisimportantto identify accurately biological factors that may predict the response to neoadjuvant therapy. These factors should identify patients who will benefit most from treatment, and spare patients from the toxicity of treat- mentthatisknowntobeineffective.Thesefactorscould also provide mechanistics insights into understanding tumour biology. Recent retrospective studies have sug- gested a correlation between HER2 overexpression and a benefit from anthracycline therapy [3,4], but a biolo- gical mechanism linking HER2 overexpression to anthracycline sensitivity is lacking. Topoisomerase II alpha (TopoII) is localised close to HER2 on chromo- some 17 q12-q21 and the enzyme is a molecular target for anthracyclines [5]. Because of the physical proximity to HER2, TopoII is frequently co-amplified with HER2 in breast cancer [6]. This co-amplification could 0959-8049/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0959-8049(03)00675-0 European Journal of Cancer 40 (2004) 205–211 www.ejconline.com * Corresponding author. Tel.: +33-3-8825-2424; fax: +33-3-8825- 2448. E-mail address: tpetit@strasbourg.fnclcc.fr (T. Petit).