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

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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 (TopoIIα) expression evaluated by immunohistochemistry (IHC), (5) HER-2 and TopoIIα 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/m2, Epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2). Tumour response was assessed clinically and by computed tomography (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-67⩾20% were predictive for a clinical CR. A high tumour grade was predictive for a pathological CR. Overexpression or amplification of HER2 or Topollcα were not predictive of response.

Introduction

As the clinical and pathological responses of breast cancer to neoadjuvant chemotherapy are short-term markers for a long-term outcome 1, 2, it is important to 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 treatment that is known to be ineffective. These factors could also provide mechanistics insights into understanding tumour biology. Recent retrospective studies have suggested a correlation between HER2 overexpression and a benefit from anthracycline therapy 3, 4, but a biological mechanism linking HER2 overexpression to anthracycline sensitivity is lacking. Topoisomerase II alpha (TopoIIα) is localised close to HER2 on chromosome 17 q12-q21 and the enzyme is a molecular target for anthracyclines [5]. Because of the physical proximity to HER2, TopoIIα is frequently co-amplified with HER2 in breast cancer [6]. This co-amplification could provide a plausible explanation for the link between HER2 overexpression and anthracycline response.

In the present study, the role of tumour grade, hormonal receptors (HR), Ki-67, HER-2 and TopoIIα status as predictive markers of response to neoadjuvant anthracycline-based chemotherapy was evaluated in primary tumour specimens from 119 patients with breast carcinomas.

Section snippets

Patient and tumour characteristics

All patients with operable breast cancer and treated between January 2000 and December 2001 at the Paul Strauss Center with neoadjuvant anthracycline-based chemotherapy were included in this retrospective study. Neo-adjuvant chemotherapy was indicated when the largest tumour diameter was equal to or larger than 20 mm. Patients with a primary inflammatory carcinoma or with a long clinical history of neglected tumour in breast were excluded. A microbiopsy was performed before the chemotherapy

Results

119 patients with operable breast cancer were treated with neoadjuvant anthracycline-based chemotherapy at the Paul Strauss Cancer Center between January 2000 and December 2001 (Table 1). All breast cancers were stage IC–IIIA invasive adenocarcinomas.

Discussion

In the present study, 119 patients with stage IC to IIIA invasive adenocarcinomas were treated with six cycles of an anthracycline-based therapy. The clinical OR was 80%, with 19% of CR. The radiological OR was 71%, with 16% of CR. No PD was observed during the chemotherapy. After surgery, a pathological CR was demonstrated in 9% of the patients according to the Chevallier classification and in 13% of the patients according to the Sataloff classification. With a higher kappa value, clinical

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