Topoisomerase II-α (topoII) and HER2 amplification in breast cancers and response to preoperative doxorubicin chemotherapy

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Abstract

A significant proportion of breast cancers with HER2 amplification have simultaneous amplification of topoisomerase II-α (topoII). Amplification of HER2 and topoII was assayed using a novel chromogenic in situ hybridisation (CISH) method. HER2 and topoII amplification status and the response to preoperative doxorubicin chemotherapy were analysed in 67 locally advanced breast cancer patients. Response to chemotherapy was increased in the cases with coamplification of HER2 and topoII (18/19), whereas the response rate was significantly decreased in the cases without HER2 and topoII amplification (17/36). The 12 cases with HER2 amplification alone showed an intermediate response rate (9/12). The findings of the current study indicate that topoII amplification may play a role in determining chemosensitivity of breast cancers to doxorubicin chemotherapy.

Introduction

The HER2 (erbB2) protein is a 185-kd transmembrane tyrosine kinase and overexpression of HER2 arises from HER2 gene amplification resulting in an increased gene copy number [1]. HER2 amplification has been shown in 20–40% of human breast carcinomas and is associated with a poor clinical outcome, even following systemic chemotherapy 2, 3, 4. Recent studies suggest that HER2 is a useful determinant of response to hormonal or cytotoxic chemotherapy. Data from the Cancer and Leukemia Group B (CALGB) 8869 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-11 have suggested that patients whose tumours overexpress HER2 may derive a preferential benefit from treatment with doxorubicin 5, 6. Doxorubicin is the single most effective drug for breast cancer, targeting topoisomeraseII-α (topoII). TopoII is a key enzyme in DNA replication and the topoII gene is located at chromosome band 17q12-21, close to the HER2 gene. In vitro studies have indicated that sensitivity to topoII inhibitors is dependent on the expression level of topoII in the target cancer cells 7, 8, 9. A significant proportion of breast cancers with HER2 amplification show simultaneous amplification or deletion of topoII10, 11. Amplification of topoII may lead to the overexpression of the topoII protein and ultimately to hypersensitivity to topoII inhibitors [11].

Most HER2 studies have been performed using immunohistochemistry (IHC) which detects HER2 protein overexpression. Measurement of HER2 gene amplification is more accurate since protein overexpression is the result of gene amplification. Fluorescence in situ hybridisation (FISH) allows the assessment of the level of gene amplification and also provides information about the distribution of gene copies in histological sections [12]. A number of reports have verified its accuracy and apparent superiority over IHC in predicting response to trastuzumab in metastatic breast carcinoma 13, 14. The main difficulty for adopting FISH in the clinical setting is the need for additional equipment such as fluorescence microscopy and multiband fluorescence filters. Recently, novel technology to detect the DNA probe has been developed. Chromogenic in situ hybridisation (CISH) uses a simple IHC-like peroxidase reaction [15]. CISH is a promising method to overcome the practical limitations of FISH, although its standardisation has not yet been validated.

In this report, the amplification of HER2 and topoII and the response to doxorubicin chemotherapy was analysed in samples taken from breast cancer patients.

Section snippets

Patients and methods

67 patients with locally advanced breast cancer underwent preoperative chemotherapy between March 1996 and December 2000 at the Inje University Sanggye Paik Hospital. The clinical characteristics of the patients are summarised in Table 1. All patients received four cycles of chemotherapy with doxorubicin prior to their operative treatment. Doxorubicin was administered at 3-weekly intervals at a dose of 50 mg/m2. All patients underwent core needle biopsy (CNB) before the chemotherapy. CISH for

Results

Before the current study, we performed CISH on a tissue array of 188 breast cancers. HER2 was amplified in 43 (23%) and topoII was amplified in 23 tumours (12%). TopoII amplification was significantly associated with HER2 amplification (Table 2).

On the basis of this preliminary result, response to preoperative doxorubicin chemotherapy was analysed according to the amplification status of topoII and HER2 in 67 breast cancers. HER2 was amplified in 31 (46%) and topoII was amplified in 19 tumours

Discussion

The results of the current study indicate that preoperative doxorubicin chemotherapy is highly effective in breast cancers that have coamplification of HER2 and topoII. In contrast, the clinical response was significantly decreased in breast cancers without HER2 and topoII amplification. A number of studies in the adjuvant setting have suggested that anthracycline-based chemotherapy is particularly effective for women with HER2-positive breast cancers 5, 17. The biological mechanism for this

Acknowledgements

This work was supported by a Korea Research Foundation Grant (KRF-2001-041-F00064) for K. Park.

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