Topoisomerase II-α (topoII) and HER2 amplification in breast cancers and response to preoperative 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.
References (20)
- et al.
Amplification and deletion of Topoisomerase IIα associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer
Am. J. Pathol.
(2000) - et al.
Chromogenic in situ hybridization. A practical alternative for fluorescence in situ hybridization to detect HER-2/neu oncogene amplification in archival breast cancer samples
Am. J. Pathol.
(2000) - et al.
p185, a product of the neu proto-oncogene, is a receptor-like protein associated with tyrosine kinase activity
Moll. Cell. Biol.
(1986) - et al.
Human breast cancercorrelation of relapse and survival with amplification of the HER-2/neu oncogene
Science
(1987) - et al.
Pathologic findings from the National Surgical Adjuvant Breast and Bowel Projectprognostic significance of erbB-2 protein overexpression in primary breast cancer
J. Clin. Oncol.
(1990) - et al.
Prognostic significance of HER-2 oncoprotein expression in breast cancera 30-yr follow-up
J. Clin. Oncol.
(1992) - et al.
erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer
J. Natl. Cancer Inst.
(1998) - et al.
c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer
N. Engl. J. Med.
(1994) - et al.
Isolation of genetic suppressor elements, inducing resistance to topoisomerase II-interactive cytotoxic drugs, from human topoisomerase II cDNA
Proc. Natl. Acad. Sci. USA
(1993) - et al.
Selection of a subpopulation with fewer DNA topoisomerase IIα gene copies in a doxorubicin-resistant cell panel
Br. J. Cancer
(1996)
Cited by (117)
Human epidermal growth factor receptor 2-positive breast cancer: Heat shock protein 90 overexpression, Ki67 proliferative index, and topoisomerase II-α Co-amplification as predictors of pathologic complete response to neoadjuvant chemotherapy with trastuzumab and docetaxel
2015, Clinical Breast CancerCitation Excerpt :Our data do not indicate significant differences in pCR with regard to the TOPO2A co-amplification (Table 3). The majority of available data on TOPO2A amplification refer to its predictive role as a marker of an incremental response to anthracycline-based chemotherapy30-37; few and conflicting evidence is available for its predictive role in patients receiving trastuzumab without anthracyclines. The largest data are reported in the context of the BCIRG006 trial, in which patients with HER2-positive early breast cancer, randomized to receive adjuvant anthracycline-based, with and without trastuzumab, and anthracycline-free chemotherapy with trastuzumab, were tested to screen the effect of TOPO2A co-amplification; according to their results, those patients seem to have no benefit from trastuzumab.38
Topoisomerase II-alfa gene as a predictive marker of response to anthracyclines in breast cancer
2014, Pathology Research and PracticeThe predictive and prognostic significance of pre- and post-treatment topoisomerase IIα in anthracycline-based neoadjuvant chemotherapy for local advanced breast cancer
2013, European Journal of Surgical OncologyCitation Excerpt :Topoisomerase IIα (Topo IIα, Topo) is a critical nuclear DNA-binding enzyme, and the gene that encodes this protein is located on chromosome 17q21, adjacent to the HER-2 gene. A series of studies have indicated that Topo IIα protein expression is a marker for predicting anthracycline activity both in vivo and in vitro, especially when it is co-amplified with HER-2.8–10 However, a recent study has reported that Topo IIα overexpression is lost in some specimens after chemotherapy,11 this may due to the direct effect of anthracyclines.
Molecular Biology in the Breast Clinics—Current status and future perspectives
2021, Indian Journal of Surgical Oncology
- 1
Tel.: +82-2-950-1263; fax: 82-2-3391-4393.