Originally published as JCO Early Release 10.1200/JCO.2006.05.9113 on May 8 2006
Journal of Clinical Oncology, Vol 24, No 16 (June 1), 2006: pp. 2409-2411
© 2006 American Society of Clinical Oncology.
Topoisomerase II Gene Amplification and Response to Anthracycline-Containing Adjuvant Chemotherapy in Breast Cancer
Aman U. Buzdar
The University of Texas, M.D. Anderson Cancer Center, Houston, TX
In this issue of the Journal of Clinical Oncology, Tanner et al1 report the therapeutic benefit from tailored and dose-escalated adjuvant anthracycline-based chemotherapy in high-risk breast cancer patients with coamplification of the genes encoding human epidermal growth factor-2 (HER2) and topoisomerase II (TOP2A). Adjuvant chemotherapy can substantially reduce the risk of recurrence and death in high-risk patients with breast cancer,2 and a number of chemotherapy combinations have established efficacy and safety data. Adjuvant chemotherapies can be broadly classified into three groups: cyclophosphamide/methotrexate/fluorouracil (CMF) combinations, anthracycline-based combinations such as doxorubicin or epirubicin, and taxane-containing combinations such as paclitaxel or docetaxel.3,4 In patients with hormone receptor-positive disease, the value of endocrine therapies (ovarian ablation or suppression, antiestrogens, and, more recently, aromatase inhibitors) have been well established also.5,6 The availability of techniques to detect hormone receptors has made it possible to identify the patients who might benefit from endocrine therapies. Patients whose tumors lack hormone receptors do not achieve any benefit from endocrine therapies and are thus treated only with adjuvant chemotherapies.
The value of chemotherapy is established from the data from individual randomized trials and from the Oxford overview's 15-year meta-analyses of randomized chemotherapy trials.5 It is now accepted that anthracycline-containing therapies are superior to CMF combinations. The Oxford overview data showed that anthracycline-based chemotherapies reduce the risk of recurrence by 11% ± 0.03% (± standard error) and reduce the risk of death by 16% ± 0.03% compared with CMF combinations.5 However, anthracycline-containing combinations carry a small risk of cardiac dysfunction.7
At the present time, there are no reliable, validated, predictive biologic markers (like hormone receptors for endocrine therapies) that can guide the selection of an appropriate type of adjuvant chemotherapy. The mechanisms of action of chemotherapy drugs are complex, and these drugs affect a number of cellular pathways.8 In the past two decades, efforts to identify a subset of patients who would benefit from a given type of systemic adjuvant therapy have met with limited success, but these efforts have resulted in a better understanding of the biology of this disease. For example, overexpression of HER2 and TOP2A, which regulate cellular processes, such as replication and transcription,9,10 has been shown in a number of retrospective studies to be associated with poor survival.1,11 Tumors overexpressing HER2 have been shown to respond more favorably to anthracycline-based chemotherapies,12-15 and HER2 has become a standard predictive marker for response to treatment with the humanized monoclonal antibody trastuzumab.16 The HER2 proto-oncogene, which is located on chromosome band 17Q21, is overexpressed or amplified in approximately 15% to 25% of invasive breast cancers.17,18 Tanner et al1 reported that HER2 was amplified in 32.7% of their patients; of those, 37% had coamplification of TOP2A. Data obtained over the past few years have established that TOP2A amplification occurs only in the presence of HER2 amplification in most patients.8 In one series, approximately 8% of HER2-negative patients had changes in TOP2A that would have been overlooked if they had not been specifically investigated.19 The number of patients with TOP2A amplification in the absence of HER2 positivity may be in the range of 1.7 to 10.9%.19
Although HER2 and TOP2A are located on chromosome 17, they are on separate amplicons,20 as supported by the fact that HER2 and TOP2A often have different copy numbers within the same tumor.21 In breast cancer, TOP2A functions as more than just a proliferation marker: topoisomerases in the cell nucleus allow access to the information stored in DNA by regulating cellular processes such as replication and transcription.20,22 Deletion of the TOP2A gene can lead to reduced protein expression and, consequently, possible chemoresistance to topoisomerase inhibitors. The subpopulation of patients in which TOP2A overexpression is induced by gene amplification may be the ones who would benefit from treatment with topoisomerase inhibitors. Tanner et al1 noted that patients who had coamplification of HER2 and TOP2A had better relapse-free survival after nine cycles of tailored dose-escalated anthracycline adjuvant therapy compared with the patients who had only three cycles of anthracycline-based therapy followed by treatment with high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin.
Similarly, in other retrospective studies, patients with topoisomerase II-amplified breast cancer treated with anthracycline-based chemotherapies had superior disease-free survival and overall survival.23 In the Breast Cancer International Research Group 06 study,24 for example, patients with TOP2A overexpression had better disease-free survival after adjuvant therapy with trastuzumab and an anthracycline-containing combination. In addition, some studies found that deletion of TOP2A was also predictive of better outcome, which was in contrast to the experimental data.19 In experimental studies, amplification of TOP2A leads to an overexpression of TOP2A enzyme and increased sensitivity to anthracyclines, and deletion to resistance.8 A decrease in the levels of TOP2A after chemotherapy in patients who had higher pretreatment expression of this molecule may predict a response to anthracycline-based chemotherapy.25 These findings strengthen the concept of TOP2A as a potential marker of chemosensitivity for anthracycline-based treatment. In the neoadjuvant setting, higher levels of TOP2A were predictive of greater pathologic response after anthracycline-based chemotherapy. At this time, the number of patients who have been evaluated in all retrospective studies is too small to determine the impact in that subset of patients. It also remains to be determined whether patients without amplification of TOP2A benefit from anthracycline-containing therapies.
There are a number of issues that need to be addressed before adopting the TOP2A values to determine the type of adjuvant chemotherapy for those patients with TOP2A overexpression. Assessment of TOP2A overexpression by immunohistochemistry, assessment of gene amplification by fluorescence in situ hybridization, chromogenic in situ hybridization have all been associated with favorable response to anthracycline-based chemotherapy.26 Each study has utilized different criteria to define the TOP2A overexpression. However, an appropriate standardization is needed when measuring TOP2A levels using these techniques. In addition, these retrospective studies have utilized varying doses and schedules of anthracycline-containing combinations, and data from earlier prospective trials, escalation of doxorubicin beyond standard doses in adjuvant therapy has not yielded any further reduction in the risk of recurrence.3,27,28 The optimal dose and schedule of anthracycline-containing therapies remain to be defined in patients overexpressing TOP2A. Until then, dose-escalated anthracycline based adjuvant therapy as reported by Tanner et al cannot be recommended as a standard of care. Prospective studies are needed to clearly define the role of TOP2A and determine how HER2-positive tumors, with or without TOP2A overexpression, would respond to anthracycline- and trastuzumab-based adjuvant therapies.
Author's Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
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| Aman U. Buzdar |
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REFERENCES
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