Topoisomerase IIα Amplification and Anthracycline-Based Chemotherapy: The Jury Is Still Out

Adjuvant anthracycline-based chemotherapy has been shown to improve disease-free survival (DFS) rates and overall survival (OS) rates in women with early-stage breast cancer, irrespective of estrogen receptor, progesterone receptor, and HER2 status. Retrospective studies using banked tumor samples from randomized clinical trials revealed a correlation between HER2 overexpression and benefit from anthracyclines. The largest of these randomized trials were the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-11 and the National Cancer Institute of Canada (NCIC) MA.5 studies. The Cancer and Leukemia Group B (CALGB) 8541 trial showed a significant improvement in DFS and OS rates for women with HER2positive tumors who received doxorubicin at 60 mg/m every 4 weeks (in combination with fluorouracil and cyclophosphamide), which is the current standard dose of doxorubicin. This dose and schedule were more effective than lower doses of the same combination in the HER2-positive subset. Interestingly, NSABP B-11 showed a correlation between HER2 overexpression and improved DFS rate despite using a significantly lower dose of doxorubicin (30 mg/m every 3 weeks). In contrast, Bartlett et al did not find a correlation between HER2 status and increased anthracycline activity in a randomized trial of cyclophoshamide, epirubicin, and fluorouracil (CEF) compared to cyclophosphamide, methotrexate, and fluorouracil (CMF). The concept that HER2-positive tumors are more sensitive to anthracycline-based chemotherapy is interesting. However, preclinical studies do not support a direct role for HER2 in this setting. Pegram et al tested the sensitivity of a panel of cell lines engineered to overexpress HER2 to doxorubicin and compared them to the parental, nontransfected cell lines. In this preclinical study, HER2 overexpression did not confer increased sensitivity to doxorubicin. So, is HER2 a surrogate marker for increased response to anthracyclines or not? Recently, attention has been turned to topoisomerase II (topo II ) as a predictor of response to anthracyclines because its function is inhibited by these agents. The topo II gene is localized on the long arm of chromosome 17, and its proximity to HER2 generated significant interest. Harris et al hypothesized that the increased benefit seen with anthracycline-based chemotherapy in patients with HER2-positive breast cancer who participated in CALGB 8541 was due to topo II amplification. In their correlative science study, the HER2 gene was amplified in 19% of tumors; the topo II gene was amplified in 7% of tumors and deleted in 11% of cases. As expected, there was a strong positive correlation between HER2 and topo II amplification. However, topo II amplification did not predict DFS in patients with HER2-positive tumors. One of the main limitations of this study was the lack of a control group treated with non–anthracycline-containing chemotherapy. The role of topo II as a predictor of response to anthracyclines in the adjuvant setting has been studied in multiple retrospective studies. The NCIC Clinical Trials Group MA.5 trial randomly assigned patients with node-positive breast cancer to CEF or to CMF. In this study, patients with HER2-positive tumors experienced a longer DFS rate if treated with CEF. Topo II amplification or deletion correlated with HER2 positivity and with improved DFS rates in patients treated with CEF. While several publications seem to point in the direction that topo II predicts for anthracycline activity, closer inspection reveals substantial heterogeneity of data. Different assays have been used by different authors: some looked at gene copy number, some at amplification, some at gene deletion, and some at protein expression, so it is unclear which of these various approaches should be used to select therapy. For example, in a randomized trial led by the Danish Breast Cancer Cooperative Group, HER2 expression was not predictive of response to CEF or CMF but topo II amplification or deletion correlated with an improved DFS rate in patients treated with CEF. Furthermore, while gene amplification would fit the hypothesis that increased presence of the target would predict increased benefit from a drug that targets topo II , the association of gene deletion with increased activity is harder to explain biologically. Moreover, with other targets, increased concentration actually predicts reduced activity of the drug (methotrexate, as an example). The predictive role of topo II must be placed in perspective of modern adjuvant systemic therapy. If it is true that HER2-positive tumors are more likely to respond to anthracycline-based chemotherapy, should we exclude anthracyclines from well-established trastuzumab-based regimens? Most patients with HER2-positive tumors are currently considered for trastuzumab-based adjuvant chemotherapy. Because doxorubicin and trastuzumab are both potentially cardiotoxic, a test that could predict benefit from anthracyclines would be clinically useful. The Breast Cancer International Research Group trial 006 randomly assigned more than 3,000 patients with HER2 gene–amplified breast cancer to doxorubicin and cyclophosphamide followed by docetaxel compared with the same regimen plus trastuzumab or a nonanthracycline regimen consisting of docetaxel, carboplatin, and trastuzumab. In this study, both trastuzumab-containing regimens resulted in superior DFS rates compared with doxorubicin and cyclophosphamide followed by docetaxel. Cardiac toxicity was lower in the docetaxel, carboplatin, and trastuzumab group than in the group JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 21 JULY 2

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