Originally published as JCO Early Release 10.1200/JCO.2009.22.6449 on May 26 2009

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

The University of Texas M. D. Anderson Cancer Center, Houston, TX

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.¹ Retrospective studies using banked tumor samples from randomized clinical trials revealed a correlation between HER2 overexpression and benefit from anthracyclines.^2–4 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.^2,3 The Cancer and Leukemia Group B (CALGB) 8541 trial showed a significant improvement in DFS and OS rates for women with HER2-positive tumors who received doxorubicin at 60 mg/m² every 4 weeks (in combination with fluorouracil and cyclophosphamide),⁵ 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/m² every 3 weeks). In contrast, Bartlett et al⁶ 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 al⁷ 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 al⁸ 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.³ 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.⁹ While several publications seem to point in the direction that topo II predicts for anthracycline activity,¹⁰ 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.¹¹ 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.¹² 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 of patients treated with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab. Interestingly, preliminary unpublished results from the BCIRG 006 trial showed a similar DFS rate for patients treated with doxorubicin and cyclophosphamide followed by docetaxel and for patients treated with trastuzumab-containing regimens if the primary tumor coamplified the HER2 and topo II genes.¹² If confirmed, these results would suggest that anthracyclines may be as effective as trastuzumab in HER2-positive breast cancers that carry topo II alterations. However, the report presented by Harris et al⁸ in this issue of Journal of Clinical Oncology does not support the hypothesis that the benefit of standard doses of doxorubicin (called high-dose CAF [cyclophoshamide, doxorubicin, and fluorouracil] in the CALGB trial⁵) are due to topo II amplification. Furthermore, preliminary data from NSABP B-31 actually shows improved outcome for patients with HER2-positive and topo II amplification when treated with AC followed by paclitaxel and trastuzumab, in contrast to BCIRG 006.^2,12 It should be noted that all analyses published to date are retrospective, post hoc, subset analyses. In addition, there is evidence of selective publication bias, with positive studies published, while important negative studies remain unpublished (NSABP B-15 and B-23; N. Wolmark, personal communication, February 2009). These unpublished studies represent up to one third or 40% of all available data and make the results of any meta-analysis much less compelling.

In summary, topo II expression can be used as a prognostic marker. However, currently available evidence does not support the use of topo II gene amplification or deletion to select patients for anthracycline-based chemotherapy in the adjuvant setting. Finding accurate predictors for all drugs (not only anthracyclines) is an important goal and should be pursued, with careful attention to methodology and design, so that the right conclusions are reached in the shortest possible time.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Francisco J. Esteva, Gabriel N. Hortobagyi

Administrative support: Gabriel N. Hortobagyi

Provision of study materials or patients: Gabriel N. Hortobagyi

Collection and assembly of data: Francisco J. Esteva, Gabriel N. Hortobagyi

Data analysis and interpretation: Francisco J. Esteva, Gabriel N. Hortobagyi

Manuscript writing: Francisco J. Esteva, Gabriel N. Hortobagyi

Final approval of manuscript: Francisco J. Esteva, Gabriel N. Hortobagyi

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7. Pegram MD, Finn RS, Arzoo K, et al: The effect of her-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 15:537–547, 1997 2.[CrossRef][Medline]

8. Harris LN, Broadwater G, Abu-Khalaf MM, et al: Topoisomerase II amplification does not predict benefit from dose-intense cyclophosphamide, doxorubicin and fluorouracil therapy in HER2-amplified, early breast cancer: Results of CALGB 8541/150013. J Clin Oncol 27:3430–3436, 2009.[Abstract/Free Full Text]

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11. Knoop AS, Knudsen H, Balslev E, et al: Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 23:7483–7490, 2005.[Abstract/Free Full Text]

12. Slamon D, Eiermann W, Robert N, et al: Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment of HER2-positive early breast cancer patients: Second interim efficacy analysis. Breast Cancer Res Treat 100: 2006 (suppl 1) abstr 52.

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