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Originally published as JCO Early Release 10.1200/JCO.2005.02.9264 on May 8 2006 © 2006 American Society of Clinical Oncology.
Topoisomerase II
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendixAuthors' Disclosures of...Author ContributionsREFERENCES |
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(TOP2A) genes has been linked to the effects of anthracyclines. Their role in predicting the outcome of anthracycline-based adjuvant chemotherapy for breast cancer patients has remained controversial. PATIENTS AND METHODS: The present substudy of the Scandinavian Breast Group trial 9401, in which an epirubicin-based regimen (nine courses of tailored and dose-escalated fluorouracil, epirubicin, and cyclophosphamide [FEC]) was compared with three or four courses of standard FEC followed by bone marrow–supported high-dose chemotherapy (cyclophosphamide, thiotepa, and carboplatin), included high-risk breast cancer patients (with eight or more positive axillary lymph nodes or at least five nodes with additional poor prognostic indicators). Amplification of HER-2/neu was determined retrospectively in paraffin-embedded tumor tissue sections by chromogenic in situ hybridization. TOP2A was tested only in HER-2/neu–amplified tumors.
RESULTS: HER-2/neu amplification alone, which was present in 32.7% of the tumors, was a strong prognostic factor for short relapse-free (P = .0034) and overall survival (P = .0008) but showed no direct association with treatment assignment. TOP2A coamplification, which was present in 37% of HER-2/neu–amplified tumors, was associated with better relapse-free survival in patients treated with tailored and dose-escalated FEC (hazard ratio [HR] = 0.45; P = .049). A statistical multivariate Cox's regression analysis confirmed the predictive significance of TOP2A coamplification (HR = 0.30; P = .020) in HER-2/neu–amplified tumors. There was no such association in patients with HER-2/neu–amplified tumors without TOP2A gene amplification.
CONCLUSION: Coamplification of HER-2/neu and TOP2A may define a subgroup of high-risk breast cancer patients who benefit from individually tailored and dose-escalated adjuvant anthracyclines.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendixAuthors' Disclosures of...Author ContributionsREFERENCES |
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The biologic mechanisms that could explain the association between HER-2/neu gene amplification and altered sensitivity to anthracyclines are poorly understood. The protein product of the HER-2/neu oncogene, p185HER2, is a ligandless growth factor receptor not known to interact directly with topoisomerase II inhibitors.11 Although the HER-2/neu oncogene is the putative target gene of amplification at chromosomal region 17q12-q21, the amplicon may also harbor other closely located genes, including topoisomerase II (TOP2A),12 which is the molecular target of topoisomerase II inhibitors.13 The TOP2A gene is frequently either coamplified or deleted in breast cancers with HER-2/neu amplification.14,15 Studies carried out in vitro suggest that cell lines with TOP2A gene amplification overexpress topoisomerase II protein and are more sensitive to doxorubicin than cell lines without TOP2A aberrations or those with TOP2A deletion.15
In this study, we examined the predictive value of HER-2/neu and TOP2A gene amplification by means of chromogenic in situ hybridization (CISH) in high-risk breast cancer patients who received adjuvant anthracycline-intensive chemotherapy (tailored and dose-escalated fluorouracil, epirubicin, and cyclophosphamide [FEC]) or standard-dose FEC combined with bone marrow–supported high-dose chemotherapy (cyclophosphamide, thiotepa, and carboplatin [CTCb]) in a previously reported randomized trial (Scandinavian Breast Group [SBG] trial 9401).16
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendixAuthors' Disclosures of...Author ContributionsREFERENCES |
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Patients randomly assigned to the FEC group received nine courses of tailored and dose-escalated FEC, depending on hematologic toxicity. Six dose levels were used (dose ranges: fluorouracil 300 to 600 mg/m2, epirubicin 38 to 120 mg/m2, and cyclophosphamide 450 to 1,800 mg/m2). Patients assigned to the marrow-supported high-dose chemotherapy group received three courses of FEC (fluorouracil, 600 mg/m2; epirubicin, 60 mg/m2; cyclophosphamide, 600 mg/m2) before harvesting of peripheral-blood stem cells, and some patients also received a fourth cycle of FEC before receiving high-dose chemotherapy with CTCb (cyclophosphamide, 6,000 mg/m2; thiotepa, 500 mg/m2; and carboplatin, 800 mg/m2).16
Both treatment groups underwent locoregional radiotherapy as soon as possible after the last chemotherapy course. All patients were to be administered tamoxifen nonconcurrently with chemotherapy at 20 mg/d for 5 years, irrespective of hormone receptor status. The median follow-up period was 76 months. The SBG 9401 study was approved by the ethics committees of participating centers, with relevant jurisdiction. Of the 525 patients randomly assigned to the trial, archival histologically representative, formalin-fixed and paraffin-embedded tissue samples from the primary tumor or unstained sections were made available for 396 patients (75%).
CISH
Digoxigenin-labeled probes for HER-2/neu and TOP2A were obtained from Zymed Inc (South San Francisco, CA). A chromosome 17 pericentromeric probe (p17H8) was used as a reference probe in cases with an equivocal copy number of HER-2/neu or TOP2A, as previously described.17 The hybridization method has previously been described in detail.17 Hybridization was evaluated with an Olympus BX50 microscope (Olympus, Tokyo, Japan) using a x40 objective. Hybridization of TOP2A was carried out only in samples showing amplification of HER-2/neu. Amplification of HER-2/neu and TOP2A was defined as the presence of six or more copies in more than 30% of nuclei or as the presence of an easily identifiable gene copy cluster, the gene copies of which could not be enumerated. Only morphologically identifiable invasive carcinoma cells were scored. When centromeric data were used to interpret HER-2/neu and TOP2A, a copy number ratio of 2 was used as a cut point. Distinction between TOP2A deletion and unaltered copy number was not made in this study because of the use of single-probe CISH. All analyses were carried out in a blind fashion (ie, without knowledge of the clinical outcome).
Statistical Analysis
Survival analyses were carried out using the Kaplan-Meier estimator of survival and analyzed using log-rank tests. Breast cancer–specific relapse-free survival was calculated from time of random assignment to the first recurrence. All P values are two tailed. A multivariate Cox regression analysis was carried out to examine independent predictive factors in both treatment arms and to study the formal test for interaction between TOP2A status and treatment effect. The interaction test was based on all patients with registered TOP2A data. It included the effect of treatment, TOP2A, and the interaction of treatment and TOP2A. The assumption that respective hazard ratios (HRs) are proportional was tested using Schoenfeld's test.18
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendixAuthors' Disclosures of...Author ContributionsREFERENCES |
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HER-2/neu and Prediction of Difference in Outcome Between Tailored and Dose-Escalated FEC Versus CTCb
We have previously reported statistically significantly fewer breast cancer relapses in the tailored and dose-escalated FEC arm compared with the CTCb arm in the 525 patients in the SBG 9401 study.16 The result was the same among the 391 patients included in this substudy (FEC v CTCb, P = .0293).
The prevalence of HER-2/neu amplification was approximately the same in the FEC and CTCb arms (31.1% and 34.1%, respectively; P = .59, Fisher's exact test; Table 1). The relapse-free and overall survival results after stratification of the study cohort according to amplification of HER-2/neu are shown in Figure 2. Breast cancer relapse-free survival was superior in the tailored FEC arm in both HER-2/neu–amplified and –nonamplified patient cohorts, but the HRs were of the same magnitude in both groups (HR = 0.72, P = .083 and HR = 0.73, P = .20, respectively; Figs 2A and 2B). There was no difference in the overall survival between the tailored FEC and CTCb arms both in the HER-2/neu–amplified (HR = 0.81; P = .29; Fig 2C) and –nonamplified (HR = 1.00; P = .85; Fig 2D) patient cohorts.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendixAuthors' Disclosures of...Author ContributionsREFERENCES |
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protein, providing more target and, thus, better efficacy of topoisomerase II inhibitor drugs.13,15 Retrospective analysis of trial SBG 9401 tumor material allowed us to study the prognostic and predictive value of HER-2/neu and TOP2A amplification in patients randomly assigned to receive adjuvant chemotherapy with either a lower dose of epirubicin (median epirubicin cumulative dose, 181 mg/m2) or a more than four times higher dose of epirubicin (median, 780 mg/m2) used in the tailored and dose-escalated FEC arms, respectively.16 The cumulative cyclophosphamide doses were more similar between the two arms (the median cyclophosphamide doses were 10238 mg/m2 in the tailored and dose-escalated FEC arms, respectively, and 8,400 mg/m2 in the CTCb arm).
The prognostic value of HER-2/neu amplification was highly significant, indicating that even among patients with highest risk of relapse (with extensive nodal involvement), HER-2/neu amplification is associated with a worse clinical outcome, as seen in multiple studies of nonselected patient cohorts.11 In our study, TOP2A amplification showed no prognostic value in the subgroup of HER-2/neu–amplified tumors in an analysis of combined treatment groups. Thus, TOP2A amplification seems to be unrelated to the intrinsic biologic aggressiveness of HER-2/neu–amplified breast tumors.
Our present results in high-risk breast cancer failed to demonstrate a clear therapy-predictive value for HER-2/neu when comparing two dose levels of anthracycline-based adjuvant chemotherapy. With respect to clinical evidence of the predictive value of the HER-2/neu oncogene, retrospective analysis of the clinical National Surgical Adjuvant Breast and Bowel Project trial B11 showed greater responsiveness of HER-2/neu overexpressors to doxorubicin-containing treatment (combination of L-phenylalanine mustard, fluorouracil, and doxorubicin) compared with chemotherapy not including topoisomerase II inhibitors (L-phenylalanine mustard plus fluorouracil).7 Similar but smaller studies have not revealed a clear correlation between HER-2/neu and the response to adjuvant topoisomerase II inhibitor–based chemotherapy.9,10 Our study design resembles that reported by Thor et al,8 who studied HER-2/neu overexpression immunohistochemically and found higher dose levels of doxorubicin more effective in the HER-2/neu–overexpressing subpopulation. However, the difference between our results and those reported by Thor et al8 could be explained by different dose levels of anthracyclines. The dose-intensity and the cumulative dose at the highest anthracycline level used in the Cancer and Leukemia Group B 8541 trial are in the same range as in the CTCb arm of the SBG 9401 study. Current practice in adjuvant anthracycline treatment involves higher dose levels and higher dose-intensity than used in the Cancer and Leukemia Group B 8541 study.21
The main goal of this study was to explore the role of HER-2/neu and TOP2A coamplification as a predictor of efficacy of chemotherapies based on lower and higher doses of epirubicin. Our results favor the hypothesis that TOP2A amplification may be a predictor of efficacy of the tailored and dose-escalated FEC in HER-2/neu–amplified high-risk breast cancer (HR = 0.45). The association was statistically significant (P = .049) despite the fact that HER-2/neu and TOP2A coamplification was found in only a relatively small subgroup of patients (48 of 391 investigated tumors). Furthermore, the difference persisted in a statistical multivariate Cox regression analysis (HR = 0.30; P = .020), suggesting that TOP2A amplification could be directly associated with treatment response in the tailored and dose-escalated FEC arm. Because HER-2/neu and TOP2A coamplification was found only in a subset of patients, it does not seem to be the only explanation for the higher efficacy of tailored and dose-escalated FEC compared with CTCb in the entire trial cohort.
Although TOP2A predicted relapse-free survival in HER-2/neu–positive patients, no clear differences were found in overall survival. One explanation is that patients treated in the CTCb arm had received anthracyclines for the metastatic disease. At the time of the SBG9401 trial, patients usually received anthracyclines as a first-line therapy for metastatic breast cancer, unless the maximal cumulative dose of anthracycline had been used.
There are five published studies concerning TOP2A gene amplification as a marker predicting the efficacy of anthracyclines in breast cancer.10,22-25 In all of these studies, evidence of a predictive value of TOP2A has been reported. Two of these studies have explored the role of TOP2A in an adjuvant setting.10,25 In a study by Di Leo et al,10 no statistically significant interaction was found, but patients with HER-2/neu amplification showed a tendency to have better disease-free survival when treated with an anthracycline-based regimen. Although the study was statistically underpowered to draw strong conclusions, the disease-free survival advantage of anthracyclines compared with cyclophosphamide, methotrexate, and fluorouracil was seen only in the subgroup of HER-2/neu–amplified and TOP2A-amplified tumors, whereas no difference between the two treatment arms was found in HER-2/neu–amplified tumors without TOP2A amplification.10 In a more recent study by Knoop et al,25 predictive value was found both for TOP2A amplification and deletion.
Two small studies have involved the predictive value of TOP2A gene amplification in patients with locally advanced breast cancer.22,23 In both of these studies, the results suggested that the increased efficacy of anthracyclines observed in HER-2/neu–overexpressing tumors was explained by concomitant amplification of the TOP2A gene.22,23 Cardoso et al24 recently reported the highest rate of TOP2A gene amplification in the cohort with a complete response to anthracyclines when treating patients with metastatic breast cancer. These studies concerned exploration of the predictive value of TOP2A in a standard dose level versus no anthracycline setting, whereas we compared chemotherapy regimens with lower and higher epirubicin doses.
Our results provide, for the first time, evidence supporting the role of TOP2A as a useful factor for choosing the most effective dose level of anthracyclines for high-risk breast cancer patients. Tumors with the highest sensitivity to anthracyclines showed the best responses when treated with individually tailored and dose-escalated FEC guided by hematologic toxicity. The high sensitivity of HER-2/neu and TOP2A–coamplified tumors to anthracyclines may also partly explain the better outcome of higher versus lower doses of epirubicin found in several randomized adjuvant studies of patient materials not selected according to any tumor biologic factors.26-28 In general, our results should be seen in the context of future oncologic therapies that will be selected for subgroups of patients based on tumor characteristics, rather than in the context of treating large patient groups with the same type of therapy. The cumulative dose of anthracyclines used in the CTCb arm is in the same range as current treatments using anthracycline and taxane regimens sequentially.29 These results suggest that this may possibly not be the most optimal treatment regimen for high-risk patients with HER-2/neu and TOP2A–coamplified tumors.
This study, as are other published studies exploring the predictive value of HER-2/neu and/or TOP2A, is retrospective, although it was based on a prospective and randomized study.7-10,22-25 However, the value of retrospective subanalyses is that they may be useful for identifying new biomarkers. In an attempt to validate the use of TOP2A as a predictive marker, the next step is to perform a large retrospective meta-analysis of tumor materials from several randomized trials. This might eventually lead to general acceptance of TOP2A as a tool to select the most appropriate anthracycline-based cytotoxic treatment at optimal doses for patients with early breast cancer.
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Appendix |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendixAuthors' Disclosures of...Author ContributionsREFERENCES |
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Authors' Disclosures of Potential Conflicts of Interest |
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Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) 
$100,000 (N/R) Not Required
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Author Contributions |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendixAuthors' Disclosures of...Author ContributionsREFERENCES |
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| Conception and design: Minna Tanner, Jorma Isola, Tom Wiklund, Pirkko Kellokumpu-Lehtinen, Per Malmström, Jonas Bergh Financial support: Minna Tanner, Jorma Isola, Jonas Bergh Administrative support: Jorma Isola, Jonas Bergh Provision of study materials or patients: Tom Wiklund, Björn Erikstein, Pirkko Kellokumpu-Lehtinen, Per Malmström, Nils Wilking, Jonas Bergh Collection and assembly of data: Minna Tanner, Jorma Isola, Tom Wiklund, Björn Erikstein, Pirkko Kellokumpu-Lehtinen, Per Malmström, Nils Wilking, Jonas Nilsson, Jonas Bergh Data analysis and interpretation: Minna Tanner, Jorma Isola, Jonas Nilsson, Jonas Bergh Manuscript writing: Minna Tanner, Jorma Isola, Tom Wiklund, Björn Erikstein, Pirkko Kellokumpu-Lehtinen, Per Malmström, Nils Wilking, Jonas Nilsson, Jonas Bergh Final approval of manuscript: Minna Tanner, Jorma Isola, Tom Wiklund, Björn Erikstein, Pirkko Kellokumpu-Lehtinen, Per Malmström, Nils Wilking, Jonas Nilsson, Jonas Bergh
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ACKNOWLEDGMENTS |
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NOTES |
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Both M.T. and J.I. contributed equally to this work.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAppendixAuthors' Disclosures of...Author ContributionsREFERENCES |
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12. Kauraniemi P, Barlund M, Monni O, et al: New amplified and highly expressed genes discovered in the ERBB2 amplicon in breast cancer by cDNA microarrays. Cancer Res 61:8235-8240, 2001
13. Di Leo A, Isola J: Topoisomerase II alpha as a marker predicting the efficacy of anthracyclines in breast cancer: Are we at the end of the beginning? Clin Breast Cancer 4:179-186, 2003[Medline]
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15. Järvinen TA, Tanner M, Rantanen V, et al: Amplification and deletion of topoisomerase II alpha associate with ErbB-2 amplification and affect sensitivity to the topoisomerase II inhibitor doxorubicin in breast cancer. Am J Pathol 156:839-847, 2000
16. Bergh J, Wiklund T, Erikstein B, et al: Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: A randomised trial—Scandinavian Breast Group 9401 study. Lancet 356:1384-1391, 2000[CrossRef][Medline]
17. Isola J, Tanner M, Forsyth A, et al: Interlaboratory comparison of HER-2 oncogene amplification as detected by chromogenic and fluorescence in situ hybridization. Clin Cancer Res 10:4793-4798, 2004
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19. 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[CrossRef][Medline]
20. Jacobson KK, Morrison LE, Henderson BT, et al: Gene copy mapping of the ERBB2/TOP2A region in breast cancer. Genes Chromosomes Cancer 40:19-31, 2004[CrossRef][Medline]
21. Goldhirsch A, Wood W, Gelber R, et al: Meeting highlights: Updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 21:3357-3365, 2003
22. Coon JS, Marcus E, Gupta-Burt S, et al: Amplification and overexpression of topoisomerase II alpha predict response to anthracycline-based therapy in locally advanced breast cancer. Clin Cancer Res 8:1061-1067, 2002
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24. Cardoso F, Durbecq V, Larsimont D, et al: Correlation between complete response to anthracycline-based chemotherapy and topoisomerase II-alpha gene amplification and protein overexpression in locally advanced/metastatic breast cancer. Int J Oncol 24:201-209, 2004[Medline]
25. 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
26. Coombes RC, Bliss JM, Wils J, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: Results of a randomized trial—The International Collaborative Cancer Group. J Clin Oncol 14:35-45, 1996[Abstract]
27. Piccart MJ, Di Leo A, Beauduin M, et al: Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol 19:3103-3110, 2001
28. Fumoleau P, Kerbrat P, Romestaing P, et al: Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial. J Clin Oncol 21:298-305, 2003
29. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003
Submitted June 5, 2005; accepted January 24, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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Gene Amplification Predicts Favorable Treatment Response to Tailored and Dose-Escalated Anthracycline-Based Adjuvant Chemotherapy in HER-2/neu–Amplified Breast Cancer: Scandinavian Breast Group Trial 9401
