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Topoisomerase 2 Alpha and the Case for Individualized Breast Cancer Therapy

  • Breast Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Many patients with breast cancer receive no benefit from their treatment. This has led to a search for novel therapeutic targets whose identification may facilitate a more tailored approach, thereby avoiding unnecessary toxicity. Of these, topoisomerase 2 alpha (TOP2A), located at the HER2/neu amplicon on chromosome 17, has generated particular interest because its expression has been shown to correlate with response to anthracycline-based therapies.

Methods

We evaluated the relationship between TOP2A and its collocated gene, HER2/neu, and summarized the evidence for and against confining anthracycline-based therapies to those patients who demonstrate increased expression or amplification of these targets.

Results

The emerging consensus supports the restriction of anthracyclines to those patients who are HER2/neu positive, with the evidence suggesting that alterations in the status of TOP2A are almost completely restricted to this group of patients.

Conclusions

It seems increasingly likely that response to anthracyclines is predicated on these alterations.

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References

  1. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(19):10869–74.

    Article  CAS  PubMed  Google Scholar 

  2. Clarke R, Liu MC, Bouker KB, et al. Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene. 2003;22:7316–39.

    Article  CAS  PubMed  Google Scholar 

  3. Jansen M, Foekens JA, van Staveren IL, et al. Molecular classification of tamoxifen-resistant breast carcinomas by gene expression profiling. J Clin Oncol. 2005;23:732–40.

    Article  CAS  PubMed  Google Scholar 

  4. Gennari A, Pronzato P. New understanding of the role of anthracyclines in early-stage breast cancer: patient selection considerations. Clin Breast Cancer. 2008;8(Suppl 4):S179–83.

    Article  CAS  PubMed  Google Scholar 

  5. Thor AD, Berry DA, Budman DR, et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst. 1998;90:1346–60.

    Article  CAS  PubMed  Google Scholar 

  6. Paik SM, Bryant J, Park CH, 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;90:1361–70.

    Article  CAS  PubMed  Google Scholar 

  7. Pritchard KI, Shepherd LE, O’Malley FP, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med. 2006;354:2103–11.

    Article  CAS  PubMed  Google Scholar 

  8. Abe O, Abe R, Enomoto K, et al. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet. 1998;352:930–42.

    Article  Google Scholar 

  9. Tanner M, Isola J, Wiklund T, et al. Topoisomerase II alpha 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. J Clin Oncol. 2006;24:2428–36.

    Article  CAS  PubMed  Google Scholar 

  10. Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst. 2008;100:14–20.

    Article  CAS  PubMed  Google Scholar 

  11. Jarvinen TA, Tanner M, Barlund M, Borg A, Isola J. Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer. Genes Chromosomes Cancer. 1999;26:142–50.

    Article  CAS  PubMed  Google Scholar 

  12. Jarvinen TA, Tanner M, Rantanen V, et al. Amplification and deletion of topoisomerase IIalpha associate with ErbB-2 amplification and affect sensitivity to topoisomerase II inhibitor doxorubicin in breast cancer. Am J Pathol. 2000;156:839–47.

    CAS  PubMed  Google Scholar 

  13. Mueller RE, Parkes RK, Andrulis I, O’Malley FP. Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples. Genes Chromosomes Cancer. 2004;39:288–97.

    Article  CAS  PubMed  Google Scholar 

  14. Bhargava R, Lal P, Chen B. HER-2/neu and topoisomerase IIa gene amplification and protein expression in invasive breast carcinomas: chromogenic in situ hybridization and immunohistochemical analyses. Am J Clin Pathol. 2005;123:889–95.

    Article  CAS  PubMed  Google Scholar 

  15. 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. 2002;8:1061–7.

    CAS  PubMed  Google Scholar 

  16. Arriola E, Rodriguez-Pinilla SM, Lambros MBK, et al. Topoisomerase II alpha amplification may predict benefit from adjuvant anthracyclines in HER2 positive early breast cancer. Breast Cancer Res Treat. 2007;106:181–9.

    Article  CAS  PubMed  Google Scholar 

  17. Beser AR, Tuzlali S, Guzey D, et al. HER-2, TOP2A and chromosome 17 alterations in breast cancer. Pathol Oncol Res. 2007;13:180–5.

    Article  PubMed  Google Scholar 

  18. Bofin AM, Ytterhus B, Hagmar BM. TOP2A and HER-2 gene amplification in fine needle aspirates from breast carcinomas. Cytopathology. 2003;14:314–9.

    Article  CAS  PubMed  Google Scholar 

  19. 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. 2005;23:7483–90. [Erratum appears in J Clin Oncol. 2006;24:1015].

    Google Scholar 

  20. Orlando L, Del Curto B, Gandini S, et al. Topoisomerase IIalpha gene status and prediction of pathological complete remission after anthracycline-based neoadjuvant chemotherapy in endocrine non-responsive Her2/neu-positive breast cancer. Breast. 2008;17:506–11.

    Article  PubMed  Google Scholar 

  21. Murphy DS, McHardy P, Coutts J, et al. Interphase cytogenetic analysis of ERBB2 and TOPOII-alpha coamplification in invasive breast-cancer and polysomy of chromosome-17 in ductal carcinoma in-situ. Int J Cancer. 1995;64:18–26.

    Article  CAS  PubMed  Google Scholar 

  22. Hicks DG, Yoder BJ, Pettay J, et al. The incidence of topoisomerase II-alpha genomic alterations in adenocarcinoma of the breast and their relationship to human epidermal growth factor receptor-2 gene amplification: a fluorescence in situ hybridization study. Hum Pathol. 2005;36:348–56.

    Article  CAS  PubMed  Google Scholar 

  23. O’Malley FP, Chia S, Tu D, et al. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst. 2009;101:644–50.

    Article  PubMed  Google Scholar 

  24. Bartlett JMS, Munro A, Cameron DA, et al. Type 1 receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial. J Clin Oncol. 2008;26:5027–35.

    Article  CAS  PubMed  Google Scholar 

  25. Usha L, Tabesh B, Morrison LE, et al. Topoisomerase II alpha gene copy loss has adverse prognostic significance in ERBB2-amplified breast cancer: a retrospective study of paraffin-embedded tumor specimens and medical charts. J Haemat Oncol. 2008;1.

  26. Withoff S, deJong S, deVries EGE, Mulder NH. Human DNA topoisomerase 2. Biochemistry and role in chemotherapy resistance (review). Anticancer Res. 1996;16:1867–80.

    CAS  PubMed  Google Scholar 

  27. Park K, Kim J, Lim S, Han S. Topoisomerase II-alpha (topoII) and HER2 amplification in breast cancers and response to preoperative doxorubicin chemotherapy. Eur J Cancer. 2003;39:631–4.

    Article  CAS  PubMed  Google Scholar 

  28. 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. 2000;356:1384–91.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, National University of Ireland, Galway, Clinical Science Institute, Costello Road, Galway, Ireland

    Ronan W. Glynn MBCHB, Nicola Miller PhD, Maria C. Whelan MD & Michael J. Kerin MD

Authors
  1. Ronan W. Glynn MBCHB
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  2. Nicola Miller PhD
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  3. Maria C. Whelan MD
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  4. Michael J. Kerin MD
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Correspondence to Nicola Miller PhD.

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Glynn, R.W., Miller, N., Whelan, M.C. et al. Topoisomerase 2 Alpha and the Case for Individualized Breast Cancer Therapy. Ann Surg Oncol 17, 1392–1397 (2010). https://doi.org/10.1245/s10434-009-0855-0

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  • DOI: https://doi.org/10.1245/s10434-009-0855-0

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