Skip to main content

Advertisement

SpringerLink
Log in

Tumour Topoisomerase II Alpha Protein Expression and Outcome After Adjuvant Dose-Dense Anthracycline-Based Chemotherapy

  • Research
  • Published:
Pathology & Oncology Research

Abstract

There is a need for the selection of those breast cancers where benefit may be attained from the addition of an anthracycline to the adjuvant chemotherapy. The expression of topoisomerase II alpha (TOP2A) protein in 3 cohorts of breast cancers treated with adjuvant dose-dense anthracycline-based chemotherapy was determined retrospectively. The TOP2A status was analysed in relation with the other standard tumour features and the outcome. TOP2A IHC results were assessable in 106 patients: with a cut-off value of 15%, 48% of the tumours were classified as TOP2A-positive. The expression of TOP2A correlated with that of Ki67 (R = 0.532, p < 0.001) and a high grade (p = 0.04), but did not correlate with the proportion of ER- or PR-positive cells in the tumour. More tumors were TOP2A-negative among the ER- or PR-positive cancers than among the ER/PR-negative cancers (p = 0.021 and p = 0.002, respectively). After a median follow-up time of 64.5 months, 31 relapses (23.5%) and 23 deaths (17.4%) had occurred in 131 patients. The overall survival was longer in the TOP2A-positive cases than in the TOP2A-negative cases. The recurrence-free survival and the overall survival were significantly more favourable in the ER/PR-negative and TOP2A-positive tumours than in other subgroups. In a Cox proportional hazards model, the grade and TOP2A remained significant determinants in the ER/PR-negative subgroup. TOP2A positivity and grade 3 indicated a decrease in the risk of death with HR = 0.211 (95% CI: 0.042–1.05, p = 0.056) and HR = 0.216 (95% CI: 0.047–0.990, p = 0.048), respectively. A higher sensitivity to anthracycline-containing regimens is suggested in ER/PR-negative and TOP2A-positive cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

A:

adriamycin

ADC:

adriamycin (A)-docetaxel (D)-cyclophosphamide (C) chemotherapy study

ATC:

adriamycin (A)-paclitaxel (T)-cyclophosphamide (C) chemotherapy study

C:

cyclophosphamide

CECOG:

Central European Cooperative Oncology Group

D:

docetaxel

ER:

estrogen receptor

FEC:

fluorouracil-epirubicin-cyclophosphamide chemotherapy

FISH:

fluorescence in situ hybridisation

GCSF:

granulocyte colony stimulating factor

IHC:

immunohistochemistry

LVI:

lymphovascular invasion

OS:

overall survival

PR:

progesterone receptor

RFS:

recurrence-free survival

RNA:

ribonucleic acid

T:

paclitaxel

TOP2A:

topoisomerase II alpha

References

  1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717

    Article  Google Scholar 

  2. Slamon D, Eiermann W, Robert N et al (2005) BCIRG 006: 2nd interim analysis phase II randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel positive early (AC®TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 94:S5 [abstr. 1]

    Google Scholar 

  3. Gianni L, Norton L, Wolmark N, Suter TM, Bonadonna G, Hortobagyi GN (2009) Role of anthracyclines int he treatment of early breast cancer. J Clin Oncol 27:4798–4808

    Article  PubMed  Google Scholar 

  4. Gennari A, Sormani MP, Pronzato P, Puntoni M, Colozza M, Pfeffer U, Bruzzi P (2008) HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100:14–20

    Article  PubMed  CAS  Google Scholar 

  5. Pritchard KI, Shepherd LE, O’Malley FP, Andrulis IL, Tu D, Bramwell VH, National Cancer Institute of Canada Clinical Trials Group (2006) HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354:2103–2111

    Article  PubMed  CAS  Google Scholar 

  6. Bartlett JM, Munro A, Cameron DA, Thomas J, Prescott R, Twelves CJ (2008) Type 1 receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial. J Clin Oncol 26:5027–5035

    Article  PubMed  CAS  Google Scholar 

  7. Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L (2005) Breast cancer subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–5685

    Article  PubMed  CAS  Google Scholar 

  8. Di Leo A, Biganzoli L, Claudion W, Licitra S, Pestrin M, Larsimont D (2008) Topoisomerase II alpha as a marker predicting anthracyclines’ activity in early breast cancer patients: ready for the primetime? Eur J Cancer 44:2791–2798

    Article  PubMed  Google Scholar 

  9. Järvinen TA, Liu ET (2003) HER-2/neu and topoisomerase II alpha in breast cancer. Breast Cancer Res Treat 78:299–311

    Article  PubMed  Google Scholar 

  10. Isaacs RJ, Davies SL, Sandri MI, Redwood C, Wells NJ, Hickson ID (1998) Physiological regulation of eukaryotic topoisomerase II. Biochim Biophys Acta 1400:121–137

    PubMed  CAS  Google Scholar 

  11. Nielsen KV, Ejlertsen B, Moller S, Jorgensen JT, Knoop A, Knudsen H, Mouridsen HT (2008) The value of TOP2A gene copy number variation as a biomarker in breast cancer: Update of DBCG trial 89D. Acta Oncol 47:725–734

    Article  PubMed  CAS  Google Scholar 

  12. Di Leo A, Gancberg D, Larsimont D, Tanner M, Jarvinen T, Rouas G, Dolci S, Leroy JY, Paesmans M, Isola J, Piccart MJ (2002) HER-2 amplification and topoisomerase II alpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 8:1107–1116

    PubMed  Google Scholar 

  13. Knoop AS, Knudsen H, Balslev E, Rasmussen BB, Overgaard J, Nielsen KV, Schonau A, Gunnarsdóttir K, Olsen KE, Mouridsen H, Ejlertsen B, Danish Breast Cancer Cooperative Group (2005) 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

    Article  PubMed  CAS  Google Scholar 

  14. O'Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Bramwell VH, Andrulis IL, Pritchard KI (2009) Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 101:644–650

    Article  PubMed  Google Scholar 

  15. Harris LN, Broadwater G, Abu-Khalaf M, Cowan D, Thor AD, Budman D, Cirrincione CT, Berry DA, Winer EP, Hudis CA, Hayes DF, Friedman P, Ellis M, Dressler L (2009) Topoisomerase II{alpha} 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

    Article  PubMed  CAS  Google Scholar 

  16. Arriola E, Rodriguez-Pinilla SM, Lambros MBK, Jones RL, James M, Savage K, Smith IE, Dowsett M, Reis-Filho JS (2007) Topoisomerase II alpha amplification may predict benefit from adjuvant anthracyclines in HER2 positive early breast cancer. Breast Cancer Res Treat 106:181–189

    Article  PubMed  CAS  Google Scholar 

  17. Schindlbeck C, Mayr D, Olivier C, Rack B, Engelstaedter V, Jueckstock J, Jenderek C, Andergassen U, Jeschke U, Friese K (2010) Topoisomerase II alpha expression rather than gene amplification predicts responsiveness of adjuvant anthracycline-based chemotherapy in women with primary breast cancer. J Cancer Res Clin Oncol 136:1029–1037

    Article  PubMed  CAS  Google Scholar 

  18. Tanner M, Isola J, Wiklund T, Erikstein B, Kellokumpu-Lehtinen P, Malmström P, Wilking N, Nilsson J, Bergh J (2006) 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 24:2428–2436

    Article  PubMed  CAS  Google Scholar 

  19. Fritz P, Cabrera CM, Dippon J, Gerteis A, Simon W, Aulitzky WE, van der Kuip H (2005) c-erbB2 and topoisomerase II alpha protein expression independently predict poor survival in primary human breast cancer: a retrospective study. Breast Cancer Res 7:R374–R384

    Article  PubMed  CAS  Google Scholar 

  20. Durbecq V, Desmed C, Paesmans M, Cardoso F, Di Leo A, Mano M, Rouas G, Leroy JY, Sotiriou C, Piccart M, Larsimont D (2004) Correlation between topoisomerase-IIalpha gene amplification and protein expression in HER-2 amplified breast cancer. Int J Oncol 25:1473–1479

    PubMed  CAS  Google Scholar 

  21. Mueller RE, Parkes RK, Andrulis I, O'Malley FP (2004) Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples. Genes Chromosomes Cancer 39:288–297

    Article  PubMed  CAS  Google Scholar 

  22. Callagy G, Pharoah P, Chin SF, Sangan T, Daigo Y, Jackson L, Caldas C (2005) Identification and validation of prognostic markers in breast cancer with the complementary use of array-CGH and tissue microarrays. J Pathol 205:388–396

    Article  PubMed  CAS  Google Scholar 

  23. Brase JC, Schmidt M, Fischbach T, Sültmann H, Bojar H, Koelbl H, Hellwig B, Rahnenführer J, Hengstler JG, Gehrmann MC (2010) ERBB2 and TOP2A in breast cancer: a comprehensive analysis of gene amplification, RNA levels, and protein expression and their influence on prognosis and prediction. Clin Cancer Res 16:2391–2401

    Article  PubMed  CAS  Google Scholar 

  24. Konecny GE, Pauletti G, Untch M, Wang HJ, Möbus V, Kuhn W, Thomssen C, Harbeck N, Wang L, Apple S, Jänicke F, Slamon DJ (2010) Association between HER2, TOP2A, and response to anthracycline-based preoperative chemotherapy in high-risk primary breast cancer. Breast Cancer Res Treat 120:481–489

    Article  PubMed  CAS  Google Scholar 

  25. Durbecq V, Paesmans M, Cardoso F, Desmedt C, Di Leo A, Chan S, Friedrichs K, Pinter T, Van Belle S, Murray E, Bodrogi I, Walpole E, Lesperance B, Korec S, Crown J, Simmonds P, Perren TJ, Leroy JY, Rouas G, Sotiriou C, Piccart M, Larsimont D (2004) Topoisomerase-II alpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Mol Cancer Ther 3:1207–1214

    PubMed  CAS  Google Scholar 

  26. Kahan Z, Uhercsak G, Hajnal-Papp R, Boda K, Thurzo L (2005) Dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy is well tolerated and safe in high-risk early breast cancer. Oncology 68:446–453

    Article  PubMed  CAS  Google Scholar 

  27. Kahán Z, Spanik S, Wagnerova M, Skacel T, Planko B, Fitzthum E, Lindner E, Soldatenkova V, Zielinski CC, Brodowicz T (2008) Feasibility of two dose-dense FEC regimens with growth factor support for adjuvant therapy in patients with early breast cancer: results from a randomised study of the Central European Cooperative Oncology Group (CECOG). Breast Cancer Res Treat 112:557–563

    Article  PubMed  Google Scholar 

  28. Nocito A, Kononen J, Kallioniemi OP, Sauter G (2001) Tissue microarrays (TMAs) for high-throughput molecular pathology research. Int J Cancer 94:1–5

    Article  PubMed  CAS  Google Scholar 

  29. Park K, Kim J, Lim S, Han S (2003) Topoisomerase II-alpha (topoII) and HER2 amplification in breast cancers and response to preoperative doxorubicin chemotherapy. Eur J Cancer 395:631–634

    Article  Google Scholar 

  30. Tubbs R, Barlow WE, Budd GT, Swain E, Porter P, Gown A, Yeh IT, Sledge G, Shapiro C, Ingle J, Haskell C, Albain KS, Livingston R, Hayes DF (2009) Outcome of patients with early-stage breast cancer treated with doxorubicin-based adjuvant chemotherapy as a function of HER2 and TOP2A status. J Clin Oncol 27:3881–3886

    Article  PubMed  CAS  Google Scholar 

  31. Gunnarsdóttir KA, Jensen MB, Zahrieh D, Gelber RD, Knoop A, Bonetti M, Mouridsen H, Ejlertsen B (2010) CEF is superior to CMF for tumours with TOP2A aberrations: a Subpopulation Treatment Effect Pattern Plot (STEPP) analysis on Danish Breast Cancer Cooperative Group Study 89D. Breast Cancer Res Treat 123:163–169

    Article  PubMed  Google Scholar 

  32. Hannemann J, Kristel P, van Tinteren H, Bontenbal M, van Hoesel QG, Smit WM, Nooij MA, Voest EE, van der Wall E, Hupperets P, de Vries EG, Rodenhuis S, van de Vijver MJ (2006) Molecular subtypes of breast cancer and amplification of topoisomerase II alpha: predictive role in dose intensive adjuvant chemotherapy. Br J Cancer 95:1334–1341

    Article  PubMed  CAS  Google Scholar 

  33. Di Leo A, Larsimont D, Gancberg D, Jarvinen T, Beauduin M, Vindevoghel A, Michel J, Focan CH, Ries F, Gobert PH, Closon-Dejardin MT, Dolci S, Rouas G, Paesmans M, Lobelle JP, Isola J, Piccart MJ (2001) HER-2 and topo-isomerase IIalpha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide. Ann Oncol 12:1081–1089

    Article  PubMed  Google Scholar 

  34. Berry DA, Cirrincione C, Henderson IC, Citron ML, Budman DR, Goldstein LJ, Martino S, Perez EA, Muss HB, Norton L, Hudis C, Winer EP (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658–1667

    Article  PubMed  CAS  Google Scholar 

  35. Rody A, Karn T, Ruckhäberle E, Müller V, Gehrmann M, Solbach C, Ahr A, Gätje R, Holtrich U, Kaufmann M (2009) Gene expression of topoisomerase II alpha (TOP2A) by microarray analysis is highly prognostic in estrogen receptor (ER) positive breast cancer. Breast Cancer Res Treat 113:4574–66

    Article  Google Scholar 

  36. Järvinen TA, Kononen J, Pelto-Huikko M, Isola J (1996) Expression of topoisomerase II alpha is associated with rapid cell proliferation, aneuploidy, and c-erbB2 overexpression in breast cancer. Am J Pathol 148:2073–2082

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncotherapy, University of Szeged, Korányi fasor 12, 6720, Szeged, Hungary

    Alíz Nikolényi, Gabriella Uhercsák, Melinda Csenki, László Thurzó & Zsuzsanna Kahán

  2. Department of Pathology, University of Szeged, Szeged, Hungary

    Sándor Hamar & Erika Csörgő

  3. Department of Medical Informatics, University of Szeged, Szeged, Hungary

    Ervin Tánczos

  4. Central European Cooperative Oncology Group, Vienna, Austria

    Thomas Brodowicz

  5. Department of Radiotherapy and Oncology, Oncology Institute, Kosice, Slovakia

    Maria Wagnerova

Authors
  1. Alíz Nikolényi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriella Uhercsák
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melinda Csenki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sándor Hamar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erika Csörgő
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ervin Tánczos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. László Thurzó
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thomas Brodowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria Wagnerova
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zsuzsanna Kahán
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zsuzsanna Kahán.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nikolényi, A., Uhercsák, G., Csenki, M. et al. Tumour Topoisomerase II Alpha Protein Expression and Outcome After Adjuvant Dose-Dense Anthracycline-Based Chemotherapy. Pathol. Oncol. Res. 18, 61–68 (2012). https://doi.org/10.1007/s12253-011-9417-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-011-9417-4

Keywords

Search

Navigation