Skip to main content

Advertisement

SpringerLink
Log in

TOP2A amplification in breast cancer is a predictive marker of anthracycline-based neoadjuvant chemotherapy efficacy

  • Clinical Trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Anthracycline is a DNA topoisomerase 2-α (TOP2A) inhibitor and its concomitant over expression with Human Epidermal Growth Factor Receptor 2 (HER2) was investigated of being predictive for the response to anthracycline-based chemotherapies in breast cancer. 309 early and local advanced breast cancer patients were treated with anthracycline-based neoadjuvant chemotherapies in intense dose dense (IDD) (CE, Cyclophosphamide + Epirubicin) or conventional (TE, Paclitaxel + Epirubicin) regimens. HER2 proteins were qualitatively analyzed by immunohistochemistry (IHC) of primary tumor core biopsies, and TOP2A gene amplification levels of HER2 over-expressing cases were quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Overall pathological complete response rate (pCR) was achieved in 14.3 %. HER2 was over expressed in 80/309 (25.9 %) cases, of which 61/80 cases have been tested for their TOP2A status. Over expression of HER2 was significantly positively correlated with higher pCR rates compared to low HER2 expression (27.5 % vs. 9.6 %, P < 0.001). Concurrent high TOP2A amplification led to a significantly higher pCR rate compared to low or no TOP2A amplification (56.3 % vs. 13.8 %, P = 0.001). HER2 over expression was associated with a significantly higher pCR rate only when TOP2A was also amplified (56.3 % vs. 9.6 %, P < 0.001), but not when it was deleted or normal (13.8 % vs. 9.6 %, P = 0.183) compared to HER2 low-expressing tumors. The interaction between HER2 or TOP2A and anthracycline-based regimen was observed in IDD and conventional neoadjuvant chemotherapies. The TOP2A amplification is related to anthracycline-based neoadjuvant chemotherapy sensitivity, and TOP2A should be included in future studies in breast cancer as a predictive marker.

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

Similar content being viewed by others

References

  1. Pritchard KI, Shepherd LE, O’Malley FP, Andrulis IL, Tu D, Bramwell VH, Levine MN (2006) HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354(20):2103–2111

    Article  PubMed  CAS  Google Scholar 

  2. Colozza M, Bisagni G, Mosconi AM, Gori S, Boni C, Sabbatini R, Frassoldati A, Passalacqua R, Bian AR, Rodino C, Rondini E, Algeri R, Di Sarra S, De Angelis V, Cocconi G, Tonato M (2002) Epirubicin versus CMF as adjuvant therapy for stage I and II breast cancer: a prospective randomised study. Eur J Cancer 38(17):2279–2288

    Article  PubMed  CAS  Google Scholar 

  3. Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG et al (1990) Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8(9):1483–1496

    PubMed  CAS  Google Scholar 

  4. Fisher B, Redmond C, Wickerham DL, Bowman D, Schipper H, Wolmark N, Sass R, Fisher ER, Jochimsen P, Legault-Poisson S et al (1989) Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 7(5):572–582

    PubMed  CAS  Google Scholar 

  5. Dhesy-Thind B, Pritchard KI, Messersmith H, O’Malley F, Elavathil L, Trudeau M (2008) HER2/neu in systemic therapy for women with breast cancer: a systematic review. Breast Cancer Res Treat 109(2):209–229

    Article  PubMed  CAS  Google Scholar 

  6. 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(1):14–20

    Article  PubMed  CAS  Google Scholar 

  7. Jarvinen TA, Tanner M, Rantanen V, Barlund M, Borg A, Grenman S, Isola J (2000) 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 156(3):839–847

    Article  PubMed  CAS  Google Scholar 

  8. 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 IIalpha 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(5):1107–1116

    PubMed  Google Scholar 

  9. 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(10):1207–1214

    PubMed  CAS  Google Scholar 

  10. Knoop AS, Knudsen H, Balslev E, Rasmussen BB, Overgaard J, Nielsen KV, Schonau A, Gunnarsdottir K, Olsen KE, Mouridsen H, Ejlertsen B (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(30):7483–7490

    Article  PubMed  CAS  Google Scholar 

  11. Tanner M, Isola J, Wiklund T, Erikstein B, Kellokumpu-Lehtinen P, Malmstrom P, Wilking N, Nilsson J, Bergh J (2006) Topoisomerase IIalpha 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(16):2428–2436

    Article  PubMed  CAS  Google Scholar 

  12. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365(14):1273–1283

    Article  PubMed  CAS  Google Scholar 

  13. Jarvinen TA, Tanner M, Barlund M, Borg A, Isola J (1999) Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer. Genes Chromosomes Cancer 26(2):142–150

    Article  PubMed  CAS  Google Scholar 

  14. Pritchard KI (2009) Are HER2 and TOP2A useful as prognostic or predictive biomarkers for anthracycline-based adjuvant chemotherapy for breast cancer? J Clin Oncol 27(24):3875–3876

    Article  PubMed  Google Scholar 

  15. Desmedt C, Di Leo A, de Azambuja E, Larsimont D, Haibe-Kains B, Selleslags J, Delaloge S, Duhem C, Kains JP, Carly B, Maerevoet M, Vindevoghel A, Rouas G, Lallemand F, Durbecq V, Cardoso F, Salgado R, Rovere R, Bontempi G, Michiels S, Buyse M, Nogaret JM, Qi Y, Symmans F, Pusztai L, D’Hondt V, Piccart-Gebhart M, Sotiriou C (2011) Multifactorial approach to predicting resistance to anthracyclines. J Clin Oncol 29(12):1578–1586

    Article  PubMed  CAS  Google Scholar 

  16. Romero A, Caldes T, Diaz-Rubio E, Martin M (2012) Topoisomerase 2 alpha: a real predictor of anthracycline efficacy? Clin Transl Oncol 14(3):163–168

    Article  PubMed  CAS  Google Scholar 

  17. Di Leo A, Isola J (2003) 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(3):179–186

    PubMed  Google Scholar 

  18. Hajduk M, Olszewski WP, Smietana A (2009) Evaluation of the predictive value of topoisomerase II alpha in patients with breast carcinoma. Pol J Pathol 60(3):115–123

    PubMed  Google Scholar 

  19. Fountzilas G, Valavanis C, Kotoula V, Eleftheraki AG, Kalogeras KT, Tzaida O, Batistatou A, Kronenwett R, Wirtz RM, Bobos M, Timotheadou E, Soupos N, Pentheroudakis G, Gogas H, Vlachodimitropoulos D, Polychronidou G, Aravantinos G, Koutras A, Christodoulou C, Pectasides D, Arapantoni P (2012) HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy. J Transl Med 10:10

    Article  PubMed  CAS  Google Scholar 

  20. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  PubMed  CAS  Google Scholar 

  21. Konecny GE, Pauletti G, Untch M, Wang HJ, Mobus V, Kuhn W, Thomssen C, Harbeck N, Wang L, Apple S, Janicke 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(2):481–489

    Article  PubMed  CAS  Google Scholar 

  22. Murphy DS, McHardy P, Coutts J, Mallon EA, George WD, Kaye SB, Brown R, Keith WN (1995) Interphase cytogenetic analysis of erbB2 and topoII alpha co-amplification in invasive breast cancer and polysomy of chromosome 17 in ductal carcinoma in situ. Int J Cancer 64(1):18–26

    Article  PubMed  CAS  Google Scholar 

  23. Pegram MD, Finn RS, Arzoo K, Beryt M, Pietras RJ, Slamon DJ (1997) The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 15(5):537–547

    Article  PubMed  CAS  Google Scholar 

  24. Press MF, Sauter G, Buyse M, Bernstein L, Guzman R, Santiago A, Villalobos IE, Eiermann W, Pienkowski T, Martin M, Robert N, Crown J, Bee V, Taupin H, Flom KJ, Tabah-Fisch I, Pauletti G, Lindsay MA, Riva A, Slamon DJ (2012) Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol 29(7):859–867

    Article  Google Scholar 

  25. Konecny GE, Pauletti G, Untch M, Wang HJ, Mobus V, Kuhn W, Thomssen C, Harbeck N, Wang L, Apple S, Janicke F, Slamon DJ (2012) Association between HER2, TOP2A, and response to anthracycline-based preoperative chemotherapy in high-risk primary breast cancer. Breast Cancer Res Treat 120(2):481–489

    Article  Google Scholar 

  26. Del Mastro L, Bruzzi P, Nicolo G, Cavazzini G, Contu A, D’Amico M, Lavarello A, Testore F, Castagneto B, Aitini E, Perdelli L, Bighin C, Rosso R, Venturini M (2005) HER2 expression and efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients. Br J Cancer 93(1):7–14

    Article  PubMed  Google Scholar 

  27. Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M et al (1994) c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330(18):1260–1266

    Article  PubMed  CAS  Google Scholar 

  28. Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC, Barcos M, Cirrincione C, Edgerton S, Allred C, Norton L, Liu ET (1998) erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 90(18):1346–1360

    Article  PubMed  CAS  Google Scholar 

  29. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13(1):25–32

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the patients who participated in this study and their families. We are grateful to the doctors in the Department of Pathology for their technical assistance. National Natural Science Foundation of China (30972934); National Natural Science Foundation of China (81000991).

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 17 Panjiayuannanli, Chaoyang District, Beijing, 100021, China

    Jiayu Wang, Binghe Xu, Peng Yuan, Pin Zhang, Qing Li, Fei Ma & Ying Fan

Authors
  1. Jiayu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Binghe Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peng Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fei Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Binghe Xu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, J., Xu, B., Yuan, P. et al. TOP2A amplification in breast cancer is a predictive marker of anthracycline-based neoadjuvant chemotherapy efficacy. Breast Cancer Res Treat 135, 531–537 (2012). https://doi.org/10.1007/s10549-012-2167-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-012-2167-5

Keywords

Search

Navigation