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Breast Cancer Research and Treatment

, Volume 150, Issue 2, pp 279–288 | Cite as

Predictive role of HER2/neu, topoisomerase-II-alpha, and tissue inhibitor of metalloproteinases (TIMP-1) for response to adjuvant taxane-based chemotherapy in patients with intermediate-risk breast cancer: results from the WSG-AGO EC-Doc trial

  • Ramona ErberEmail author
  • Oleg GluzEmail author
  • Nils Brünner
  • Hans Heinrich Kreipe
  • Enrico Pelz
  • Ronald Kates
  • Annette Bartels
  • Jens Huober
  • Svjetlana Mohrmann
  • Zehra Moustafa
  • Cornelia Liedtke
  • Volker Möbus
  • Doris Augustin
  • Christoph Thomssen
  • Fritz Jänicke
  • Marion Kiechle
  • Walther Kuhn
  • Ulrike Nitz
  • Nadia Harbeck
  • Arndt Hartmann
Preclinical Study

Abstract

Taxane–anthracycline-based adjuvant chemotherapy is standard of care in patients with node-positive breast cancer (BC) but is also associated with severe side effects and significant costs. It is yet unclear, which biomarkers would predict benefit from taxanes and/or general chemoresistance. In this study, we investigate a large cohort of patients with intermediate-risk BC treated within the WSG EC-DOC Trial for the predictive impact of topoisomerase-II-alpha, HER2/neu, and TIMP-1. Tumor tissue was available in a representative cohort of 772 cases of the WSG EC-DOC Trial collective which compared 4xEC-4xDoc versus 6xCEF/CMF. In addition to hormone receptor status and Ki-67, HER2/neu+ and topoisomerase-II-alpha status using fluorescence in situ hybridisation (FISH) and immunohistochemistry, TIMP-1 using immunohistochemistry, and aneuploidy of chromosome 17 using FISH were evaluated and correlated with outcome and taxane benefit. There was significant superiority of EC-Doc over CEF regarding 5-year DFS (90 vs. 80 %, respectively, p = 0.006) particularly in patient subgroups defined by HR+, HER2/neu+, high proliferation (i.e., Ki-67 ≥ 20 %), patient age >50 years old and normal chromosome 17 status, high TIMP-1 and low topoisomerase-II-alpha protein expression. Significant prognostic factors in multivariate analysis were EC-Doc therapy (HR = 0.61; 95 %CI 0.38–0.986), age <50 years old (HR = 1.682; 95 %CI 1.025–2.579), centrally assessed grade 3 (HR = 4.657; 95 %CI 1.809–11.989), and high Ki-67 (HR = 2.232; 95 %CI 1.209–4.121). Interestingly, we observed a significant interaction between treatment arm (EC-Doc vs. CEF) and high topoisomerase-II-alpha protein expression (HR = 0.427; 95 %CI 0.203–0.900) in multivariate interaction analysis. Despite of univariate predictive effect of HER2/neu status among other factors only topoisomerase-II-alpha protein expression was associated with significant benefit from EC-Doc compared to CEF by multivariate interaction analysis.

Keywords

Breast cancer Taxanes Topoisomerase-II-alpha TIMP-1 HER2/neu 

Notes

Acknowledgments

We thank Rudolf Jung for excellent technical assistance. We thank all the patients who took part in the trial and consented to provide their dataand all the investigators for treating the patients and reporting their data. We thank all pathologists who provided tumor blocks to our tumor bank. Our special thanks to D. Hofmann, D. Schindowski, I. Renner, C. Buehne, F. Werner, S. Martens, and K. Riedel for study management; G. Schuett, MD, for medical support. The present work was performed in fulfillment of the requirements for obtaining the degree “Dr. med.” at the Friedrich-Alexander.University Erlangen-Nuremberg (FAU).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Martin M, Pienkowski T, Mackey J et al (2005) Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302–2313CrossRefPubMedGoogle Scholar
  2. 2.
    Roche H, Fumoleau P, Spielmann M et al (2006) Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 trial. J Clin Oncol 24:5664–5671CrossRefPubMedGoogle Scholar
  3. 3.
    Nitz U, Gluz O, Huober J et al (2014) Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression. Ann Oncol 25:1551–1557CrossRefPubMedGoogle Scholar
  4. 4.
    Sorlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci 98:10869–10874CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Hugh J, Hanson J, Cheang MCU et al (2009) Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 27:1168–1176CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Hayes DF, Thor AD, Dressler LG et al (2007) HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 357:1496–1506CrossRefPubMedGoogle Scholar
  7. 7.
    Penault-Llorca F, Andre F, Sagan C et al (2009) Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27:2809–2815CrossRefPubMedGoogle Scholar
  8. 8.
    Goldhirsch A, Winer EP, Coates AS et al (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2013. Ann Oncol 24:2206–2223CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Gennari A, Sormani MP, Pronzato P et al (2008) HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100:14–20CrossRefPubMedGoogle Scholar
  10. 10.
    Paik S, Bryant J, Tan-Chiu E et al (2000) HER2 and choice of adjuvant chemotherapy for invasive breast cancer: national surgical adjuvant breast and bowel project protocol B-15. J Natl Cancer Inst 92:1991–1998CrossRefPubMedGoogle Scholar
  11. 11.
    Pritchard KI, Shepherd LE, O’Malley FP et al (2006) HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354:2103–2111CrossRefPubMedGoogle Scholar
  12. 12.
    Tanner M, Isola J, Wiklund T et al (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 24:2428–2436CrossRefPubMedGoogle Scholar
  13. 13.
    Press MF, Sauter G, Buyse M et al (2011) Alteration of topoisomerase ii–alpha gene in human breast cancer: association With responsiveness to anthracycline-based chemotherapy. J Clin Oncol 29:859–867CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    O’Malley FP, Chia S, Tu D et al (2011) Topoisomerase II alpha protein and responsiveness of breast cancer to adjuvant chemotherapy with CEF compared to CMF in the NCIC CTG randomized MA.5 adjuvant trial. Breast Cancer Res Treat 128:401–409CrossRefPubMedGoogle Scholar
  15. 15.
    Knoop AS, Knudsen H, Balslev E et al (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 23:7483–7490CrossRefPubMedGoogle Scholar
  16. 16.
    Bartlett JMS, Munro AF, Dunn JA et al (2010) Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant trial (NEAT/BR9601). Lancet Oncol 11:266–274CrossRefPubMedGoogle Scholar
  17. 17.
    Pritchard K, Munro A, O’Malley F et al (2012) Chromosome 17 centromere (CEP17) duplication as a predictor of anthracycline response: evidence from the NCIC Clinical Trials Group (NCIC CTG) MA.5 trial. Breast Cancer Res Treat 131:541–551CrossRefPubMedGoogle Scholar
  18. 18.
    Leo AD, Desmedt C, Bartlett JMS et al (2011) HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data. Lancet Oncol 12:1134–1142CrossRefPubMedGoogle Scholar
  19. 19.
    Ejlertsen B, Jensen M-B, Nielsen KV et al (2010) HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline-containing chemotherapy in high-risk breast cancer patients. J Clin Oncol 28:984–990CrossRefPubMedGoogle Scholar
  20. 20.
    Munro A, Bartels A, Balslev E et al (2013) Is TIMP-1 immunoreactivity alone or in combination with other markers a predictor of benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial? Breast Cancer Res 15:R31CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    McShane LM, Altman DG, Sauerbrei W et al (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97:1180–1184CrossRefPubMedGoogle Scholar
  22. 22.
    Elston CW (1991) EI: pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403–410CrossRefPubMedGoogle Scholar
  23. 23.
    Klopocki E, Kristiansen G, Wild P, Klaman I, Castanos-Velez E, Singer G, Stöhr R, Simon R, Sauter G, Leibiger H, Essers L, Weber B, Hermann K, Rosenthal A, Hartmann A, Dahl E (2004) Loss of SFRP1 is associated with breast cancer progression and poor prognosis in early stage tumors. Int J Oncol 25:641–649PubMedGoogle Scholar
  24. 24.
    Sassen A, Rochon J, Wild P et al (2008) Cytogenetic analysis of HER1/EGFR, HER2, HER3 and HER4 in 278 breast cancer patients. Breast Cancer Res 10:R2CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Wolff AC, Hammond MEH, Hicks DG et al (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol 31(31):3997–4013CrossRefPubMedGoogle Scholar
  26. 26.
    Watters AD, Going JJ, Cooke TG et al (2003) Chromosome 17 aneusomy is associated with poor prognostic factors in invasive breast carcinoma. Breast Cancer Res Treat 77:109–114CrossRefPubMedGoogle Scholar
  27. 27.
    Early Breast Cancer Trialists’ Collaborative (2012) G: comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 379:432–444CrossRefGoogle Scholar
  28. 28.
    Brase JC, Schmidt M, Fischbach T et al (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 16:2391–2401CrossRefPubMedGoogle Scholar
  29. 29.
    Dumontet C, Krajewska M, Treilleux I et al (2010) BCIRG 001 molecular analysis: prognostic factors in node-positive breast Cancer patients receiving adjuvant chemotherapy. Clin Cancer Res 16:3988–3997CrossRefPubMedGoogle Scholar
  30. 30.
    Fountzilas G, Dafni U, Bobos M et al (2013) Evaluation of the prognostic role of centromere 17 gain and HER2/topoisomerase II alpha gene status and protein expression in patients with breast cancer treated with anthracycline-containing adjuvant chemotherapy: pooled analysis of two Hellenic Cooperative Oncology Group (HeCOG) phase III trials. BMC Cancer 13:163. doi: 10.1186/1471-2407-13-163 CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Rody A, Karn T, Ruckhäberle E et al (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 113:457–466CrossRefPubMedGoogle Scholar
  32. 32.
    Sparano JA, Goldstein LJ, Childs BH et al (2009) Relationship between topoisomerase 2A RNA expression and recurrence after adjuvant chemotherapy for breast cancer. Clin Cancer Res 15:7693–7700CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Jacquemier J, Boher J-M, Roche H et al (2011) Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC—PACS 01 randomized trial. Breast Cancer Res 13:R109CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Milde-Langosch K, Karn T, Müller V et al (2013) Validity of the proliferation markers Ki67, TOP2A, and RacGAP1 in molecular subgroups of breast cancer. Breast Cancer Res Treat 137:57–67CrossRefPubMedGoogle Scholar
  35. 35.
    Krishnamurti U, Hammers JL, Atem FD et al (2009) Poor prognostic significance of unamplified chromosome 17 polysomy in invasive breast carcinoma. Mod Pathol 22:1044–1048CrossRefPubMedGoogle Scholar
  36. 36.
    Di Leo A, Chan S, Paesmans M et al (2004) HER-2/neu as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Breast Cancer Res Treat 86:197–206CrossRefPubMedGoogle Scholar
  37. 37.
    Martin M, Romero A, Cheang M et al (2011) Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer. Breast Cancer Res Treat 128:127–136CrossRefPubMedGoogle Scholar
  38. 38.
    Jones S, Holmes FA, O’Shaughnessy J et al (2009) Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US oncology research trial 9735. J Clin Oncol 27:1177–1183CrossRefPubMedGoogle Scholar
  39. 39.
    Durbecq V, Paesmans M, Cardoso F et al (2004) Topoisomerase-IIα 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 3:1207–1214PubMedGoogle Scholar
  40. 40.
    Martin M, Romero A, Lopez Garcia-Asenjo J et al (2010) Molecular and genomic predictors of response to single-agent doxorubicin (ADR) versus single-agent docetaxel (DOC) in primary breast cancer (PBC). J Clin Oncol (Meeting Abstracts) 28:502Google Scholar
  41. 41.
    Rody A, Karn T, Gätje R et al (2007) Gene expression profiling of breast cancer patients treated with docetaxel, doxorubicin, and cyclophosphamide within the GEPARTRIO trial: HER-2, but not topoisomerase II alpha and microtubule-associated protein tau, is highly predictive of tumor response. Breast 16:86–93CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ramona Erber
    • 1
    Email author
  • Oleg Gluz
    • 2
    • 3
    Email author
  • Nils Brünner
    • 4
  • Hans Heinrich Kreipe
    • 5
  • Enrico Pelz
    • 6
  • Ronald Kates
    • 2
  • Annette Bartels
    • 4
  • Jens Huober
    • 7
    • 8
  • Svjetlana Mohrmann
    • 9
  • Zehra Moustafa
    • 2
  • Cornelia Liedtke
    • 10
  • Volker Möbus
    • 11
  • Doris Augustin
    • 12
  • Christoph Thomssen
    • 13
  • Fritz Jänicke
    • 14
  • Marion Kiechle
    • 15
  • Walther Kuhn
    • 16
  • Ulrike Nitz
    • 2
    • 3
    • 9
  • Nadia Harbeck
    • 2
    • 17
  • Arndt Hartmann
    • 1
  1. 1.Institute of PathologyUniversity Erlangen-NürnbergErlangenGermany
  2. 2.West German Study GroupMönchengladbachGermany
  3. 3.Breast Center NiederrheinEv. Bethesda HospitalMoenchengladbachGermany
  4. 4.Section of Molecular Disease Biology, Faculty of Health and Medical Sciences, Institute of Veterinary Disease BiologyUniversity of CopenhagenCopenhagenDenmark
  5. 5.Institute of PathologyHannover Medical SchoolHannoverGermany
  6. 6.Institute of PathologyViersenGermany
  7. 7.Department of Obstetrics and GynecologyUniversity Clinics TuebingenTūebingenGermany
  8. 8.Department of Obstetrics and GynecologyUniversity Clinics UlmUlmGermany
  9. 9.Department of Obstetrics and GynecologyUniversity Clinics DüsseldorfDūsseldorfGermany
  10. 10.Department of Obstetrics and GynecologyUniversity Clinics Schleswig-HolstenLūbeckGermany
  11. 11.Department of Obstetrics and GynecologyStaedtisches KlinikumFrankfurtGermany
  12. 12.Clinics Deggendorf Mammacenter OstbayernDeggendorfGermany
  13. 13.Department of GynecologyMartin-Luther-University Halle-WittenbergHalle/SaaleGermany
  14. 14.Department of GynecologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  15. 15.Department of Obstetrics and GynecologyTechnical University Clinics Rechts der Isar MunichMunichGermany
  16. 16.Department of Obstetrics and GynecologyUniversity Clinics BonnBonnGermany
  17. 17.Breast CenterLudwig Maximilian University of MunichMunichGermany

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