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Open Access Research article

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

George Fountzilas1*, Urania Dafni2, Mattheos Bobos3, Vassiliki Kotoula4, Anna Batistatou5, Ioannis Xanthakis1, Christos Papadimitriou6, Ioannis Kostopoulos4, Triantafillia Koletsa4, Eleftheria Tsolaki3, Despina Televantou3, Eleni Timotheadou1, Angelos Koutras7, George Klouvas8, Epaminontas Samantas9, Nikolaos Pisanidis10, Charisios Karanikiotis11, Ioanna Sfakianaki1, Nicholas Pavlidis12, Helen Gogas13, Helena Linardou14, Konstantine T Kalogeras115, Dimitrios Pectasides16 and Meletios A Dimopoulos6

  • * Corresponding author: George Fountzilas fountzil@auth.gr

  • † Equal contributors

Author Affiliations

1 Department of Medical Oncology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

2 Laboratory of Biostatistics, University of Athens School of Nursing, Athens, Greece

3 Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

4 Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

5 Department of Pathology, Ioannina University Hospital, Ioannina, Greece

6 Department of Clinical Therapeutics, “Alexandra” Hospital, University of Athens School of Medicine, Athens, Greece

7 Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece

8 Second Department of Medical Oncology, “Metropolitan” Hospital, Athens, Greece

9 Third Department of Medical Oncology, “Agii Anargiri”, Cancer Hospital, Athens, Greece

10 Department of Medical Oncology, IKA Hospital, Thessaloniki, Greece

11 Department of Medical Oncology, 424 Army General Hospital, Thessaloniki, Greece

12 Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

13 First Department of Medicine, “Laiko” General Hospital, University of Athens School of Medicine, Athens, Greece

14 First Department of Medical Oncology, “Metropolitan” Hospital, Athens, Greece

15 Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece

16 Oncology Section, Second Department of Internal Medicine, “Hippokration” Hospital, Athens, Greece

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BMC Cancer 2013, 13:163  doi:10.1186/1471-2407-13-163

Published: 28 March 2013

Abstract

Background

The HER2 gene has been established as a valid biological marker for the treatment of breast cancer patients with trastuzumab and probably other agents, such as paclitaxel and anthracyclines. The TOP2A gene has been associated with response to anthracyclines. Limited information exists on the relationship of HER2/TOP2A gene status in the presence of centromere 17 (CEP17) gain with outcome of patients treated with anthracycline-containing adjuvant chemotherapy.

Methods

Formalin-fixed paraffin-embedded tumor tissue samples from 1031 patients with high-risk operable breast cancer, enrolled in two consecutive phase III trials, were assessed in a central laboratory by fluorescence in situ hybridization for HER2/TOP2A gene amplification and CEP17 gain (CEP17 probe). Amplification of HER2 and TOP2A were defined as a gene/CEP17 ratio of >2.2 and ≥2.0, respectively, or gene copy number higher than 6. Additionally, HER2, TopoIIa, ER/PgR and Ki67 protein expression was assessed by immunohistochemistry (IHC) and patients were classified according to their IHC phenotype. Treatment consisted of epirubicin-based adjuvant chemotherapy followed by hormonal therapy and radiation, as indicated.

Results

HER2 amplification was found in 23.7% of the patients and TOP2A amplification in 10.1%. In total, 41.8% of HER2-amplified tumors demonstrated TOP2A co-amplification. The median (range) of HER2, TOP2A and CEP17 gain was 2.55 (0.70-45.15), 2.20 (0.70-26.15) and 2.00 (0.70-26.55), respectively. Forty percent of the tumors had CEP17 gain (51% of those with HER2 amplification). Adjusting for treatment groups in the Cox model, HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with time to relapse or time to death.

Conclusion

HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with outcome in high-risk breast cancer patients treated with anthracycline-based adjuvant chemotherapy.

Trial registration

Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12611000506998 and ACTRN12609001036202

Keywords:
HER2; TOP2A; TopoIIa; Prognostic factors; Predictive factors; Adjuvant chemotherapy; Anthracyclines; Taxanes; Breast cancer