HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy

Journal of Translational Medicine

Petroula Arapantoni^1,11  Dimitrios Pectasides⁶  Christos Christodoulou^1,10  Angelos Koutras^1,15  Gerasimos Aravantinos^1,16  Genovefa Polychronidou^1,13  Dimitrios Vlachodimitropoulos¹  Helen Gogas⁵  George Pentheroudakis²  Nikolaos Soupos^1,14  Eleni Timotheadou^1,13  Mattheos Bobos⁷  Ralph M Wirtz³  Ralf Kronenwett³  Anna Batistatou⁴  Olympia Tzaida^1,11  Konstantine T Kalogeras^1,12  Anastasia G Eleftheraki⁸  Vassiliki Kotoula⁹  Christos Valavanis^1,11  George Fountzilas^1,13 

[1] Laboratory of Pathology, Evgenidion Hospital, University of Athens Medical School, Greece;Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece;Siemens Healthcare Diagnostics, Cologne, Germany;Department of Pathology, Ioannina University Hospital, Ioannina, Greece;First Department of Medicine, Laiko General Hospital, University of Athens, Medical School, Athens, Greece;Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece;Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece;Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece;Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece;Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece;Department of Pathology, Metaxas Cancer Hospital, Piraeus, Greece;Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece;Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece;Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece;Department of Medicine, Division of Oncology, University Hospital, University of Patras Medical School, Patras, Greece;Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece

关键词: taxanes;    anthracyclines;    randomized study;    early breast cancer;    mRNA expression;    CISH;    gene amplification;    TOP2A;    HER2;   

Others  :  1207785
DOI  :  10.1186/1479-5876-10-10

 received in 2011-07-05, accepted in 2012-01-12,  发布年份 2012

【 摘 要 】

Background

HER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy.

Methods

In a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry).

Results

HER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02-0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel.

Conclusions

This study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines.

Trial registration

Australian New Zealand Clinical Trials Registry ACTRN12611000506998.

【 授权许可】

   
2012 Fountzilas et al; licensee BioMed Central Ltd.

【 图 表 】

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