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Triple-negative phenotype is of adverse prognostic value in patients treated with dose-dense sequential adjuvant chemotherapy: a translational research analysis in the context of a Hellenic Cooperative Oncology Group (HeCOG) randomized phase III trial

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Abstract

Purpose

It is well recognized that breast cancer is a heterogeneous disease. The purpose of the current study was to classify patients according to the immunohistochemical phenotype of their tumors in an effort to evaluate the outcome of the respective groups of patients and specifically of those with triple-negative breast cancer (TNBC) following dose-dense sequential adjuvant chemotherapy.

Methods

A total of 595 patients with high-risk breast cancer were treated with adjuvant anthracycline-based dose-dense sequential chemotherapy with or without paclitaxel in the context of a randomized study. ER, PgR, HER2, Ki67, EGFR, and CK5 protein expression were evaluated in 298 formalin-fixed paraffin-embedded tumor samples by immunohistochemistry (IHC). HER2 was also evaluated by chromogen in situ hybridization (CISH). HER2 status and Ki67 protein expression differentiated luminal IHC subtypes (luminal B tumors being HER2 and/or Ki67-positive).

Results

Among the 298 tumors, the immunohistochemical panel classified 37 (12%) as luminal A, 198 (66%) as luminal B, 27 (9%) as HER2 enriched, and 36 (12%) as TNBC. The median follow-up time was 97 months. Patients with luminal A tumors had the best prognosis, with improved disease-free survival (log-rank, P = 0.033) and overall survival (P = 0.006) compared with the other three tumor subtypes. The three subtypes had an increased risk for relapse and death compared with luminal A in multivariate analysis, as well. No benefit from paclitaxel treatment was detected in any of the four subtypes or the total cohort. Hierarchical clustering based on mRNA expression of ER, PgR, and HER2 by quantitative RT-PCR identified patient groups that were comparable to the subtypes identified by IHC.

Conclusions

The results of this study confirm that triple negative, luminal B and HER2-enriched phenotypes identified by IHC are of adverse prognostic value in high-risk breast cancer patients treated with dose-dense sequential adjuvant chemotherapy.

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Acknowledgments

The authors are deeply indebted to all patients who participated in the study and provided biological material for translational research. The authors also wish to thank Evita Fragou and Dimitra Katsala for monitoring the study, Maria Moschoni for coordinating the data management, and Thalia Spinari for tissue sample collection and Ioanna Panou for secretarial assistance. On behalf of the Hellenic Foundation for Cancer Research, Athens, Greece, the senior investigator author (GF) has pending patent applications with Siemens Healthcare Diagnostics, Tarrytown, NY, USA. Translational research was supported by a HeCOG research grant: HE TRANS_BR. The senior investigator (GF) has received Commercial Research Funding by Roche Hellas SA and Genesis Pharma SA, Athens, Greece.

Author information

Author notes

  1. R. Kronenwett

    Present address: Sividon Diagnostics GmbH, Nattermann Allee 1, 50829, Cologne, Germany

  2. R. M. Wirtz

    Present address: Stratifyer Molecular Pathology GmbH, Werthmannstrasse 1, 50935, Cologne, Germany

Authors and Affiliations

  1. Department of Radiotherapy, Agios Savvas Cancer Hospital, Athens, Greece

    P. Skarlos

  2. Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece

    C. Christodoulou & D. V. Skarlos

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

    K. T. Kalogeras

  4. Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

    K. T. Kalogeras, E. Timotheadou & G. Fountzilas

  5. Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece

    A. G. Eleftheraki

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

    M. Bobos & D. Televantou

  7. Department of Pathology, Ioannina University Hospital, Ioannina, Greece

    A. Batistatou

  8. Department of Pathology, Metaxas Cancer Hospital, Piraeus, Greece

    C. Valavanis, O. Tzaida & P. Arapantoni

  9. Siemens Healthcare Diagnostics, Cologne, Germany

    R. Kronenwett & R. M. Wirtz

  10. Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

    I. Kostopoulos

  11. Department of Pathology, Metropolitan Hospital, Piraeus, Greece

    E. Koutselini

  12. Department of Pathology, Alexandra Hospital, Athens, Greece

    I. Papaspirou

  13. Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece

    C. A. Papadimitriou

  14. Second Department of Internal Medicine, Oncology Section, Hippokration Hospital, Athens, Greece

    D. Pectasides

  15. First Department of Medicine, Laiko General Hospital, University of Athens Medical School, Athens, Greece

    H. Gogas

  16. Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece

    G. Aravantinos

  17. Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

    N. Pavlidis

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  1. P. Skarlos
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  2. C. Christodoulou
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  22. D. V. Skarlos
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Corresponding author

Correspondence to G. Fountzilas.

Additional information

The first two authors P. Skarlos and C. Christodoulou have contributed equally to this work.

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Skarlos, P., Christodoulou, C., Kalogeras, K.T. et al. Triple-negative phenotype is of adverse prognostic value in patients treated with dose-dense sequential adjuvant chemotherapy: a translational research analysis in the context of a Hellenic Cooperative Oncology Group (HeCOG) randomized phase III trial. Cancer Chemother Pharmacol 69, 533–546 (2012). https://doi.org/10.1007/s00280-011-1730-9

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