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Gene expression profile predicts outcome after anthracycline-based adjuvant chemotherapy in early breast cancer

  • Preclinical study
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Abstract

Prognosis of early beast cancer is heterogeneous. Today, no histoclinical or biological factor predictive for clinical outcome after adjuvant anthracycline-based chemotherapy (CT) has been validated and introduced in routine use. Using DNA microarrays, we searched for a gene expression signature associated with metastatic relapse after adjuvant anthracycline-based CT without taxane. We profiled a multicentric series of 595 breast cancers including 498 treated with such adjuvant CT. The identification of the prognostic signature was done using a metagene-based supervised approach in a learning set of 323 patients. The signature was then tested on an independent validation set comprising 175 similarly treated patients, 128 of them from the PACS01 prospective clinical trial. We identified a 3-metagene predictor of metastatic relapse in the learning set, and confirmed its independent prognostic impact in the validation set. In multivariate analysis, the predictor outperformed the individual current prognostic factors, as well as the Nottingham Prognostic Index-based classifier, both in the learning and the validation sets, and added independent prognostic information. Among the patients treated with adjuvant anthracycline-based CT, with a median follow-up of 68 months, the 5-year metastasis-free survival was 82% in the “good-prognosis” group and 56% in the “poor-prognosis” group. Our predictor refines the prediction of metastasis-free survival after adjuvant anthracycline-based CT and might help tailoring adjuvant CT regimens.

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Abbreviations

CT:

Chemotherapy

IPC:

Institut Paoli-Calmettes

CLB:

Centre Léon Bérard

IB:

Institut Bergonié

SBR:

Scarff-Bloom-Richardson

IHC:

Immunohistochemistry

ER:

Estrogen receptor

PR:

Progesterone receptor

FEC:

5-Fluoro-uracile + epirubicine + cyclophosphamide

PCR:

Polymerase chain reaction

MFS:

Metastasis-free survival

HR:

Hazard ratio

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Acknowledgments

We are grateful to L. Xerri and C. Mawas for encouragements. We thank F. Bonnet, S. Mathoulin-Pélissier, V. Brouste for their technical assistance and S. Deraco for his help in data analysis. This study was supported in part by Inserm, Institut Paoli-Calmettes, and grants from Programme Hospitalier de Recherche Clinique 2001 (PHRC N° 24-01 FB) and 2003 (N° 24-01 FB), Ligue Nationale Contre le Cancer (label DB), Association pour la Recherche sur le Cancer, Fédération Nationale des Centres de Lutte Contre le Cancer and Institut National du Cancer (ACI2004, PL2006, recherche translationnelle). The Biological Resource Centres in Oncology at Institut Paoli-Calmettes and Centre Léon Bérard were supported by grants “Tumorothèques” from the French Ministry of Health and INCa, by grants “Collections 2003” from Inserm and the French Ministry of Research, and by grants “CEBS 2006” from the Agence Nationale de la Recherche (ANR).

Conflict of interest

Ipsogen employees: N Borie, JM Le Doussal, S Debono, A Martinec, F Hermitte, V Fert. Ipsogen shareholders: S Debono, F Hermitte, V Fert. The other authors declare they have no competing interest.

Author information

Authors and Affiliations

  1. Département d’Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille, UMR891 Inserm, Institut Paoli-Calmettes (IPC), IFR137, 232, bd Sainte-Marguerite, 13273, Marseille, France

    François Bertucci, Pascal Finetti, Jocelyne Jacquemier & Daniel Birnbaum

  2. Département d’Oncologie Médicale, Institut Paoli-Calmettes (IPC), Marseille, France

    François Bertucci, Jean-Marc Extra & Patrice Viens

  3. Université de la Méditerranée, Marseille, France

    François Bertucci & Patrice Viens

  4. Ipsogen S.A., Marseille, France

    Nathalie Borie, Jean-Marc Le Doussal, Stéphane Debono, Agnès Martinec, Fabienne Hermitte & Vincent Fert

  5. Département d’Oncologie Médicale, Institut Claudius Régaud, Toulouse, France

    Henri Roche

  6. Département d’Oncologie Médicale, Centre Léon Bérard, Lyon, France

    Thomas Bachelot

  7. Département d’Anatomopathologie, Institut Bergonié, Bordeaux, France

    Gaëtan Macgrogan

  8. Département d’Anatomopathologie, Centre Léon Bérard, Lyon, France

    Isabelle Treilleux

  9. Bureau d’Etudes Cliniques et Thérapeutiques, Institut Paoli-Calmettes (IPC), Marseille, France

    Benjamin Esterni

  10. Bureau d’Etudes Cliniques et Thérapeutiques, Fédération Nationale des Centres de Lutte contre le Cancer, Paris, France

    Jean Geneve & Anne-Laure Martin

  11. Centre de Ressources Biologiques en Oncologie, Institut Paoli-Calmettes (IPC), Marseille, France

    Christian Chabannon

  12. Département de BioPathologie, Institut Paoli-Calmettes (IPC), Marseille, France

    Jocelyne Jacquemier

  13. Laboratoire de Génétique Moléculaire, Institut Bergonié, Bordeaux, France

    Michel Longy

  14. Institut National du Cancer, Paris, France

    Dominique Maraninchi

Authors
  1. François Bertucci
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  2. Nathalie Borie
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  3. Henri Roche
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  9. Isabelle Treilleux
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  13. Jean Geneve
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  20. Vincent Fert
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  22. Patrice Viens
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Corresponding author

Correspondence to François Bertucci.

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10549_2010_1003_MOESM1_ESM.tif

Supplementary Fig. 1: Kaplan–Meier MFS for patients treated with adjuvant anthracycline-based chemotherapy. a MFS for all 498 patients. b–d MFS in the “good-prognosis group” or the “poor-prognosis group” defined using the genomic predictor; c MFS for all 498 patients; cMFS for 417 patients with N+ cancer; d MFS for 80 patients with N− cancer. HR means hazard ratio for metastasis in the “poor-prognosis group” as compared to the “good-prognosis group.” (TIFF 492 kb)

Supplementary material 2 (DOC 31 kb)

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Bertucci, F., Borie, N., Roche, H. et al. Gene expression profile predicts outcome after anthracycline-based adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat 127, 363–373 (2011). https://doi.org/10.1007/s10549-010-1003-z

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