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A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer

Nature Medicine volume 15, pages 68–74 (2009)Cite this article

An Erratum to this article was published on 01 February 2009

Abstract

To better understand the relationship between tumor-host interactions and the efficacy of chemotherapy, we have developed an analytical approach to quantify several biological processes observed in gene expression data sets. We tested the approach on tumor biopsies from individuals with estrogen receptor–negative breast cancer treated with chemotherapy. We report that increased stromal gene expression predicts resistance to preoperative chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) in subjects in the EORTC 10994/BIG 00-01 trial. The predictive value of the stromal signature was successfully validated in two independent cohorts of subjects who received chemotherapy but not in an untreated control group, indicating that the signature is predictive rather than prognostic. The genes in the signature are expressed in reactive stroma, according to reanalysis of data from microdissected breast tumor samples. These findings identify a previously undescribed resistance mechanism to FEC treatment and suggest that antistromal agents may offer new ways to overcome resistance to chemotherapy.

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Figure 1: Flow chart showing how the metagenes were created and tested.
Figure 2: Stromal gene expression and metagene scores.
Figure 3: Prognostic versus predictive value of the proliferation and stromal metagenes.
Figure 4: Biological interpretation of the stromal metagene.

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Acknowledgements

We thank the subjects, doctors and nurses involved in the EORTC 10994/BIG01 study for their generous participation. We thank the staff of the EORTC data center (M. de Vos, S. Lejeune, I. Delmotte and M. Karina) and the technician in the Iggo laboratory (A.-L. Nicoulaz) for assistance with data management and sample processing. We thank I. Xenarios, V. Praz and T. Sengstag for support with bioinformatics. We thank H. Chebab (Pathology Institute, University Lausanne) for supplying human colon tumors. We thank M. Zahn for critical reading of the manuscript. We thank the University of Lausanne DNA array facility and the Swiss Institute for Bioinformatics Vital-IT project for infrastructure support. We thank the Fondation Medic, Fondation Widmer, Oncosuisse, Swiss National Science Foundation and Swiss National Center for Competence in Research (NCCR) Molecular Oncology, EORTC Translational Research Fund, Swedish Cancer Society, King Gustav the Fifth Jubilee Fund and Swedish Research Council for financial support.

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Author notes

  1. Pierre Farmer, David Cameron & Véronique Becette

    Present address: Present addresses: Merck Serono International S.A. Switzerland, 9, chemin des Mines, 1202 Geneva, Switzerland (P.F.), UK National Cancer Research Network Coordinating Centre, 24 Hyde Terrace, Leeds LS2 9LN, UK (D.C.), Centre François Baclesse, 3 avenue du Général Harris, BP 5026, 14076 CAEN Cedex 5, France (V.B.).,

Authors and Affiliations

  1. Swiss National Centre of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, 155, Chemin des Boveresses, 1066 Epalinges s/Lausanne, Switzerland

    Pierre Farmer, Pascale Anderle, Sylvie André, Michel Aguet, Richard Iggo & Mauro Delorenzi

  2. Swiss Institute of Bioinformatics, Génopode Building, Quartier Sorge, Lausanne, CH-1015, Switzerland

    Pierre Farmer, Pratyakasha Wirapati & Mauro Delorenzi

  3. Institut Bergonié and Bordeaux 2 University, Institute National de la Santé et de la Recherche Médicale unit U916, 229 Cours de l'Argonne, Bordeaux, 33076, Cedex, France

    Hervé Bonnefoi, Gaëtan MacGrogan & Richard Iggo

  4. Hôpitaux Universitaires de Genève, 24 rue Micheli-du-Crest, Geneva, CH-1211, Switzerland

    Hervé Bonnefoi

  5. Swiss Group for Clinical Cancer Research, Effingerstrasse 40, Bern, CH-3008, Switzerland

    Hervé Bonnefoi

  6. European Organisation for Research and Treatment of Cancer (EORTC), Avenue E. Mounier, 83, Brussels, 1200, Belgium

    Hervé Bonnefoi & Jan Bogaerts

  7. Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Via Vincenza Vela 6, Bellinzona, 6500, Switzerland

    Pascale Anderle

  8. University Department of Oncology, for the Anglo-Celtic Cooperative Oncology Group, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, Scotland

    David Cameron

  9. Centre René Huguenin, 35, rue Dailly, Saint-Cloud, 92210, France

    Véronique Becette & Etienne Brain

  10. Institut Jules Bordet, Boulevard de Waterloo 125, Brussels, B-1000, Belgium

    Martine Piccart

  11. Institut du Cancer Nantes Atlantique, Centre de Lutte Contre le Cancer René Gauducheau, Centre de Cancérologie, Institute National de la Santé et de la Recherche Médicale 892, Boulevard Jacques Monod, Nantes Cedex, 44 805, Saint Herbalin, France

    Mario Campone

  12. Centre Paul Strauss, 3, rue de la Porte de l'Hôpital, Strasbourg Cedex, 67065, France

    Thierry Petit

  13. Medical University, 7, Debinki Street, Gdansk, 80-211, Poland

    Jacek Jassem

  14. Centre Val d'Aurelle - Paul Lamarque, 208 rue des Apothicaires, Montpellier Cedex 5, 34298, France

    Frédéric Bibeau

  15. Centre Henri Becquerel, rue d'Amiens, Rouen Cedex, 76038, France

    Emmanuel Blot

  16. Swedish Breast Cancer Group, Karolinska Institutet and Karolinska University Hospital, Radiumhemmet, 171 76, Stockholm, Sweden

    Jonas Bergh

  17. Bute Medical School, Westburn Lane, University of St. Andrews, Fife, KY16 9TS, Scotland

    Richard Iggo

Authors
  1. Pierre Farmer
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Contributions

J.B., F.B., E. Blot, H.B., D.C., M.C., J.J., G.M., T.P., M.P. and E. Brain supplied tumor tissues and collected the clinical follow-up data. V.B. did the central pathology review. R.I. supervised the laboratory experiments. S.A. performed laboratory experiments. P.F., P.W. and M.D. developed the statistical models. P.F., M.D. and R.I. analyzed the data. J.B. performed additional statistical analyses. P.A. and M.A. performed and supervised additional laboratory experiments. H.B., R.I., P.F. and M.D. designed the study. P.F., M.D., H.B., P.A., J.B., M.A., D.C. and R.I. wrote the report. All investigators contributed to and reviewed the final report.

Corresponding author

Correspondence to Mauro Delorenzi.

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Farmer, P., Bonnefoi, H., Anderle, P. et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 15, 68–74 (2009). https://doi.org/10.1038/nm.1908

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