Article abstract
Nature Medicine 15, 68 - 74 (2008)
Published online: 4 January 2009 | doi:10.1038/nm.1908
There is an Erratum (February 2009) associated with this Article.
A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer
Pierre Farmer1,2,18, Hervé Bonnefoi3,4,5,6, Pascale Anderle1,7, David Cameron8,18, Pratyakasha Wirapati2, Véronique Becette9,18, Sylvie André1, Martine Piccart10, Mario Campone11, Etienne Brain9, Gaëtan MacGrogan3, Thierry Petit12, Jacek Jassem13, Frédéric Bibeau14, Emmanuel Blot15, Jan Bogaerts6, Michel Aguet1, Jonas Bergh16, Richard Iggo1,3,17 & Mauro Delorenzi1,2
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.
- 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.
- Swiss Institute of Bioinformatics, Génopode Building, Quartier Sorge, CH-1015 Lausanne, Switzerland.
- Institut Bergonié and Bordeaux 2 University, Institute National de la Santé et de la Recherche Médicale unit U916, 229 Cours de l'Argonne, 33076 Bordeaux Cedex, France.
- Hôpitaux Universitaires de Genève, 24 rue Micheli-du-Crest CH-1211 Geneva, Switzerland.
- Swiss Group for Clinical Cancer Research, Effingerstrasse 40 CH-3008 Bern, Switzerland.
- European Organisation for Research and Treatment of Cancer (EORTC), Avenue E. Mounier, 83, 1200 Brussels, Belgium.
- Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, Via Vincenza Vela 6, 6500 Bellinzona, Switzerland.
- for the Anglo-Celtic Cooperative Oncology Group, University Department of Oncology, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, Scotland.
- Centre René Huguenin, 35, rue Dailly, 92210 Saint-Cloud, France.
- Institut Jules Bordet, Boulevard de Waterloo 125, B-1000 Brussels, Belgium.
- 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, 44 805 Nantes Cedex, Saint Herbalin, France.
- Centre Paul Strauss, 3, rue de la Porte de l'Hôpital 67065 Strasbourg Cedex, France.
- Medical University, 7, Debinki Street, 80-211 Gdansk, Poland.
- Centre Val d'Aurelle - Paul Lamarque, 208 rue des Apothicaires, 34298 Montpellier Cedex 5, France.
- Centre Henri Becquerel, rue d'Amiens, 76038 Rouen Cedex, France.
- Swedish Breast Cancer Group, Karolinska Institutet and Karolinska University Hospital, Radiumhemmet, 171 76 Stockholm, Sweden.
- Bute Medical School, Westburn Lane, University of St. Andrews, Fife KY16 9TS, Scotland.
- 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.).
Correspondence to: Mauro Delorenzi1,2 e-mail: mauro.delorenzi@isb-sib.ch
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