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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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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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.
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Supplementary Table 1, Supplementary Figs. 1–7 and Supplementary Methods (PDF 1286 kb)
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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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DOI: https://doi.org/10.1038/nm.1908
