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

• Published in: Nature medicine Vol. 15; no. 1; pp. 68 - 74
• Main Authors: Farmer, Pierre, Bonnefoi, Hervé, Anderle, Pascale, Cameron, David, Wirapati, Pratyakasha, Becette, Véronique, André, Sylvie, Piccart, Martine, Campone, Mario, Brain, Etienne, MacGrogan, Gaëtan, Petit, Thierry, Jassem, Jacek, Bibeau, Frédéric, Blot, Emmanuel, Bogaerts, Jan, Aguet, Michel, Bergh, Jonas, Iggo, Richard, Delorenzi, Mauro
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2009; Nature Publishing Group
• Subjects: Algorithms; Biomedical and Life Sciences; Biomedicine; Biopsy; Breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer Research; Chemotherapy; Drug resistance; Drug Resistance, Neoplasm - genetics; Drug therapy; Estrogens; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Health aspects; Humans; Infectious Diseases; Metabolic Diseases; Molecular Medicine; Neoadjuvant Therapy; Neurosciences; Oligonucleotide Array Sequence Analysis; Oncogenes - physiology; Physiological aspects; Predictive Value of Tests; Prognosis; Stromal Cells - metabolism; Stromal Cells - pathology; Tumors
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.1908

Identifying factors that influence response to cancer chemotherapy is crucial for improving its efficacy. Mauro Delorenzi and his colleagues report that a stromal gene expression signature predicts resistance to a commonly used chemotherapy regimen in individuals with estrogen receptor–negative breast tumors. These findings underline the potential of the tumor microenvironment to modulate tumor phenotype and the clinical response to treatment. 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.