A head and neck cancer tumor response-specific gene signature for cisplatin, 5-fluorouracil induction chemotherapy fails with added taxanes

• Published in: PloS one Vol. 7; no. 10; p. e47170
• Main Authors: Tomkiewicz, Céline, Hans, Stéphane, Mucchielli, Marie Hélène, Agier, Nicolas, Delacroix, Hervé, Marisa, Laetitia, Brasnu, Daniel, Aggerbeck, Lawrence P, Badoual, Cécile, Barouki, Robert, Aggerbeck, Martine
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.10.2012; Public Library of Science (PLoS)
• Subjects: 5-Fluorouracil; Adult; Aged; Analysis; Biology; Cancer genetics; Cancer therapies; Care and treatment; Chemotherapy; Cisplatin; Cisplatin - therapeutic use; Deoxyribonucleic acid; DNA; DNA microarrays; DNA polymerases; Fluorouracil; Fluorouracil - therapeutic use; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genetic aspects; Genomes; Genomics; Head; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Health aspects; Humans; Induction Chemotherapy; Laryngeal cancer; Male; Medical research; Medicine; Middle Aged; Patients; Precision medicine; Predictions; Protein Binding; Proteins; Radiation therapy; Reagents; Reverse Transcriptase Polymerase Chain Reaction; RNA-directed DNA polymerase; Squamous cell carcinoma; Studies; Taxanes; Taxoids - therapeutic use; Technology; Toxicity; Tumors; France
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0047170

It is a major clinical challenge to predict which patients, with advanced stage head and neck squamous cell carcinoma, will not exhibit a reduction in tumor size following induction chemotherapy in order to avoid toxic effects of ineffective chemotherapy and delays for instituting other therapeutic options. Further, it is of interest to know to what extent a gene signature, which identifies patients with tumors that will not respond to a particular induction chemotherapy, is applicable when additional chemotherapeutic agents are added to the regimen. To identify genes that predict tumor resistance to induction with cisplatin/5-fluorouracil (PF) or PF and a taxane, we analyzed patient tumor biopsies with whole genome microarrays and quantitative reverse transcriptase-PCR (TLDA) cards. A leave one out cross-validation procedure allowed evaluation of the prediction tool. A ten-gene microarray signature correctly classified 12/13 responders and 7/10 non-responders to PF (92% specificity, 82.6% accuracy). TLDA analysis (using the same classifier) of the patients correctly classified 12/12 responders and 8/10 non-responders (100% specificity, 90.9% accuracy). Further, TLDA analysis correctly predicted the response of 5 new patients and, overall, 12/12 responders and 13/15 non-responders (100% specificity, 92.6% accuracy). The protein products of the genes constituting the signature physically associate with 27 other proteins, involved in regulating gene expression, constituting an interaction network. In contrast, TLDA-based prediction (with the same gene signature) of responses to induction with PF and either of two taxanes was poor (0% specificity, 25% accuracy and 33.3% specificity, 25% accuracy). Successful transfer of the microarray-based gene signature to an independent, PCR-based technology suggests that TLDA-based signatures could be a useful hospital-based technology for determining therapeutic options. Although highly specific for tumor responses to PF induction, the gene signature is unsuccessful when taxanes are added. The results illustrate the subtlety in developing "personalized medicine".