Gene expression profile predictive of response to chemotherapy in metastatic colorectal cancer

Estévez-García, Purificación et al.Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal cancer (mCRC) for years. Response rates are only observed, however, in about half of treated patients, and there are no reliable tools to prospectively identify patients more likely to benefit from therapy. The purpose of our study was to identify a gene expression profile predictive of CT response in mCRC. Whole genome expression analyses (Affymetrix GeneChip® HG-U133 Plus 2.0) were performed in fresh frozen tumor samples of 37 mCRC patients (training cohort). Differential gene expression profiles among the two study conditions (responders versus non-responders) were assessed using supervised class prediction algorithms. A set of 161 differentially expressed genes in responders (23 patients; 62%) versus non-responders (14 patients; 38%) was selected for further assessment and validation by RT-qPCR (TaqMan®Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards) in an independent multi-institutional cohort (53 mCRC patients). Seven of these genes were confirmed as significant predictors of response. Patients with a favorable predictive signature had significantly greater response rate (58% vs 13%, p = 0.024), progression-free survival (61% vs 13% at 1 year, HR = 0.32, p = 0.009) and overall survival (32 vs 16 months, HR = 0.21, p = 0.003) than patients with an unfavorable gene signature. This is the first study to validate a gene-expression profile predictive of response to CT in mCRC patients. Larger and prospective confirmatory studies are required, however, in order to successfully provide oncologists with adequate tools to optimize treatment selection in routine clinical practice.This work was supported by a grant of the Fundacion Mutua Madrileña (FMM) (P0497/2006) and from the Fondo de Investigación Sanitaria/Instituto de Salud Carlos III Spanish Cancer Networks RTICC (R12/0036/0008 and R12/0036/0028). RGC is funded by Fondo de Investigación Sanitaria (PI10/02164, PI13/02295), Servicio Andaluz de Salud (PI-0259/2007) and RTICC (R12/0036/0028). PEG is funded by a Rio Hortega grant (09/00207) from the Instituto de Salud Carlos III (ISCiii), Ministerio de Sanidad, Spain and Consejeria de Salud of the Junta de Andalucia (PI-0135–2010). SMP is funded by Fondo de Investigación Sanitaria (CD1100153) and Fundación Científica de la Asociación Española Contra el Cáncer. MDP is funded by Fondo de Investigación Sanitaria (CD0900148). LPA is funded by the ISCiii (PI081156, PI1102688, RTICC R12/0036/0008), Consejería de Innovacion, Ciencia y Empresa – Junta de Andalucia (P08-CVI-04090) and the 75th Anniversary Roche Spain Fellowship. AC is funded by the Spanish Ministry of Science and Innovation (SAF2009–08605), FIS (PI12/00137), Consejeria de Ciencia e Innovacion and Consejeria de Salud of the Junta de Andalucia (CTS-6844 and PI-0142), and by Fundacion Oncologica FERO, supported by Fundació Josep Botet.Peer Reviewe