Gene expression profile predictive of response to chemotherapy in metastatic colorectal cancer.
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.
Laboratorio de Oncología Molecular y Nuevas Terapias, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.|Medical Oncology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain.
Purificacion
P
Estevez-Garcia
Medical Oncology Department, Hospital Universitario Marques de Valdecilla, Santander, Spain.
Fernando
F
Rivera
Laboratorio de Oncología Molecular y Nuevas Terapias, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.
Sonia
S
Molina-Pinelo
Laboratorio de Oncología Molecular y Nuevas Terapias, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.|Medical Oncology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain.
Marta
M
Benavent
Pathology Department, Hospital Universitario Marques de Valdecilla, Santander, Spain.
Javier
J
Gómez
Medical Oncology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain.
Maria Luisa
ML
Limón
Laboratorio de Oncología Molecular y Nuevas Terapias, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.
Maria Dolores
MD
Pastor
Laboratorio de Oncología Molecular y Nuevas Terapias, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.|Medical Oncology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain.
Julia
J
Martinez-Perez
Laboratorio de Oncología Molecular y Nuevas Terapias, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.|Medical Oncology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain.
Luis
L
Paz-Ares
Laboratorio de Biología Molecular del Cáncer, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.
Amancio
A
Carnero
Laboratorio de Oncología Molecular y Nuevas Terapias, Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain.|Medical Oncology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain.
Rocio
R
Garcia-Carbonero
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D046228:Microarray Analysis; D009362:Neoplasm Metastasis; D011237:Predictive Value of Tests; D059467:Transcriptome
chemotherapy; colorectal cancer; gene expression; microarray; predictive