title: A combined strategy of SAGE and quantitative PCR Provides a 13-gene signature that predicts preoperative chemoradiotherapy response and outcome in rectal cancer.
abstract: OBJECTIVE
  Preoperative chemoradiotherapy (CRT) is the treatment of choice for rectal cancer (RC), but half of the patients do not respond, suffer unnecessary toxicities, and surgery delays. We aimed to develop a model that could predict a clinically meaningful response to CRT by using formalin-fixed paraffin-embedded (FFPE) biopsies.
  
  
  METHODS
  We first carried out an exploratory screening of candidate genes by using SAGE technology to evaluate dynamic changes in the RC transcriptome in selected refractory patients before and after CRT. Next, 53 genes (24 from SAGE and 29 from the literature) were analyzed by qPCR arrays in FFPE initial biopsies from 94 stage II/III RC patients who were preoperatively treated with CRT. Tumor response was defined by using Dworak's tumor regression grade (2-3-4 vs. 0-1). Multivariate Cox methods and stepwise algorithms were applied to generate an optimized predictor of response and outcome.
  
  
  RESULTS
  In the training cohort (57 patients), a 13-gene signature predicted tumor response with 86% accuracy, 87% sensitivity, and 82% specificity. In a testing cohort (37 patients), the model correctly classified 6 of 7 nonresponders, with an overall accuracy of 76%. A signature-based score identified patients with a higher risk of relapse in univariate (3-year disease-free survival 64% vs. 90%, P = 0.001) and multivariate analysis (HR = 4.35 95% CI: 1.2-15.75, P = 0.02), in which it remained the only statistically significant prognostic factor.
  
  
  CONCLUSIONS
  A basal 13-gene signature efficiently predicted CRT response and outcome. Multicentric validation by the GEMCAD collaborative group is currently ongoing. If confirmed, the predictor could be used to improve patient selection in RC studies.
authors.affiliation: Unidad de Oncología; Unidad de Gastroenterología, Hospital Infanta Sofía, Spain. enrique.casado@salud.madrid.org
authors.forename: Enrique
authors.initials: E
authors.lastname: Casado
authors.forename: Victor Moreno
authors.initials: VM
authors.lastname: García
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Sánchez
authors.forename: Montserrat
authors.initials: M
authors.lastname: Blanco
authors.forename: Joan
authors.initials: J
authors.lastname: Maurel
authors.forename: Jaime
authors.initials: J
authors.lastname: Feliu
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Martos
authors.forename: Javier
authors.initials: J
authors.lastname: de Castro
authors.forename: Beatriz
authors.initials: B
authors.lastname: Castelo
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Belda-Iniesta
authors.forename: María
authors.initials: M
authors.lastname: Sereno
authors.forename: Benito
authors.initials: B
authors.lastname: Sánchez-Llamas
authors.forename: Emilio
authors.initials: E
authors.lastname: Burgos
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: García-Cabezas
authors.forename: Noemí
authors.initials: N
authors.lastname: Manceñido
authors.forename: Rosa
authors.initials: R
authors.lastname: Miquel
authors.forename: Damián
authors.initials: D
authors.lastname: García-Olmo
authors.forename: Manuel
authors.initials: M
authors.lastname: González-Barón
authors.forename: Paloma
authors.initials: P
authors.lastname: Cejas
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020360:Neoadjuvant Therapy; D011379:Prognosis; D012004:Rectal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor