title: YKL-40/c-Met expression in rectal cancer biopsies predicts tumor regression following neoadjuvant chemoradiotherapy: a multi-institutional study.
abstract: BACKGROUND
  Neoadjuvant chemo-radiotherapy (CRT) followed by surgical resection is the standard treatment for locally advanced rectal cancer, although complete tumor pathological regression is achieved in only up to 30% of cases. A clinicopathological and molecular predictive stratification of patients with advanced rectal cancer is still lacking. Here, c-Met and YKL-40 have been studied as putative predictors of CRT response in rectal cancer, due to their reported involvement in chemoradioresistance in various solid tumors.
  
  
  METHODS
  A multicentric study was designed to assess the role of c-Met and YKL-40 expression in predicting chemoradioresistance and to correlate clinical and pathological features with CRT response. Immunohistochemistry and fluorescent in situ hybridization for c-Met were performed on 81 rectal cancer biopsies from patients with locally advanced rectal adenocarcinoma. All patients underwent standard (50.4 gy in 28 fractions + concurrent capecitabine 825 mg/m2) neoadjuvant CRT or the XELOXART protocol. CRT response was documented on surgical resection specimens and recorded as tumor regression grade (TRG) according to the Mandard criteria.
  
  
  RESULTS
  A significant correlation between c-Met and YKL-40 expression was observed (R = 0.43). The expressions of c-Met and YKL-40 were both significantly associated with a lack of complete response (86% and 87% of c-Met and YKL-40 positive cases, p< 0.01 and p = 0.006, respectively). Thirty of the 32 biopsies co-expressing both markers had partial or absent tumor response (TRG 2-5), strengthening their positive predictive value (94%). The exclusive predictive role of YKL-40 and c-Met was confirmed using a multivariate analysis (p = 0.004 and p = 0.007 for YKL-40 and c-Met, respectively). TRG was the sole morphological parameter associated with poor outcome.
  
  
  CONCLUSIONS
  c-Met and YKL-40 expression is a reliable predictor of partial/absent response to neoadjuvant CRT in rectal cancer. Targeted therapy protocols could take advantage of prior evaluations of c-MET and YKL-40 expression levels to increase therapeutic efficacy.
authors: Department of Medical Sciences, University of Turin, Turin, Italy.
authors: Rebecca
authors: R
authors: Senetta
authors: Department of Oncology, University of Turin, Turin, Italy.
authors: Eleonora
authors: E
authors: Duregon
authors: SSCVD Colorectal Cancer Unit, City of Health and Science Hospital of Turin, Turin, Italy.
authors: Cristina
authors: C
authors: Sonetto
authors: SSCVD Colorectal Cancer Unit, City of Health and Science Hospital of Turin, Turin, Italy.
authors: Rossella
authors: R
authors: Spadi
authors: Digestive and Colorectal Surgery, Centre of Minimal Invasive Surgery, University of Turin, Turin, Italy.
authors: Massimiliano
authors: M
authors: Mistrangelo
authors: SSCVD Colorectal Cancer Unit, City of Health and Science Hospital of Turin, Turin, Italy.
authors: Patrizia
authors: P
authors: Racca
authors: Department of Medical Sciences, University of Turin, Turin, Italy.
authors: Luigi
authors: L
authors: Chiusa
authors: Department of Oncology, University of Turin, Turin, Italy.
authors: Fernando H
authors: FH
authors: Munoz
authors: Department of Oncology, University of Turin, Turin, Italy.
authors: Umberto
authors: U
authors: Ricardi
authors: Digestive and Colorectal Surgery, Centre of Minimal Invasive Surgery, University of Turin, Turin, Italy.
authors: Alberto
authors: A
authors: Arezzo
authors: Department of Medical Sciences, University of Turin, Turin, Italy.
authors: Adele
authors: A
authors: Cassenti
authors: Department of Medical Sciences, University of Turin, Turin, Italy.
authors: Isabella
authors: I
authors: Castellano
authors: Department of Oncology, University of Turin, Turin, Italy.
authors: Mauro
authors: M
authors: Papotti
authors: Digestive and Colorectal Surgery, Centre of Minimal Invasive Surgery, University of Turin, Turin, Italy.
authors: Mario
authors: M
authors: Morino
authors: Candiolo Cancer Institute-FPO (Fondazione del Piemonte per l'0ncologia), IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), Candiolo, Turin, Italy.
authors: Mauro
authors: M
authors: Risio
authors: Department of Medical Sciences, University of Turin, Turin, Italy.
authors: Paola
authors: P
authors: Cassoni
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D054392:Adipokines / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001706:Biopsy; D000069287:Capecitabine / Q000008:administration & dosage; D059186:Chemoradiotherapy, Adjuvant / Q000379:methods; D000071451:Chitinase-3-Like Protein 1; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005720:Gamma Rays / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D037102:Lectins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D012004:Rectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D054392:Adipokines; D014408:Biomarkers, Tumor; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins; D000069287:Capecitabine; D019859:Proto-Oncogene Proteins c-met