title: Dicer and Drosha expression and response to Bevacizumab-based therapy in advanced colorectal cancer patients.
abstract: OBJECTIVE
  The miRNA-regulating enzymes Dicer and Drosha exhibit aberrant expression in several cancer types. Dicer and Drosha play a crucial role during the angiogenetic process in vitro and, for Dicer, in vivo. We aimed to investigate the potential role of Dicer and Drosha in predicting response to Bevacizumab-based therapy in advanced colorectal cancer (CRC) patients.
  
  
  METHODS
  Dicer and Drosha mRNA levels were analysed in formalin-fixed paraffin-embedded specimens from patients affected by advanced CRC treated with or without Bevacizumab-containing regimens (n=116 and n=50, respectively) and from patients with diverticulosis as control group (n=20). The experimental data were obtained using qRT-PCR, analysed comparing Dicer and Drosha expression levels in tumour samples versus normal mucosa and then compared to clinical outcome.
  
  
  RESULTS
  The tumour samples from Bevacizumab-treated patients showed a significantly higher Drosha expression (P<.001) versus normal mucosa, while Dicer levels did not differ. Intriguingly, we found that low Dicer levels predicted a longer progression-free survival (PFS) (P<.0001) and overall survival (OS) (P=.009). In addition, low Dicer levels were associated with better response to Bevacizumab-based treatments versus high Dicer levels (1.7% complete responses and 53.4% partial responses versus 0% and 32.7%, respectively; P=.0067). Multivariate analysis identified three independent predictors of improved OS: high performance status (PS) (relative risk (RR) 1.45; P=.011), lower organs involvement (RR 0.79; P=.034) and low Dicer expression (RR 0.71; P=.008). Conversely, Drosha levels were not associated with prognosis and outcome associated with treatment. In non-Bevacizumab-treated patients, Dicer and Drosha expression did not correlate with outcome.
  
  
  CONCLUSIONS
  These findings suggest that low Dicer mRNA levels seem to be independent predictors of favourable outcome and response in patients affected by advanced CRCs treated with Bevacizumab-based therapy.
authors.affiliation: Medical Oncology, University Hospital Campus Bio-Medico, Via Alvaro del Portillo 200, 00128 Rome, Italy. b.vincenzi@unicampus.it
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.forename: Alice
authors.initials: A
authors.lastname: Zoccoli
authors.forename: Gaia
authors.initials: G
authors.lastname: Schiavon
authors.forename: Michele
authors.initials: M
authors.lastname: Iuliani
authors.forename: Francesco
authors.initials: F
authors.lastname: Pantano
authors.forename: Emanuela
authors.initials: E
authors.lastname: Dell'aquila
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ratta
authors.forename: Andrea Onetti
authors.initials: AO
authors.lastname: Muda
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perrone
authors.forename: Chiara
authors.initials: C
authors.lastname: Brunelli
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Correale
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Riva
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000068258:Bevacizumab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; C408087:DICER1 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases