title: Prognostic significance of K-Ras mutation rate in metastatic colorectal cancer patients.
abstract: BACKGROUND
  Activating mutations of K-Ras gene have a well-established role as predictors of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) patients. Their prognostic value is controversial, and no data regarding the prognostic value of mutation rate, defined as the percentage of mutated alleles/tumor sample, are available. We aimed to evaluate the prognostic value of K-Rasmutation rate in a homogenous cohort of mCRC patients receiving first-line doublet plus bevacizumab.
  
  
  METHODS
  This retrospective study enrolled 397 K-Ras mutant mCRC patients from 6 Italian centers, and 263 patients were fully evaluable for our analysis. K-Ras mutation rate was assessed by pyrosequencing. Patients with less than 60% of cancer cells in tumor tissue were excluded. No patients received anti-EGFR containing anticancer therapy, at any time. Median mutation rate was 40% and was adopted as cut-off. The primary and secondary endpoints were PFS and OS respectively.
  
  
  RESULTS
  At univariate analysis, K-Ras mutation rate higher than 40% was significantly associated with lower PFS (7.3 vs 9.1 months; P < 0.0001) and OS (21 vs 31 months; P = 0.004). A multivariate model adjusted for age at diagnosis, site of origin of tumor tissue (primary vs metastases), referral center, number of metastatic sites, and first-line chemotherapy backbone, showed that K-Ras mutation rate remained a significant predictor of PFS and OS in the whole population.
  
  
  CONCLUSIONS
  Our data demonstrate an association between K-Ras mutation rate and prognosis in mCRC patients treated with bevacizumab-containing first-line therapy. These data deserve to be verified in an independent validation set.
authors.affiliation: Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.affiliation: Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Russo
authors.affiliation: Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mannavola
authors.affiliation: Department of Anatomical Pathology, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perrone
authors.affiliation: Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pantano
authors.affiliation: Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Rossini
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero-Universitaria, Udine, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ongaro
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Bonazzina
authors.affiliation: Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Dell'Aquila
authors.affiliation: Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Imperatori
authors.affiliation: Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Zoccoli
authors.affiliation: Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bronte
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero-Universitaria, Udine, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: De Maglio
authors.affiliation: Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell'Area Critica, Università di Pisa, Pisa, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio", Chieti, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Natoli
authors.affiliation: Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.affiliation: Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.affiliation: Department of Anatomical Pathology, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Onetti-Muda
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.affiliation: Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
authors.affiliation: Department of Medical Oncology, Azienda Ospedaliero-Universitaria, Udine, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Aprile
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: K-Ras; bevacizumab; colorectal cancer; mutation rate; prognosis