title: Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer.
abstract: NRAS mutations occur in 3-5% of colorectal cancer. Differently from KRAS and BRAF mutations, the role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer (mCRC) has been investigated to a lesser extent. A retrospective series suggested the role of NRAS mutations as predictors of resistance to anti-EGFR monoclonal antibodies (MoAbs) in chemo-refractory patients with mCRC. In our study, KRAS codons 12, 13, 61 and BRAF codon 600 mutational status were evaluated in mCRCs referred to our Institution from 2009 to 2012. NRAS codons 12, 13 and 61 mutational status was analyzed in KRAS/BRAF wt patients. We collected pathological and clinical features in the overall population and outcome data in a subset of NRAS mutated chemo-refractory patients treated with anti-EGFR MoAbs in advanced lines. NRAS was mutated in 47/786 (6%) mCRCs. NRAS and KRAS mutated tumors did not show significant differences in terms of clinical and pathological characteristics, except for a lower prevalence of mucinous histology (p = 0.012) and lung metastases (p = 0.012) among NRAS mutated tumors. In the uni- and multivariate model, NRAS mutations were associated with shorter overall survival (OS) compared to all wt patients (median OS 25.6 vs 42.7 months; univ: HR = 1.91, 95% CI 1.39-3.86, p = 0.0013; multiv: HR = 1.75, 95% CI 1.1.3-2.72, p = 0.013). None of the chemo-refractory NRAS mutated patients evaluable for response to anti-EGFRs achieved response. In conclusion, NRAS mutations have a relevant incidence in patients with mCRC and showed an association with specific clinical and pathological features. NRAS mutations affect mCRC patients' prognosis and predict lack of response to anti-EGFRs.
authors.affiliation: Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Schirripa
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Manfredi
authors.initials: M
authors.lastname: Morvillo
authors.forename: Francesca
authors.initials: F
authors.lastname: Bergamo
authors.forename: Federica
authors.initials: F
authors.lastname: Zoratto
authors.forename: Lisa
authors.initials: L
authors.lastname: Salvatore
authors.forename: Carlotta
authors.initials: C
authors.lastname: Antoniotti
authors.forename: Federica
authors.initials: F
authors.lastname: Marmorino
authors.forename: Elisa
authors.initials: E
authors.lastname: Sensi
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lupi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
authors.forename: Veronica
authors.initials: V
authors.lastname: De Gregorio
authors.forename: Riccardo
authors.initials: R
authors.lastname: Giannini
authors.forename: Fulvio
authors.initials: F
authors.lastname: Basolo
authors.forename: Gianluca
authors.initials: G
authors.lastname: Masi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab
keywords: BRAF; KRAS; NRAS; anti-EGFR; metastatic colorectal cancer