title: G12V and G12A KRAS mutations are associated with poor outcome in patients with metastatic colorectal cancer treated with bevacizumab.
abstract: The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in 35-45 % of colorectal cancer (CRC) cases. Although the association between the RAS signaling and angiogenesis is well known, the negative predictive value of KRAS mutation has not been established in patients treated with bevacizumab. The aim of this study was to evaluate the association between specific KRAS mutation types and outcome of patients with metastatic CRC treated with bevacizumab. The study included 404 patients with metastatic CRC (mCRC) treated with bevacizumab. Clinical data obtained from the clinical registry CORECT were retrospectively analyzed. The shortest survival was observed in patients with tumors harboring G12V or G12A KRAS mutation (G12V/A). The median progression-free survival (PFS) and overall survival (OS) for patients with tumors harboring G12V/A KRAS mutation was 6.6 and 16.8 compared to 11.6 and 26.3 months for patients with tumors harboring other KRAS mutation type (p < 0.001 and p < 0.001), while the survival of patients harboring other KRAS mutation types was comparable to those with tumors harboring wild-type KRAS gene. In the Cox multivariable analysis, KRAS G12V/A mutation type remains a significant factor predicting both PFS (HR = 2.18, p < 0.001) and OS (HR = 2.58, p < 0.001). In conclusion, the results of the present study indicate that there is a significant difference in biological behavior between tumors harboring G12V/A and other KRAS mutations. Moreover, comparison of the survival of patients with tumors harboring G12V/A KRAS mutations with those harboring wild-type KRAS gene revealed that G12V/A KRAS mutations are prognostic biomarker for inferior PFS and OS in patients with mCRC treated with bevacizumab in univariate as well as multivariable analyses.
authors.affiliation: Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen, Charles University in Prague, alej Svobody 80, CZ-304 60, Pilsen, Czech Republic. fiala.o@centrum.cz.|Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Plzeň, Czech Republic. fiala.o@centrum.cz.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Fiala
authors.affiliation: Department of Oncology and First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Buchler
authors.affiliation: Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Mohelnikova-Duchonova
authors.affiliation: Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors.forename: Bohuslav
authors.initials: B
authors.lastname: Melichar
authors.affiliation: Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen, Charles University in Prague, alej Svobody 80, CZ-304 60, Pilsen, Czech Republic.
authors.forename: Vit Martin
authors.initials: VM
authors.lastname: Matejka
authors.affiliation: Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen, Charles University in Prague, alej Svobody 80, CZ-304 60, Pilsen, Czech Republic.
authors.forename: Lubos
authors.initials: L
authors.lastname: Holubec
authors.affiliation: Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen, Charles University in Prague, alej Svobody 80, CZ-304 60, Pilsen, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kulhankova
authors.affiliation: Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Bortlicek
authors.affiliation: Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Bartouskova
authors.affiliation: Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Plzeň, Czech Republic.|Department of Surgery, Medical School and Teaching Hospital Pilsen, Charles University in Prague, Pilsen, Czech Republic.
authors.forename: Vaclav
authors.initials: V
authors.lastname: Liska
authors.affiliation: Department of Nuclear Medicine, Medical School and Teaching Hospital Pilsen, Charles University in Prague, Pilsen, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Topolcan
authors.affiliation: Bioptic Laboratory, Ltd., Molecular Pathology Laboratory, Plzeň, Czech Republic.
authors.forename: Monika
authors.initials: M
authors.lastname: Sedivcova
authors.affiliation: Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen, Charles University in Prague, alej Svobody 80, CZ-304 60, Pilsen, Czech Republic.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Finek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000068258:Bevacizumab / Q000627:therapeutic use; D003062:Codon; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D019233:Retreatment; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D003062:Codon; D000068258:Bevacizumab; D018631:ras Proteins
keywords: Bevacizumab; Chemotherapy; Colorectal cancer; KRAS; Mutation