title: BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer.
abstract: BACKGROUND
  Low-grade serous (LGS) ovarian cancer is a chemoresistant disease that accounts for 10% of serous ovarian cancers. Prior studies have reported that 28% to 35% of serous borderline (SB)/LGS ovarian tumors harbor a BRAF mutation, suggesting that BRAF inhibitors may be a rational therapeutic approach for this disease. In the current study, the authors sought to determine whether BRAF or KRAS mutation status was associated with disease stage and/or histology in patients with SB and LGS ovarian cancer.
  
  
  METHODS
  Genetic profiles were constructed for 75 SB and LGS ovarian tumors to determine BRAF and KRAS mutation status. The incidence and identity of BRAF and KRAS mutations were defined, and the results were correlated with disease stage, response to treatment, and overall survival.
  
  
  RESULTS
  Of 75 samples examined, 56 tumors (75%) had SB histology, and 19 tumors (25%) had LGS histology. Fifty-seven percent of tumors harbored either a KRAS mutation (n = 17) or a BRAF mutation (a valine-to-glutamate substitution at residue 600 [V600E]; n = 26). The BRAF V600E mutation was associated significantly with early disease stage (stage I/II; P < .001) and SB histology (P = .002). KRAS mutations were not associated significantly with disease stage or histology. Of the 22 patients (29%) who required chemotherapy, 20 had tumors with wild-type KRAS/BRAF, 2 had KRAS mutant tumors, and none had tumors that harbored a BRAF mutation. All patients with BRAF tumors remained alive at a median follow-up of 3.6 years (range, 1.9-129.3 months).
  
  
  CONCLUSIONS
  V600E BRAF mutations were present in 35% of patients who had SB/LGS ovarian cancers. The presence of the BRAF V600E mutation in SB/LGS ovarian cancer was associated with early stage disease and improved prognosis. The authors concluded that patients with SB/LGS ovarian cancer who require systemic therapy are unlikely to have BRAF mutant tumors.
authors.affiliation: Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 E 66 Street, New York, NY 10065, USA.
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Grisham
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 408 E 69 Street, New York, NY, 10065, USA.
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Karuna
authors.initials: K
authors.lastname: Garg
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Delair
authors.affiliation: Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 E 66 Street, New York, NY 10065, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Hyman
authors.affiliation: Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 207 E 63 Street, New York, NY, 10065, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 207 E 63 Street, New York, NY, 10065, USA.
authors.forename: Alexia
authors.initials: A
authors.lastname: Iasonos
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Fanny
authors.initials: F
authors.lastname: Dao
authors.affiliation: Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 E 66 Street, New York, NY 10065, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
authors.affiliation: Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.affiliation: Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 E 66 Street, New York, NY 10065, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Aghajanian
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 408 E 69 Street, New York, NY, 10065, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D018293:Cystadenoma, Serous / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense / Q000502:physiology; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000502:physiology; D016019:Survival Analysis; D014633:Valine / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D018698:Glutamic Acid; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D014633:Valine