title: Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?
abstract: Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mangana
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Phil F
authors.initials: PF
authors.lastname: Cheng
authors.affiliation: Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Katja
authors.initials: K
authors.lastname: Schindler
authors.affiliation: Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
authors.affiliation: Horten Centre for Patient Oriented Research and Knowledge Transfer, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Held
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Frauchiger
authors.affiliation: Department of Oncology CHUV Lausanne, Lausanne, Switzerland.
authors.forename: Emanuella
authors.initials: E
authors.lastname: Romano
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: Katharina C
authors.initials: KC
authors.lastname: Kähler
authors.affiliation: Department of Dermatology, Stanford University School of Medicine, Stanford, United States of America.
authors.forename: Sima
authors.initials: S
authors.lastname: Rozati
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Rechsteiner
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Department of Oncology CHUV Lausanne, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.affiliation: Department of Dermatology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.affiliation: Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hoeller
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Goldinger
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human