title: Clinicopathologic features associated with efficacy and long-term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors.
abstract: BACKGROUND
  The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown.
  
  
  METHODS
  For 142 consecutive immunotherapy- and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n = 111) or a combination of dabrafenib and trametinib (n = 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival.
  
  
  RESULTS
  The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients.
  
  
  CONCLUSIONS
  Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur.
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.|Royal North Shore Hospital, Sydney, Australia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Drummond
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.
authors.forename: Serigne
authors.initials: S
authors.lastname: Lo
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.
authors.forename: Megan
authors.initials: M
authors.lastname: Lyle
authors.affiliation: Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australia.
authors.forename: Matthew M K
authors.initials: MM
authors.lastname: Chan
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.|Royal Prince Alfred Hospital, Sydney, Australia.|Mater Hospital, Sydney, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.|Royal North Shore Hospital, Sydney, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Guminski
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.|Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australia.
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.|Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.|Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australia.|Macquarie University, Sydney, Australia.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: Melanoma Institute Australia, Sydney, Australia.|The University of Sydney, Sydney, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D007770:L-Lactate Dehydrogenase / Q000097:blood; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000503:physiopathology* / Q000556:secondary; D008875:Middle Aged; D010091:Oximes / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011728:Pyridones / Q000627:therapeutic use; D011744:Pyrimidinones / Q000627:therapeutic use; D012737:Sex Factors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000503:physiopathology* / Q000556:secondary; D013449:Sulfonamides / Q000627:therapeutic use; D015996:Survival Rate; D016896:Treatment Outcome; D000077484:Vemurafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; D007770:L-Lactate Dehydrogenase; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; C561627:dabrafenib
keywords: BRAF; biomarker; inhibitor; lactate dehydrogenase (LDH); melanoma; survival