title: Sunitinib therapy for melanoma patients with KIT mutations.
abstract: OBJECTIVE
  Recent studies have shown activating KIT mutations in melanoma originating from mucosa, acral, or cumulative sun-damaged skin sites. We aimed to assess the predictive role of KIT mutation, amplification, or overexpression for response to treatment with the kinase inhibitor sunitinib.
  
  
  METHODS
  Tumor tissues from 90 patients with stage III or IV acral, mucosal, or cumulative sun-damaged skin melanoma underwent sequencing of KIT, BRAF, NRAS, and GNAQ genes, FISH analysis for KIT amplification, and immunohistochemistry of KIT protein (CD117). Patients with mutations, amplifications, or overexpression of KIT were treated with sunitinib and responses measured by Response Evaluation Criteria in Solid Tumors (RECIST).
  
  
  RESULTS
  Eleven percent of the melanomas tested had mutations in KIT, 23% in BRAF, 14% in NRAS, and none in GNAQ. Of 12 patients treated with sunitinib, 10 were evaluable. Of the 4 evaluable patients with KIT mutations, 1 had a complete remission for 15 months and 2 had partial responses (1- and 7-month duration). In contrast, only 1 of the 6 patients with only KIT amplification or overexpression alone had a partial response. In 1 responder with rectal melanoma who later progressed, the recurring tumor had a previously undetected mutation in NRAS, which was found in addition to the persisting mutation in KIT. Interestingly, among patients with manifest stage IV disease, KIT mutations were associated with a significantly shortened survival time (P < 0.0001).
  
  
  CONCLUSIONS
  Sunitinib may have activity in patients with melanoma and KIT mutations; more study is needed. KIT mutations may represent an adverse prognostic factor in metastatic melanoma.
authors.affiliation: California Pacific Center for Melanoma Research and Treatment, University of California San Francisco, San Francisco, California, USA. minord@sutterhealth.org
authors.forename: David R
authors.initials: DR
authors.lastname: Minor
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kashani-Sabet
authors.forename: Maria
authors.initials: M
authors.lastname: Garrido
authors.forename: Steven J
authors.initials: SJ
authors.lastname: O'Day
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D019009:Proto-Oncogene Proteins c-kit; D000077210:Sunitinib