Impact of MET expression on outcome in BRAF(V600E/K) advanced melanoma

Histopathology. 2013 Sep;63(3):351-61. doi: 10.1111/his.12169. Epub 2013 Jun 26.

Abstract

Aims: Preclinical data suggest that signalling through the HGF-MET pathway may confer resistance to BRAF inhibition in BRAF(V600E/K) melanoma. Therefore, blockade of HGF-MET signalling might be a valid therapeutic strategy, in combination with BRAF inhibition, in BRAF(V600E/K) melanoma. The aim of this study was to investigate the clinical relevance of these observations by evaluating the survival impact of MET expression in patients with BRAF(V600E/K) advanced melanoma treated with vemurafenib.

Methods and results: Formalin-fixed tissue blocks were obtained of tumours from patients enrolled in the BRIM2 (n = 59) and BRIM3 (n = 150) trials of vemurafenib in advanced BRAF(V600E/K) melanoma. Immunohistochemistry for MET (SP44 rabbit monoclonal antibody) was performed with a highly validated assay and clinically validated scoring system. Pretreatment MET expression was frequent at the ≥1 + cutoff (BRIM3, 31%; BRIM2, 49%), but relatively infrequent at the ≥2 + cutoff (BRIM3, 9%; BRIM2, 19%). Retrospective subset analyses showed that, irrespective of the cutoff used or the treatment arm, MET expression did not show prognostic significance, in terms of objective response rate, progression-free survival, or overall survival.

Conclusions: MET is expressed in a proportion of BRAF(V600E/K) advanced melanomas. Further analyses on appropriately powered subsets are needed to determine the prognostic and predictive significance of MET in vemurafenib-treated melanoma.

Keywords: BRAF; HGF; MET; SP44; melanoma.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Disease-Free Survival
  • Female
  • Humans
  • Immunohistochemistry
  • Indoles / therapeutic use
  • Kaplan-Meier Estimate
  • Male
  • Melanoma / metabolism*
  • Melanoma / pathology*
  • Melanoma / therapy
  • Middle Aged
  • Mutant Proteins / antagonists & inhibitors
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Prognosis
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Proto-Oncogene Proteins c-met / metabolism*
  • Rabbits
  • Retrospective Studies
  • Signal Transduction
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology*
  • Skin Neoplasms / therapy
  • Sulfonamides / therapeutic use
  • Vemurafenib
  • Young Adult

Substances

  • Indoles
  • Mutant Proteins
  • Sulfonamides
  • Vemurafenib
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf