Copy Number Changes Are Associated with Response to Treatment with Carboplatin, Paclitaxel, and Sorafenib in Melanoma

Clin Cancer Res. 2016 Jan 15;22(2):374-82. doi: 10.1158/1078-0432.CCR-15-1162. Epub 2015 Aug 25.

Abstract

Purpose: Copy number alterations have been shown to be involved in melanoma pathogenesis. The randomized phase III clinical trial E2603: carboplatin, paclitaxel, ± sorafenib (CP vs. CPS) offers a large collection of tumor samples to evaluate association of somatic mutations, genomic alterations, and clinical outcomes, prior to current FDA-approved therapies.

Experimental design: Copy number and mutational analysis on 119 pretreatment samples was performed.

Results: CPS therapy was associated with improved progression-free survival (PFS) compared with CP in patients with tumors with RAF1 (cRAF) gene copy gains (HR, 0.372; P = 0.025) or CCND1 gene copy gains (HR, 0.45; P = 0.035). CPS therapy was associated with improved overall survival (OS) compared with CP in patients with tumors with KRAS gene copy gains (HR, 0.25; P = 0.035). BRAF gene copy gain and MET amplification were more common in samples with V600K versus V600E mutations (P < 0.001), which was validated in The Cancer Genome Atlas (TCGA) dataset.

Conclusions: We observed improved treatment response with CPS in patients with melanoma whose tumors have RAF1 (cRAF), KRAS, or CCND1 amplification, all of which can be attributed to sorafenib targeting CRAF. These genomic alterations should be incorporated in future studies for evaluation as biomarkers.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carboplatin / therapeutic use*
  • DNA Copy Number Variations / drug effects*
  • DNA Copy Number Variations / genetics
  • DNA Mutational Analysis / methods
  • Disease-Free Survival
  • Double-Blind Method
  • Genes, ras / genetics
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / genetics*
  • Mutation / drug effects
  • Mutation / genetics
  • Neoplasm Staging / methods
  • Niacinamide / analogs & derivatives*
  • Niacinamide / therapeutic use
  • Paclitaxel / therapeutic use*
  • Phenylurea Compounds / therapeutic use*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-met / genetics
  • Sorafenib
  • Treatment Outcome

Substances

  • Phenylurea Compounds
  • Niacinamide
  • Sorafenib
  • Carboplatin
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins B-raf
  • Paclitaxel