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Clin Cancer Res. 2014 Jun 15;20(12):3328-37. doi: 10.1158/1078-0432.CCR-14-0093. Epub 2014 Apr 8.

Correlation of somatic mutations and clinical outcome in melanoma patients treated with Carboplatin, Paclitaxel, and sorafenib.

Author information

  • 1Authors' Affiliations: Hematology/Oncology, Department of Medicine, University of Pennsylvania; Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania; Abramson Cancer Center of the University of Pennsylvania, Philadelphia; University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; Dana Farber Cancer Institute; Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Pathology, Yale University School of Medicine; and Section of Medical Oncology, Yale Cancer Center, New Haven, Connecticut.
  • 2Authors' Affiliations: Hematology/Oncology, Department of Medicine, University of Pennsylvania; Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania; Abramson Cancer Center of the University of Pennsylvania, Philadelphia; University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; Dana Farber Cancer Institute; Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Pathology, Yale University School of Medicine; and Section of Medical Oncology, Yale Cancer Center, New Haven, ConnecticutAuthors' Affiliations: Hematology/Oncology, Department of Medicine, University of Pennsylvania; Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania; Abramson Cancer Center of the University of Pennsylvania, Philadelphia; University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; Dana Farber Cancer Institute; Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Pathology, Yale University School of Medicine; and Section of Medical Oncology, Yale Cancer Center, New Haven, Connecticut.
  • 3Authors' Affiliations: Hematology/Oncology, Department of Medicine, University of Pennsylvania; Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania; Abramson Cancer Center of the University of Pennsylvania, Philadelphia; University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; Dana Farber Cancer Institute; Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Pathology, Yale University School of Medicine; and Section of Medical Oncology, Yale Cancer Center, New Haven, ConnecticutAuthors' Affiliations: Hematology/Oncology, Department of Medicine, University of Pennsylvania; Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania; Abramson Cancer Center of the University of Pennsylvania, Philadelphia; University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; Dana Farber Cancer Institute; Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Pathology, Yale University School of Medicine; and Section of Medical Oncology, Yale Cancer Center, New Haven, Connecticut knathans@exchange.upenn.edu.

Abstract

PURPOSE:

Sorafenib is an inhibitor of VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and RAF kinases, amongst others. We assessed the association of somatic mutations with clinicopathologic features and clinical outcomes in patients with metastatic melanoma treated on E2603, comparing treatment with carboplatin, paclitaxel ± sorafenib (CP vs.

CPS) EXPERIMENTAL DESIGN:

Pretreatment tumor samples from 179 unique individuals enrolled on E2603 were analyzed. Genotyping was performed using a custom iPlex panel interrogating 74 mutations in 13 genes. Statistical analysis was performed using Fisher exact test, logistic regression, and Cox proportional hazards models. Progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier methods.

RESULTS:

BRAF and NRAS mutations were found at frequencies consistent with other metastatic melanoma cohorts. BRAF-mutant melanoma was associated with worse performance status, increased number of disease sites, and younger age at diagnosis. NRAS-mutant melanoma was associated with better performance status, fewer sites of disease, and female gender. BRAF and NRAS mutations were not significantly predictive of response or survival when treated with CPS versus CP. However, patients with NRAS-mutant melanoma trended toward a worse response and PFS on CP than those with BRAF-mutant or WT/WT melanoma, an association that was reversed for this group on the CPS arm.

CONCLUSIONS:

This study of somatic mutations in melanoma is the last prospectively collected phase III clinical trial population before the era of BRAF-targeted therapy. A trend toward improved clinical response in patients with NRAS-mutant melanoma treated with CPS was observed, possibly due to the effect of sorafenib on CRAF.

©2014 American Association for Cancer Research.

PMID:
24714776
[PubMed - in process]
PMCID:
PMC4058354
[Available on 2015-06-15]
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