Correlation of somatic mutations and clinical outcome in melanoma patients treated with Carboplatin, Paclitaxel, and sorafenib.
OBJECTIVE
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.
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.
Authors' 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.
Melissa A
MA
Wilson
Authors' 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.
Fengmin
F
Zhao
Authors' 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.
Richard
R
Letrero
Authors' 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.
Kurt
K
D'Andrea
Authors' 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.
David L
DL
Rimm
Authors' 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.
John M
JM
Kirkwood
Authors' 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.
Harriet M
HM
Kluger
Authors' 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.
Sandra J
SJ
Lee
Authors' 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.
Lynn M
LM
Schuchter
Authors' 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.
Keith T
KT
Flaherty
Authors' 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.
Katherine L
KL
Nathanson
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D016190:Carboplatin / Q000008:administration & dosage; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D017239:Paclitaxel / Q000008:administration & dosage; D010671:Phenylurea Compounds / Q000008:administration & dosage; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000077157:Sorafenib; D015996:Survival Rate
D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D016190:Carboplatin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D017239:Paclitaxel