title: Next generation sequencing analysis of platinum refractory advanced germ cell tumor sensitive to Sunitinib (Sutent®) a VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor in a phase II trial.
abstract: BACKGROUND
  Germ cell tumors (GCT) are the most common solid tumors in adolescent and young adult males (age 15 and 35 years) and remain one of the most curable of all solid malignancies. However a subset of patients will have tumors that are refractory to standard chemotherapy agents. The management of this refractory population remains challenging and approximately 400 patients continue to die every year of this refractory disease in the United States.
  
  
  METHODS
  Given the preclinical evidence implicating vascular endothelial growth factor (VEGF) signaling in the biology of germ cell tumors, we hypothesized that the vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib (Sutent) may possess important clinical activity in the treatment of this refractory disease. We proposed a Phase II efficacy study of sunitinib in seminomatous and non-seminomatous metastatic GCT's refractory to first line chemotherapy treatment (ClinicalTrials.gov Identifier: NCT00912912). Next generation targeted exome sequencing using HiSeq 2000 (Illumina Inc., San Diego, CA, USA) was performed on the tumor sample of the unusual responder.
  
  
  RESULTS
  Five patients are enrolled into this Phase II study. Among them we report here the clinical course of a patient (Patient # 5) who had an exceptional response to sunitinib. Next generation sequencing to understand this patient's response to sunitinib revealed RET amplification, EGFR and KRAS amplification as relevant aberrations. Oncoscan MIP array were employed to validate the copy number analysis that confirmed RET gene amplification.
  
  
  CONCLUSIONS
  Sunitinib conferred clinical benefit to this heavily pre-treated patient. Next generation sequencing of this 'exceptional responder' identified the first reported case of a RET amplification as a potential basis of sensitivity to sunitinib (VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor) in a patient with refractory germ cell tumor. Further characterization of GCT patients using biomarkers for clinical response and patient selection is warranted.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT00912912.
authors.affiliation: Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston 77030, Texas, USA. vsubbiah@mdanderson.org.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Kenna R Mills
authors.initials: KR
authors.lastname: Shaw
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Bailey
authors.forename: Priya
authors.initials: P
authors.lastname: Rao
authors.forename: John F
authors.initials: JF
authors.lastname: Ward
authors.forename: Lance C
authors.initials: LC
authors.lastname: Pagliaro
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008479:Mediastinal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D017671:Platinum Compounds / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D011758:Pyrroles / Q000627:therapeutic use*; D012186:Retroperitoneal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D000077210:Sunitinib; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D017671:Platinum Compounds; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D000077210:Sunitinib
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