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

Vivek Subbiah, Funda Meric-Bernstam, Gordon B. Mills, Kenna R.Mills Shaw, Ann Marie Bailey, Priya Rao, John F. Ward, Lance C. Pagliaro

    Research output: Contribution to journalArticle

    25 Scopus citations

    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.

    Conclusion: 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. Trial registration. ClinicalTrials.gov Identifier:.

    Original languageEnglish (US)
    Article number52
    JournalJournal of Hematology and Oncology
    Volume7
    Issue number1
    DOIs
    StatePublished - Aug 1 2014

    Keywords

    • Adolescent and young adult
    • EGFR
    • Exceptional responder
    • Germ cell tumor
    • Next generation sequencing
    • Outlier responder
    • Phase II trials
    • RET
    • Sunitinib
    • Targeted therapy
    • Unusual responder
    • VEGF
    • Vascular endothelial growth factor receptor

    ASJC Scopus subject areas

    • Molecular Biology
    • Hematology
    • Oncology
    • Cancer Research

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