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

Journal of Hematology & Oncology

Lance C Pagliaro²  John F Ward³  Priya Rao⁴  Ann Marie Bailey¹  Kenna R Mills Shaw¹  Gordon B Mills¹  Funda Meric-Bernstam¹  Vivek Subbiah¹ 

[1] Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT), The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

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

Others  :  1144430
DOI  :  10.1186/s13045-014-0052-x

 received in 2014-06-08, accepted in 2014-07-07,  发布年份 2014

【 摘 要 】

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: NCT00912912 webcite

【 授权许可】

   
2014 Subbiah et al.; licensee BioMed Central Ltd.

【 图 表 】

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