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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

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 managemen...

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Autores principales: Subbiah, Vivek, Meric-Bernstam, Funda, Mills, Gordon B, Shaw, Kenna R Mills, Bailey, Ann Marie, Rao, Priya, Ward, John F, Pagliaro, Lance C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237879/
https://www.ncbi.nlm.nih.gov/pubmed/25085632
http://dx.doi.org/10.1186/s13045-014-0052-x
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author Subbiah, Vivek
Meric-Bernstam, Funda
Mills, Gordon B
Shaw, Kenna R Mills
Bailey, Ann Marie
Rao, Priya
Ward, John F
Pagliaro, Lance C
author_facet Subbiah, Vivek
Meric-Bernstam, Funda
Mills, Gordon B
Shaw, Kenna R Mills
Bailey, Ann Marie
Rao, Priya
Ward, John F
Pagliaro, Lance C
author_sort Subbiah, Vivek
collection PubMed
description 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
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spelling pubmed-42378792014-11-21 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 Subbiah, Vivek Meric-Bernstam, Funda Mills, Gordon B Shaw, Kenna R Mills Bailey, Ann Marie Rao, Priya Ward, John F Pagliaro, Lance C J Hematol Oncol Research 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 BioMed Central 2014-08-01 /pmc/articles/PMC4237879/ /pubmed/25085632 http://dx.doi.org/10.1186/s13045-014-0052-x Text en Copyright © 2014 Subbiah et al.; licensee BioMed Central Ltd.
spellingShingle Research
Subbiah, Vivek
Meric-Bernstam, Funda
Mills, Gordon B
Shaw, Kenna R Mills
Bailey, Ann Marie
Rao, Priya
Ward, John F
Pagliaro, Lance C
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237879/
https://www.ncbi.nlm.nih.gov/pubmed/25085632
http://dx.doi.org/10.1186/s13045-014-0052-x
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