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Personalized Medicine and Imaging

MultiDimensional ClinOmics for Precision Therapy of Children and Adolescent Young Adults with Relapsed and Refractory Cancer: A Report from the Center for Cancer Research

Wendy Chang, Andrew S. Brohl, Rajesh Patidar, Sivasish Sindiri, Jack F. Shern, Jun S. Wei, Young K. Song, Marielle E. Yohe, Berkley Gryder, Shile Zhang, Kathleen A. Calzone, Nityashree Shivaprasad, Xinyu Wen, Thomas C. Badgett, Markku Miettinen, Kip R. Hartman, James C. League-Pascual, Toby N. Trahair, Brigitte C. Widemann, Melinda S. Merchant, Rosandra N. Kaplan, Jimmy C. Lin and Javed Khan
Wendy Chang
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
2Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
3Department of Pediatrics, Molecular Genetics, Columbia University Medical Center, New York, New York.
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Andrew S. Brohl
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
4Sarcoma Department, Moffitt Cancer Center, Tampa, Florida.
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Rajesh Patidar
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Sivasish Sindiri
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Jack F. Shern
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
2Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Jun S. Wei
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Young K. Song
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Marielle E. Yohe
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
2Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Berkley Gryder
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Shile Zhang
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Kathleen A. Calzone
5Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Nityashree Shivaprasad
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Xinyu Wen
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Thomas C. Badgett
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
6Pediatric Hematology-Oncology, Kentucky Children's Hospital, Lexington, Kentucky.
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Markku Miettinen
7Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
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Kip R. Hartman
8Walter Reed National Military Medical Center, Bethesda, Maryland.
9Uniformed Services University of the Health Sciences, Bethesda, Maryland.
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James C. League-Pascual
2Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
8Walter Reed National Military Medical Center, Bethesda, Maryland.
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Toby N. Trahair
10Centre for Children's Cancer and Blood Disorders, Sydney Children's Hospital, Randwick, New South Wales, Australia.
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Brigitte C. Widemann
2Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Melinda S. Merchant
2Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Rosandra N. Kaplan
2Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Jimmy C. Lin
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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Javed Khan
1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
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  • For correspondence: khanjav@mail.nih.gov
DOI: 10.1158/1078-0432.CCR-15-2717 Published August 2016
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Abstract

Purpose: We undertook a multidimensional clinical genomics study of children and adolescent young adults with relapsed and refractory cancers to determine the feasibility of genome-guided precision therapy.

Experimental Design: Patients with non-central nervous system solid tumors underwent a combination of whole exome sequencing (WES), whole transcriptome sequencing (WTS), and high-density single-nucleotide polymorphism array analysis of the tumor, with WES of matched germline DNA. Clinically actionable alterations were identified as a reportable germline mutation, a diagnosis change, or a somatic event (including a single nucleotide variant, an indel, an amplification, a deletion, or a fusion gene), which could be targeted with drugs in existing clinical trials or with FDA-approved drugs.

Results: Fifty-nine patients in 20 diagnostic categories were enrolled from 2010 to 2014. Ages ranged from 7 months to 25 years old. Seventy-three percent of the patients had prior chemotherapy, and the tumors from these patients with relapsed or refractory cancers had a higher mutational burden than that reported in the literature. Thirty patients (51% of total) had clinically actionable mutations, of which 24 (41%) had a mutation that was currently targetable in a clinical trial setting, 4 patients (7%) had a change in diagnosis, and 7 patients (12%) had a reportable germline mutation.

Conclusions: We found a remarkably high number of clinically actionable mutations in 51% of the patients, and 12% with significant germline mutations. We demonstrated the clinical feasibility of next-generation sequencing in a diverse population of relapsed and refractory pediatric solid tumors. Clin Cancer Res; 22(15); 3810–20. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received November 10, 2015.
  • Revision received January 28, 2016.
  • Accepted February 21, 2016.
  • ©2016 American Association for Cancer Research.
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Clinical Cancer Research: 22 (15)
August 2016
Volume 22, Issue 15
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MultiDimensional ClinOmics for Precision Therapy of Children and Adolescent Young Adults with Relapsed and Refractory Cancer: A Report from the Center for Cancer Research
Wendy Chang, Andrew S. Brohl, Rajesh Patidar, Sivasish Sindiri, Jack F. Shern, Jun S. Wei, Young K. Song, Marielle E. Yohe, Berkley Gryder, Shile Zhang, Kathleen A. Calzone, Nityashree Shivaprasad, Xinyu Wen, Thomas C. Badgett, Markku Miettinen, Kip R. Hartman, James C. League-Pascual, Toby N. Trahair, Brigitte C. Widemann, Melinda S. Merchant, Rosandra N. Kaplan, Jimmy C. Lin and Javed Khan
Clin Cancer Res August 1 2016 (22) (15) 3810-3820; DOI: 10.1158/1078-0432.CCR-15-2717

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MultiDimensional ClinOmics for Precision Therapy of Children and Adolescent Young Adults with Relapsed and Refractory Cancer: A Report from the Center for Cancer Research
Wendy Chang, Andrew S. Brohl, Rajesh Patidar, Sivasish Sindiri, Jack F. Shern, Jun S. Wei, Young K. Song, Marielle E. Yohe, Berkley Gryder, Shile Zhang, Kathleen A. Calzone, Nityashree Shivaprasad, Xinyu Wen, Thomas C. Badgett, Markku Miettinen, Kip R. Hartman, James C. League-Pascual, Toby N. Trahair, Brigitte C. Widemann, Melinda S. Merchant, Rosandra N. Kaplan, Jimmy C. Lin and Javed Khan
Clin Cancer Res August 1 2016 (22) (15) 3810-3820; DOI: 10.1158/1078-0432.CCR-15-2717
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