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Cancer Therapy: Clinical

HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer

Chun-Fang Xu, Toby Johnson, Xiaojing Wang, Chris Carpenter, Alan P. Graves, Liling Warren, Zhengyu Xue, Karen S. King, Dana J. Fraser, Sandy Stinnett, Linda P. Briley, Ionel Mitrica, Colin F. Spraggs, Matthew R. Nelson, Hiroomi Tada, Andreas du Bois, Thomas Powles, Neil Kaplowitz and Lini N. Pandite
Chun-Fang Xu
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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  • For correspondence: chun-fang.2.xu@gsk.com
Toby Johnson
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Xiaojing Wang
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Chris Carpenter
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Alan P. Graves
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Liling Warren
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Zhengyu Xue
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Karen S. King
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Dana J. Fraser
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Sandy Stinnett
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Linda P. Briley
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Ionel Mitrica
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Colin F. Spraggs
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Matthew R. Nelson
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Hiroomi Tada
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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Andreas du Bois
Department of Gynecology & Gynecologic Oncology, Kliniken Essen Mitte, Essen, Germany.
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Thomas Powles
Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
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Neil Kaplowitz
Keck School of Medicine, University of Southern California, Los Angeles, California.
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Lini N. Pandite
GlaxoSmithKline Research and Development, Stevenage, UK, Research Triangle Park, North Carolina and King of Prussia, Pennsylvania.
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DOI: 10.1158/1078-0432.CCR-15-2044
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    • Supplement - Supplementary Table S1. Summary of eight pazopanib (monotherapy) clinical studies included in the discovery pharmacogenetic liver toxicity analysis Supplementary Table S2. Summary of 23 pazopanib clinical studies included in the confirmatory pharmacogenetic liver toxicity analysis Supplementary Table S3. Primary tumor types for patients in the pharmacogenetic analyses Supplementary Table S4. Association between HLA-B*57:01 carriage and ALT elevation in pazopanib-treated patients with cancer. Sensitivity analyses in the combined dataset excluding 192 patients with baseline ALT>ULN Supplementary Table S5. Assessment of patients who had concurrent ALT (>3×ULN) and total bilirubin (>2×ULN) elevations Supplementary Table S6. Association between rs1800625 (chr6:32152442) genotype and ALT elevation in pazopanib-treated patients with cancer Supplementary Table S7. Joint analysis of HLA-B*57:01 and rs1800625 (chr6:32152442) genotype association with time to ALT>3xULN in pazopanib-treated patients with cancer Supplementary Figure S1. Genome-wide association study (GWAS) of common genetic variants (minor allele frequency {greater than or equal to}5%) associated with time to first ALT>3×ULN.
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Published OnlineFirst January 8, 2016
doi: 10.1158/1078-0432.CCR-15-2044

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HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer
Chun-Fang Xu, Toby Johnson, Xiaojing Wang, Chris Carpenter, Alan P. Graves, Liling Warren, Zhengyu Xue, Karen S. King, Dana J. Fraser, Sandy Stinnett, Linda P. Briley, Ionel Mitrica, Colin F. Spraggs, Matthew R. Nelson, Hiroomi Tada, Andreas du Bois, Thomas Powles, Neil Kaplowitz and Lini N. Pandite
Clin Cancer Res January 8 2016 DOI: 10.1158/1078-0432.CCR-15-2044

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HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer
Chun-Fang Xu, Toby Johnson, Xiaojing Wang, Chris Carpenter, Alan P. Graves, Liling Warren, Zhengyu Xue, Karen S. King, Dana J. Fraser, Sandy Stinnett, Linda P. Briley, Ionel Mitrica, Colin F. Spraggs, Matthew R. Nelson, Hiroomi Tada, Andreas du Bois, Thomas Powles, Neil Kaplowitz and Lini N. Pandite
Clin Cancer Res January 8 2016 DOI: 10.1158/1078-0432.CCR-15-2044
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