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Personalized Medicine and Imaging

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy

Daniel L. Hertz, Kouros Owzar, Sherrie Lessans, Claudia Wing, Chen Jiang, William Kevin Kelly, Jai Patel, Susan Halabi, Yoichi Furukawa, Heather E. Wheeler, Alexander B. Sibley, Cameron Lassiter, Lois Weisman, Dorothy Watson, Stefanie D. Krens, Flora Mulkey, Cynthia L. Renn, Eric J. Small, Phillip G. Febbo, Ivo Shterev, Deanna L. Kroetz, Paula N. Friedman, John F. Mahoney, Michael A. Carducci, Michael J. Kelley, Yusuke Nakamura, Michiaki Kubo, Susan G. Dorsey, M. Eileen Dolan, Michael J. Morris, Mark J. Ratain and Howard L. McLeod
Daniel L. Hertz
1Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan.
2UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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Kouros Owzar
3Duke Cancer Institute, Durham, North Carolina.
4Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
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Sherrie Lessans
5Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, Maryland.
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Claudia Wing
6Department of Medicine, University of Chicago, Chicago, Illinois.
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Chen Jiang
4Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
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William Kevin Kelly
7Thomas Jefferson University, Philadelphia, Pennsylvania.
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Jai Patel
2UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
8Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.
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Susan Halabi
3Duke Cancer Institute, Durham, North Carolina.
4Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
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Yoichi Furukawa
9Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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Heather E. Wheeler
6Department of Medicine, University of Chicago, Chicago, Illinois.
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Alexander B. Sibley
3Duke Cancer Institute, Durham, North Carolina.
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Cameron Lassiter
5Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, Maryland.
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Lois Weisman
10Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
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Dorothy Watson
4Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
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Stefanie D. Krens
2UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
11Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht, the Netherlands.
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Flora Mulkey
4Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
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Cynthia L. Renn
5Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, Maryland.
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Eric J. Small
12Department of Medicine, UCSF, San Francisco, California.
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Phillip G. Febbo
13Genomic Health, Redwood City, California.
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Ivo Shterev
14Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
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Deanna L. Kroetz
15Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.
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Paula N. Friedman
6Department of Medicine, University of Chicago, Chicago, Illinois.
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John F. Mahoney
8Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.
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Michael A. Carducci
16The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.
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Michael J. Kelley
17Durham VA Medical Center, Duke University Medical Center, Durham, North Carolina.
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Yusuke Nakamura
6Department of Medicine, University of Chicago, Chicago, Illinois.
9Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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Michiaki Kubo
18Lab for Genotyping Development, Riken Center for Integrative Medical Sciences, Kanagawa, Japan.
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Susan G. Dorsey
5Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, Maryland.
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M. Eileen Dolan
6Department of Medicine, University of Chicago, Chicago, Illinois.
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Michael J. Morris
19Memorial Sloan Kettering Cancer Center, New York.
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Mark J. Ratain
6Department of Medicine, University of Chicago, Chicago, Illinois.
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Howard L. McLeod
2UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
20Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida.
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  • For correspondence: Howard.mcleod@moffitt.org
DOI: 10.1158/1078-0432.CCR-15-2823 Published October 2016
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Abstract

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy.

Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy.

Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001).

Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.

Footnotes

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

  • Prior presentation: This study was presented in part at the 2013 American Society of Clinical Oncology Annual Meeting.

  • Received November 19, 2015.
  • Revision received March 11, 2016.
  • Accepted April 4, 2016.
  • ©2016 American Association for Cancer Research.
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Clinical Cancer Research: 22 (19)
October 2016
Volume 22, Issue 19
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Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy
Daniel L. Hertz, Kouros Owzar, Sherrie Lessans, Claudia Wing, Chen Jiang, William Kevin Kelly, Jai Patel, Susan Halabi, Yoichi Furukawa, Heather E. Wheeler, Alexander B. Sibley, Cameron Lassiter, Lois Weisman, Dorothy Watson, Stefanie D. Krens, Flora Mulkey, Cynthia L. Renn, Eric J. Small, Phillip G. Febbo, Ivo Shterev, Deanna L. Kroetz, Paula N. Friedman, John F. Mahoney, Michael A. Carducci, Michael J. Kelley, Yusuke Nakamura, Michiaki Kubo, Susan G. Dorsey, M. Eileen Dolan, Michael J. Morris, Mark J. Ratain and Howard L. McLeod
Clin Cancer Res October 1 2016 (22) (19) 4890-4900; DOI: 10.1158/1078-0432.CCR-15-2823

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Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy
Daniel L. Hertz, Kouros Owzar, Sherrie Lessans, Claudia Wing, Chen Jiang, William Kevin Kelly, Jai Patel, Susan Halabi, Yoichi Furukawa, Heather E. Wheeler, Alexander B. Sibley, Cameron Lassiter, Lois Weisman, Dorothy Watson, Stefanie D. Krens, Flora Mulkey, Cynthia L. Renn, Eric J. Small, Phillip G. Febbo, Ivo Shterev, Deanna L. Kroetz, Paula N. Friedman, John F. Mahoney, Michael A. Carducci, Michael J. Kelley, Yusuke Nakamura, Michiaki Kubo, Susan G. Dorsey, M. Eileen Dolan, Michael J. Morris, Mark J. Ratain and Howard L. McLeod
Clin Cancer Res October 1 2016 (22) (19) 4890-4900; DOI: 10.1158/1078-0432.CCR-15-2823
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