The sum of gains and losses of genes encoding the protein tyrosine kinase targets predicts response to multi-kinase inhibitor treatment: Characterization, validation, and prognostic value

Oncotarget
Xiaojun JiangJean-Yves Blay

Abstract

Validated predictive biomarkers for multi-tyrosine kinase inhibitors (MTKI) efficacy are lacking. We hypothesized that interindividual response variability is partially dependent on somatic DNA copy number alterations (SCNAs), particularly those of genes encoding the protein tyrosines targeted by MTKI (called target genes). Genomic alterations were investigated in MTKI responsive and non responsive patients with different histological subtypes included in the ProfiLER protocol (NCT 01774409). From March 2013 to August 2014, 58 patients with advanced cancer treated with one of 7 MTKIs were included in the ProfiLER trial and split into one discovery cohort (n = 13), and 2 validation cohorts (n = 12 and 33). An analysis of the copy number alterations of kinase-coding genes for each of 7 MTKIs was conducted. A prediction algorithm (SUMSCAN) based on the presence of specific gene gains (Tumor Target Charge, TTC) and losses (Tumor Target Losses, TTL) was conceived and validated in 2 independent validation cohorts. MTKI sensitive tumors present a characteristic SCNA profile including a global gain profile, and specific gains for target genes while MTKI resistant tumors present the opposite. SUMSCAN favorable patients achieved longer p...Continue Reading

References

Dec 4, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Michael C HeinrichJonathan A Fletcher
Mar 11, 2004·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·M Debiec-RychterUNKNOWN EORTC Soft Tissue and Bone Sarcoma Group
Jul 11, 2006·The New England Journal of Medicine·Arlo J Miller, Martin C Mihm
Jan 12, 2007·The New England Journal of Medicine·Robert J MotzerRobert A Figlin
Jun 11, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Ezra E W CohenRoger B Cohen
Jul 25, 2008·The New England Journal of Medicine·Josep M LlovetUNKNOWN SHARP Investigators Study Group
Dec 23, 2008·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·E A EisenhauerJ Verweij
Apr 11, 2009·Nature·Michael R StrattonP Andrew Futreal
Jan 27, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Cora N SternbergRobert E Hawkins
May 11, 2010·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Fergal C Kelleher, Ray McDermott
Jul 24, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Carol PeñaRonald M Bukowski
Sep 8, 2010·The New England Journal of Medicine·Keith T FlahertyPaul B Chapman
Sep 18, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Laurie L CarrRenato G Martins
Sep 18, 2010·Nature Reviews. Genetics·Matthew MeyersonGad Getz
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
May 18, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Chun-Fang XuLini N Pandite
Mar 30, 2013·Science·Bert VogelsteinKenneth W Kinzler
Sep 28, 2013·Nature Genetics·Giovanni CirielloChris Sander

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Citations

Mar 24, 2018·Future Oncology·Christelle de la Fouchardière
Dec 30, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Nicolas Penel, Isabelle Ray-Coquard
Dec 5, 2015·Targeted Oncology·Christelle de la Fouchardière
Dec 9, 2017·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Rick L HaasAxel Le Cesne
Apr 19, 2018·Nature Reviews. Clinical Oncology·Armelle DufresneJean-Yves Blay
Sep 21, 2018·American Society of Clinical Oncology Educational Book·Elizabeth H BaldiniJonathan C Trent

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Methods Mentioned

BETA
targeted mutation
scraping
Feature Extraction

Clinical Trials Mentioned

NCT01774409

Software Mentioned

SPSS
NextGENe
SUMSCAN
Agilent Genomic Workbench
Agilent Feature Extraction
COSMIC

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