title: Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib.
abstract: The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from prospective clinical trials of new anticancer agents.
authors.affiliation: Clinical Research/Translational Medicine, Millennium Pharmaceuticals Inc., 40 Landsdowne Street, Cambridge, MA 02139, USA. george.mulligan@mpi.com
authors.forename: George
authors.initials: G
authors.lastname: Mulligan
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Barb
authors.initials: B
authors.lastname: Bryant
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.forename: Wee J
authors.initials: WJ
authors.lastname: Chng
authors.forename: Steven
authors.initials: S
authors.lastname: Roels
authors.forename: Erik
authors.initials: E
authors.lastname: Koenig
authors.forename: Andrew
authors.initials: A
authors.lastname: Fergus
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Huang
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: William L
authors.initials: WL
authors.lastname: Trepicchio
authors.forename: Annemiek
authors.initials: A
authors.lastname: Broyl
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: David
authors.initials: D
authors.lastname: Schenkein
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.forename: Anthony
authors.initials: A
authors.lastname: Boral
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D003907:Dexamethasone / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000008:administration & dosage*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage*; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone