Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib.
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.
Mulligan
George
G
Clinical Research/Translational Medicine, Millennium Pharmaceuticals Inc., 40 Landsdowne Street, Cambridge, MA 02139, USA. george.mulligan@mpi.com
Mitsiades
Constantine
C
Bryant
Barb
B
Zhan
Fenghuang
F
Chng
Wee J
WJ
Roels
Steven
S
Koenig
Erik
E
Fergus
Andrew
A
Huang
Yongsheng
Y
Richardson
Paul
P
Trepicchio
William L
WL
Broyl
Annemiek
A
Sonneveld
Pieter
P
Shaughnessy
John D
JD
Bergsagel
P Leif
PL
Schenkein
David
D
Esseltine
Dixie-Lee
DL
Boral
Anthony
A
Anderson
Kenneth C
KC
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
D018931:Antineoplastic Agents, Hormonal; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone