Objective: To develop a predictive genetic signature for the development of bortezomib-induced peripheral neuropathy (PN).
Methods: Two thousand and sixteen single-nucleotide polymorphisms (SNPs) were genotyped in 139 samples from myeloma patients treated with bortezomib–melphalan–prednisone in the VISTA phase 3 trial. Single-marker association analysis for PN onset and time/cumulative dose to PN onset using the Cox proportional hazards model and multiple covariates was performed under additive, dominant, and recessive genotypic models, followed by correction for multiplicity. Associations were also pursued in a cohort of 212 samples from patients treated with bortezomib–dexamethasone in the IFM 2005-01 phase 3 trial.
Results: In the VISTA cohort, after Bonferroni correction, two SNPs significantly associated with time to onset of PN [CTLA4 rs4553808, false discovery rate (FDR)=0.002] and time to onset of grade of at least 2 PN (PSMB1 rs1474642, FDR=0.014). Using FDR less than 0.05 as the threshold, two additional SNPs significantly associated with time to onset of grade of at least 2 (CTSS rs12568757, FDR=0.027) or grade of at least 3 PN (GJE1 rs11974610, FDR=0.041). DYNC1I1 rs916758 significantly associated (FDR=0.012) with cumulative dose to onset of grade of at least 2 PN. These associations were generally not detected in the IFM 2005-01 cohort, although CTLA4 rs4553808 showed the same trend in association with time to onset (P=0.138). In addition, in the IFM 2005-01 cohort, TCF4 rs1261134 significantly associated with onset of any neurologic event (FDR=0.048).
Conclusion: Genes associated with immune function (CTLA4, CTSS), reflexive coupling within Schwann cells (GJE1), drug binding (PSMB1), and neuron function (TCF4, DYNC1I1) associated with bortezomib-induced PN in this study.
aJohnson and Johnson Pharmaceutical Research and Development, Raritan, New Jersey
bMillennium Pharmaceuticals, Inc., Cambridge, Massachusetts
cDana-Farber Cancer Institute, Boston, Massachusetts, USA
dJohnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium
eCentre René Gauducheau, Nantes/St Herblain, France
Correspondence to Deborah S. Ricci, PhD, Johnson and Johnson Pharmaceutical Research and Development, 920 Route 202, Raritan, NJ 08869, USA Tel: +1 908 218 7482; fax: +1 908 526 1242; e-mail: DRicci@its.jnj.com
Reyna Favis and Yu Sun contributed equally to the study.
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Received August 17, 2010
Accepted December 5, 2010