180P - Genome-wide association study (GWAS) identifies candidate neurotoxicity markers in platinum-taxane treated ovarian cancer patients in ICON7

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Ovarian Cancer
Complications of Treatment
Translational Research
Presenter Osvaldo Espin-Garcia
Citation Annals of Oncology (2014) 25 (suppl_4): iv58-iv84. 10.1093/annonc/mdu326
Authors O. Espin-Garcia1, G. Liu1, K. Owzar2, D. Kroetz3, S. Marsh4, T. Perrin5, C. Adusei6, L. Farrelly6, A. Embleton6, A.M. Swart7, M.K. Parmar8, R. Kaplan9, M. Kubo10, M. Ratain11, K. Matsuda10, A.M. Oza12, W. Xu1, H. Mackay13
  • 1Department Of Medical Oncology, Princess Margaret Hospital, University Health Network, M5G 2M9 - Toronto/CA
  • 2Biostatistics, Duke University, DUrham/US
  • 3Pharmaceutical Sciences, UCSF, San Francisco/US
  • 4Pharmacy, University of Alberta, Edmonton/CA
  • 5Department Of Medical Oncology, University of Leeds, London/GB
  • 6Oncology, Medical Research Council, Manchester/GB
  • 7Cancer Group, MRC Clinical Trials Unit, London/GB
  • 8Research, Medical Research Council (MRC)MRC Clinical Trials Unit, GB-NW1 2DA - London/GB
  • 9Ncrn, National Cancer Research Network NCRN Coordinating Centre, London/GB
  • 10Riken, RIKEN CGM, Yokohama/JP
  • 11Department Of Medicine, University of Chicago, Chicago/US
  • 12Dept. Of Medicine, Princess Margaret Hospital, CA-M5G 2M9 - Toronto/CA
  • 13Medical Oncology, Princess Margret Hospital, Toronto/CA

Abstract

Aim

Neurotoxicity is known of both platinum and taxane agents. Factors associated with increased risk of peripheral neuropathy (PN) include cumulative dose and comorbidity. Individual genetic susceptibility may play a role. Applying GWAS methods to patients of ICON7 (NCT00483782), a phase 3 ovarian cancer trial of adding bevacizumab to carboplatin and paclitaxel, we evaluated the association of heritable genetic markers with PN.

Methods

Germline DNA from 437 patients were genotyped using an Illumina Omni-Platform. In a cumulative-dose/m2-to-toxicity analysis, Cox proportional hazard models generated hazard ratios (HR) and 95% confidence intervals for the development of Grade 2 or higher PN. Baseline clinical multivariate models of toxicity, stratified by treatment arm, were compared with and without inclusion of individual genetic markers through likelihood ratio tests (LRT), assuming an additive genetic inheritance model.

Results

After quality control steps, 396 predominantly genetic European patient samples and 727,683 markers were evaluable. 28% of patients developed Grade 2+ PN. Study country but not pre-existing diabetes was significantly associated with PN in clinical multivariate models; the bevacizumab arm was associated with a trend for increased PN (adjusted HR, aHR, 1.32 (1.0-1.7; P = 0.054). Although no single marker reached genome-wide significance level after adjustment for clinical factors, top identified multiple markers associated with PN were in the pyrin (PYR; P = 9.9x10−7) and RNA editing pathways (REP; P = 1.3x10−6 by LRT). In both, the presence of each additional at-risk allele was associated with a doubled odds of developing Grade 2+ PN: for PYR, the top variant had an a HR of 1.92 (95%CI: 1.5-2.5), while for REP, the top variant had an a HR of 2.12 (95%CI: 1.5-2.9). PYR pathway is associated with a caspase-activating platform, the inflammasone, and Schwann cell damage. The REP affects neuronal structure and physiology in several animal model systems.

Conclusions

PYR and REP polymorphisms were the top markers associated with PN in carboplatin-paclitaxel treated ovarian cancer patients. Validation in other trials is warranted.

Disclosure

M.J. Ratain: I am a consultant to Genentech and coinventor on a provisional patent application related to genomic prescribing; A.M. Oza: Travel support for ROCHE advisory PI on ROSIA -Roche supported clinical trial. Institutional funding from ROCHE for clinical trials; H. Mackay: Roche supports institutional trials.

All other authors have declared no conflicts of interest.