ABCC2 polymorphisms and survival in the Princess Margaret cohort study and the NCIC clinical trials group BR.24 trial of platinum-treated advanced stage non-small cell lung cancer patients

Sinead Cuffe, Abul Kalam Azad, Xiaoping Qiu, Xin Qiu, Yonathan Brhane, Qin Kuang, Sharon Marsh, Sevtap Savas, Zhuo Chen, Dangxiao Cheng, Natasha B. Leighl, Glenwood Goss, Scott A. Laurie, Lesley Seymour, Penelope A. Bradbury, Frances A. Shepherd, Ming Sound Tsao, Bingshu E. Chen, Wei Xu, Geoffrey Liu

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: The drug transporter ABCC2 is upregulated in non-small cell lung cancer (NSCLC) and implicated in platinum resistance. We evaluated the association between germline polymorphisms in the ABCC2 gene and survival outcomes of platinum-treated advanced NSCLC patients. Material and methods: Ten candidate and tagging germline polymorphisms in the ABCC2 gene were genotyped in a discovery cohort of 170 platinum-treated stage IV NSCLC patients from the Princess Margaret Cancer Centre. Associations with overall survival were assessed using multivariate Cox proportional hazard models adjusted for prognostic variables. To validate our results, we analyzed the association of the two top polymorphisms in the ABCC2 gene on survival outcomes of 219 stage IIIB-IV NSCLC patients enrolled on the NCIC Clinical Trials Group BR.24 clinical trial. Results: Only one polymorphism was validated across both cohorts for an association with overall survival: the A allele of the ABCC2 polymorphism, rs8187710 (4544G > A), was associated with adverse overall survival (adjusted hazard ratio [aHR] 2.22; 95% CI: 1.2-4.0; p = 0.009) among our stage IV NSCLC patients. A significant association with overall survival (aHR 1.73; 95% CI: 1.0-2.9; p = 0.036) was observed for the same ABCC2 polymorphism in the BR.24 validation cohort. No other ABCC2 polymorphisms were associated with outcome. Conclusion: The ABCC2 polymorphism, rs8187710 (4544G > A), is associated with overall survival in platinum-treated advanced NSCLC patients. Additional studies are needed to evaluate the predictive versus prognostic nature of this relationship, and to explore the functional effect of this polymorphism on the pharmacokinetics of platinum drugs.

Original languageEnglish (US)
Pages (from-to)50-56
Number of pages7
JournalCancer Epidemiology
Volume41
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Keywords

  • ABCC2 polymorphisms
  • Non-small cell lung cancer
  • Platinum resistance
  • Survival outcomes

ASJC Scopus subject areas

  • Epidemiology
  • Oncology
  • Cancer Research

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