title: 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.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada; HOPE Directorate, St James's Hospital, Dublin 8, Ireland. Electronic address: scuffe@stjames.ie.
authors.forename: Sinead
authors.initials: S
authors.lastname: Cuffe
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Abul Kalam
authors.initials: AK
authors.lastname: Azad
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Yonathan
authors.initials: Y
authors.lastname: Brhane
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Qin
authors.initials: Q
authors.lastname: Kuang
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Sharon
authors.initials: S
authors.lastname: Marsh
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada; Discipline of Genetics, Memorial University of Newfoundland, St. John's, NL, Canada.
authors.forename: Sevtap
authors.initials: S
authors.lastname: Savas
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Dangxiao
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Natasha B
authors.initials: NB
authors.lastname: Leighl
authors.affiliation: Division of Medical Oncology, Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Glenwood
authors.initials: G
authors.lastname: Goss
authors.affiliation: Division of Medical Oncology, Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Laurie
authors.affiliation: NCIC Clinical Trials Group, Queens University, Kingston, ON, Canada.
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada; NCIC Clinical Trials Group, Queens University, Kingston, ON, Canada.
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Bradbury
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: Department of Pathology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Ming Sound
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: NCIC Clinical Trials Group, Queens University, Kingston, ON, Canada.
authors.forename: Bingshu E
authors.initials: BE
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome
chemical_list: D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human
keywords: ABCC2 polymorphisms; Non-small cell lung cancer; Platinum resistance; Survival outcomes