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. (April 2016)

• Record Type: Journal Article
• Authors: Cuffe, Sinead; Azad, Abul Kalam; Qiu, Xiaoping; Qiu, Xin; Brhane, Yonathan; Kuang, Qin; Marsh, Sharon; Savas, Sevtap; Chen, Zhuo; Cheng, Dangxiao; Leighl, Natasha B.; Goss, Glenwood; Laurie, Scott A.; Seymour, Lesley; Bradbury, Penelope A.; Shepherd, Frances A.; Tsao, Ming Sound; Chen, Bingshu E.; Xu, Wei; Liu, Geoffrey
• Is Part Of: Cancer epidemiology. Volume 41(2016:Apr.)
• Page Start: 50
• Page End: 56
• Publication Date: 2016-04
• Subjects: NSCLC non-small cell lung cancer -- ABC adenosine triphosphate-binding cassette -- NCIC CTG NCIC Clinical Trials Group -- OS overall survival -- HWE Hardy–Weinberg equilibrium -- 95% CI 95% confidence intervals -- aHR adjusted Hazard Ratios; Non-small cell lung cancer -- Platinum resistance -- ABCC2 polymorphisms -- Survival outcomes; Cancer -- Epidemiology -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Diagnosis -- Periodicals; Carcinogenesis -- Periodicals; 616.994005
• DOI: 10.1016/j.canep.2015.12.012
• Languages: English
• ISSNs: 1877-7821

Abstract

Highlights: ABCC2 is upregulated in NSCLC and has been implicated in platinum resistance. A allele of ABCC2 4544G > A was linked to adverse survival among 170 NSCLC patients. This result was validated among 219 NSCLC patients from the BR.24 clinical trial. 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.