Common variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes among women with advanced stage ovarian cancer treated with platinum and taxane-based chemotherapy: a Gynecologic Oncology Group study

Abstract

Purpose: Efflux transporters of the ATP-binding cassette (ABC) family are major determinants of chemoresistance in tumor cells. This study examined associations between functional variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian/primary peritoneal cancer (EOC/PPC) following platinum and taxane-based chemotherapy.

Methods: Sequenom iPLEXTMGOLD Assay and MALDI-TOF platform were used to genotype the non-synonymous G2677T/A (rs2032582; encoding Ala893Ser/Thr) and synonymous C3435T (rs1045642; encoding Ile1145Ile) variants in ABCB1, the non-synonymous G1249A variant in ABCC2 (rs2273697; encoding Val417Ile), and the non-synonymous C421A variant in ABCG2 (rs2231142; encoding Q141K, Gln141Lys) in normal DNA from up to 511 women in Gynecologic Oncology Group (GOG) phase III trials, GOG-172 or GOG-182. Progression-free survival (PFS) and overall survival (OS) were analyzed in relation to genetic polymorphisms using Kaplan-Meier and Cox proportional hazards model.

Results: The C421A variant (CA+AA versus CC) in ABCG2 was associated with a 6-month longer median PFS (22.7 versus 16.8 months, p=0.041). In multivariate analysis, patients with variant genotypes were at a reduced risk of disease progression (hazard ratio [HR]=0.75, 95% confidence interval [CI]=0.59-0.96, p=0.022). The association between C421A and OS was not statistically significant (HR=0.88, 95% CI=0.67-1.15, p=0.356). None of the other variants measured in either ABCB1 or ABCC2 was associated with PFS or OS.

Conclusion: The C421A variant in ABCG2, previously shown to be associated with enhanced protein degradation and drug sensitivity, was associated with longer PFS in advanced stage EOC/PPC patents treated with platinum+taxane-based chemotherapy. This finding requires further validation.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1

Kaplan-Meier estimates of progression-free survival (PFS) by the G2677T/A polymorphorism in ABCB1 (A), the C3435T polymorphorism in ABCB1 (B), or the G1249A polymorphorism in ABCC2 (C).

Figure 2

Kaplan-Meier estimates of progression-free survival (PFS) (A) and overall survival (OS) (B) by the C421A polymorphism in the ABCG2 gene.

Figure 3

Plots with hazard ratios (HR) and 95% confidence intervals (CI) for disease progression for women with the CA+AA genotypes versus the CC genotype in the C421A variant in the ABCG2 gene in the full cohort (A) and by treatment protocol (B), the aggregate of stage and residual disease status (C) and treatment regimen (D). Cis: cisplatin; P: paclitaxel; C: carboplatin; G: gemcitabine; D: doxil; T: topotecan

Figure 3

Plots with hazard ratios (HR) and 95% confidence intervals (CI) for disease progression for women with the CA+AA genotypes versus the CC genotype in the C421A variant in the ABCG2 gene in the full cohort (A) and by treatment protocol (B), the aggregate of stage and residual disease status (C) and treatment regimen (D). Cis: cisplatin; P: paclitaxel; C: carboplatin; G: gemcitabine; D: doxil; T: topotecan