Elsevier

Gynecologic Oncology

Volume 124, Issue 3, March 2012, Pages 575-581
Gynecologic Oncology

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,☆☆,,★★

https://doi.org/10.1016/j.ygyno.2011.11.022Get rights and content

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.

Highlights

► Common variants in the ABC transporter genes are associated with survival in advanced stage EOC Patients ► The C421A ( CA + AA) variant in the ABCG2 gene shows improved PFS in patients with advanced stage EOC

Introduction

Staging laparotomy with cytoreduction followed by platinum/taxane-based chemotherapy is the standard of care for women with advanced stage epithelial ovarian cancer (EOC). About 30% of advanced staged patients fail to respond initially to standard of care treatment, and a majority of the responders ultimately relapse over time [1], [2], [3]. While the mechanisms underlying inherent and acquired chemoresistance are not fully understood, there is growing evidence that ATP-binding cassette (ABC) multidrug efflux pumps play an important role. ABC transporters constitute a super-family of proteins with 48 members that transport a variety of endogenous or exogenous compounds across the cell membrane, using the energy provided by ATP hydrolysis [4], [5], [6], [7]. The ABC transporters are subdivided into seven distinct subfamilies (ABCA through ABCG) with overlapping and/or unique selectivity for targets [7]. When properly functioning, these transporters effectively transport compounds out of cells.

Of the ABC transporters, ABCB1, ABCC1, ABCC2, ABCC3 and ABCG2 are most often associated with resistance of cancer cell to multiple drugs termed multidrug resistance (MDR) [7], [8]. ABCB1, previously known as multidrug resistance 1 (MDR1) gene, encodes p-glycoprotein (PgP). This was the first ABC transporter found to selectively confer MDR in cancer cell by directly pumping out a broad spectrum of anticancer drugs, including paclitaxel and doxorubicin [6], [7]. Increased expression of ABCB1 in tumor cells has been shown to correlate with a poor response to paclitaxel [9], [10]. ABCC1, ABCC2 and ABCC3 encode multidrug resistance-associated protein 1 (MRP1), 2 (MRP2) and 3 (MRP3), respectively, and transport drugs conjugated to glutathione including platinum agents [5], [7], [11], [12] and taxanes [13], [14]. Glutathione conjugation is a major cellular mechanism for inactivating exogenous compounds. Once conjugated, platinum agents are efficiently exported from the cell via ABCC transporters and cannot re-enter the cell. The ABCC2 gene is overexpressed in some platinum-resistant ovarian cancer cells [5], [8], [11], [12]. ABCG2, also known as mitoxanthrone-resistance gene (MXR), breast cancer resistance protein (BCRP), or the ABC transporter in placenta (ABCP), encodes a broad-specificity transmembrane transporter [5], [15] for a variety of compounds including platinum agents, paclitaxel, doxorubicin, and topotecan [16], [17], [18]. The list of ABCG2 substrates currently includes nucleoside analogues such as gemcitabine, tyrosine kinase inhibitors, anti-virals, HMG-CoA reductase inhibitors, and flavonoids [17], [18].

Functional variants have been identified in a number of the MDR-associated ABC genes that appear to influence drug sensitivity/resistance through various mechanisms including expression level, stability, degradation, substrate-specificity and/or activity of these transporters [5], [7], [19], [20], [21], [22], [23], [24]. The current study utilized germline DNA from two phase III Gynecologic Oncology Group (GOG) clinical trials, GOG-172 [25] and GOG-182 [26], to determine if functional variants in ABCB1, ABCC2, and ABCG2 genes in EOC patients were associated with progression-free survival (PFS) and/or overall survival (OS) following platinum + taxane-based chemotherapy. We evaluated variants of ABCB1, ABCC2 and ABCG2 because the substrates of these genes include the standard agents used to treat advanced, persistent or recurrent EOC, such as cisplatin, carboplatin, topotecan, paclitaxel, doxorubicin and gemcitabine. The four common variants were selected based on the previous publications in which these polymorphisms were extensively studied in ovarian cancer and other cancers, with variable results. We assessed their prognostic values by taking advantage of the clinical data from GOG phase III trials. Subset analyses were performed to explore if the relationship between functional variants in ABC transporter genes and clinical outcomes were influenced by protocol, tumor stage, residual disease, or treatment regimen.

Section snippets

Study Population

This study focused on the subset of patients who participated in GOG-172 [25] or GOG-182 [26] with non-tumor DNA available for genotyping. All of the women gave written informed consent and provided a blood specimen for research consistent with all federal, state and local requirements. Details regarding eligibility criteria, treatment and clinical outcomes of these two protocols have been reported elsewhere [25], [26]. In brief, GOG-172 was a randomized two-arm phase III clinical trial to

Results

This study included 511 eligible women with germline DNA available for genotyping. The patient characteristics of this cohort are provided in Table 1. The median age for the cohort was 58 years with 91% Caucasians, 94% with a 0 to 1 baseline GOG performance score, 78% had serous adenocarcinoma and 75% had optimal-resected stage III (none, microscopic or < 1 cm residual) disease after surgical debulking. There were 232 patients from GOG-172 who were randomized to intraperitoneal or intravenous

Discussion

This study focused on functional variants in ABCB1, ABCC2 and ABCG2 based on the role that these genes play in drug resistance [6], [7], [8], [9], [10], MDR [7], [8], and specifically in the efflux of cisplatin, carboplatin, paclitaxel, gemcitabine, doxorubicin and/or topotecan [5], [6], [7], [11], [12], [13], [14], [16], [17], [18]. We found that the C421A variants in ABCG2 were associated with longer PFS in advanced stage EOC/PPC treated with platinum + paclitaxel-based chemotherapy. ABCG2

Conflict of interest statement

The authors wish to report that they have no conflicts of interest. However, Dr. Holly Gallion wishes to disclose that she is a stockowner of Precision Therapeutics and was an employee of Precision Therapeutics until 6/1/11.

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    All authors meet the criteria for authorship, and each certifies that the manuscript represents valid work and has not been previously published nor is under consideration for publication elsewhere.

    ☆☆

    This original research was presented in part at the 2009 Annual ASCO meeting (citation: J Clin Oncol 27(15S):Abstract #5567, s293, 2009.

    This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469), the GOG Statistical and Data Center (CA 37517) and to Roswell Park Cancer Institute (CA 016056–01) as well as grants from the Gynecologic Oncology Group/Ovarian Cancer Research Fund New Investigator Award (TK), The Jennie K. Scaife Foundation (JAD) and The Pittsburgh Foundation (JAD).

    ★★

    The following GOG member institutions participated in this translational research study: University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, University of Rochester Medical Center, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical School, Emory University Clinic, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group, P.C., University of California at Los Angeles, University of Washington, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, Georgetown University Hospital, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University Medical Center, Wake Forest University School of Medicine, Albany Medical College, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St. Luke's Medical Center, SUNY Downstate Medical Center, University of Kentucky, Community Clinical Oncology Program, The Cleveland Clinic Foundation, Johns Hopkins Oncology Center, SUNY at Stony Brook, Eastern Pennsylvania GYN/ONC Center, PC, Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical Center, Fox Chase Cancer Center, Medical University of South Carolina, Women's Cancer Center, University of Oklahoma, University of Virginia, University of Chicago, Tacoma General Hospital, Thomas Jefferson University Hospital, Case Western Reserve University, Tampa Bay Cancer Consortium, North Shore University Hospital, Brookview Research, Inc.

    1

    Dr. Tian's present address is: Precision Therapeutics Inc, Pittsburgh, PA.

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