Are ABCB1 (P-glycoprotein) polymorphisms clinically relevant in ovarian cancer? - Finally an Answer!

Gynecologic Oncology 131 (2013) 1–2 Contents lists available at ScienceDirect Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno Editorial Are ABCB1 (P-glycoprotein) polymorphisms clinically relevant in ovarian cancer? – Finally an Answer! Existing medical treatments for ovarian cancer, including chemo- therapeutic, hormonal and biologic agents are merely effective in a sub- set of patients, often only produce partial responses of short duration, and are frequently associated with signiﬁcant side effects. The hope is that through pharmacogenetics we will be able to personalize the use of these treatments to maximize their efﬁcacy and tolerability [1]. A growing number of pharmacogenetic studies have focused on inherit- able variations in candidate genes believed to inﬂuence the absorption, distribution, or clearance of anticancer drugs. This issue of the Journal contains an important article as to whether genetic variations of the ABCB1 gene in ovarian cancer patients give rise to differing responses to chemotherapy [2]. The product of the ABCB1 gene, P-glycoprotein, is a transmembrane efﬂux pump which moves substrates across the cell membrane and out of the cell. It is a member of a superfamily of ATP binding cassette (ABC) membrane transporters and has been described to be a putative mech- anism of multidrug resistance in a range of diseases, including ovarian cancer. Chemotherapeutic agents that are affected by P-glycoprotein in- clude vinca alkaloids, anthracyclines and paclitaxel and resistance may result because increased drug efﬂux lowers intracellular drug concen- trations of these agents. Although it seems likely that cancer cells use several different types of ABC transporters to gain drug resistance most clinical studies have focused on P-glycoprotein. Increased expres- sion of P-glycoprotein in tumor tissues has been associated with adverse clinical outcome in ovarian cancer [3–7]. However, many of these stud- ies were small and most used varying methods to assess P-glycoprotein levels, thus uniform conclusions on the clinical relevance of P- glycoprotein expression for drug response in ovarian cancer cannot yet be made. Most importantly, however, membrane transporters, such as P-glycoprotein are critically involved in drug clearance and alter systemic drug levels by actively transporting substrate drugs be- tween organs and normal tissues. As such, heritable germ line polymor- phisms in genes encoding these membrane transporters may have signiﬁcant effects on the absorption, distribution and excretion of che- motherapeutic agents and may alter the pharmacodynamics of many agents. More than 50 of these polymorphisms have been described in the ABCB1 gene [8]. Several of these genetic variants result in alterations in mRNA expression levels (e.g., promoter variants), translational ef- ﬁciency (e.g., alterations in mRNA folding), and protein function (e.g., coding polymorphisms) [9]. However, there are three single- nucleotide polymorphisms (SNPs) that are common in most ethnic groups: A synonymous transition at nucleotide C1236T (Gly411Gly) (rs1128503) in exon 12, a nonsynonymous transition G2677T/A (Ala893Ser/Thr) (rs2032582) in exon 21, and a synonymous 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.09.001 transition C3435T (Ile1145Ile) (rs1045642) in exon 26. It is postulat- ed that these polymorphisms contribute to variability in P- glycoprotein function, and that therefore multidrug resistance is, at least in part, genetically determined. Previous clinical studies, how- ever, have produced inconsistent results. To date six studies of adju- vant platinum and taxane-based therapy have assessed the association between the abovementioned three common polymor- phisms in ABCB1 and treatment outcome in ovarian cancer [10–15]. In four of these studies no associations were found between clinical outcome and the polymorphisms tagging either T1236C [11,12] or G2677T/A and C3435T [12,14,15]. In contrast, two studies demon- strated that the SNP tagging G2677T/A was associated with im- proved outcome [10,13]. However, the latter two studies only reported on progression free survival and only one included a multi- variate analysis [13]. Many of these studies were relatively small and thus likely underpowered for pharmacogenetics studies. In contrast, the article by Johnatty et al. in this issue represents an impressive example of pharmacogenomic research at its best [2]. It is the most comprehensive study conducted to date on ABCB1 polymor- phisms in ovarian cancer. The authors investigated ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) in 4616 European ovarian cancer patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and the Cancer Genome Atlas (TCGA) research Network. This well designed observational study has many strengths, such as its long median follow-up of 5.9 years, geno- type data that conforms to quality assurance criteria, detailed and com- plete information on the type of adjuvant chemotherapy and the number of cycles given. Additional strengths are its rigorous statistical approach, its restriction of the analysis to an ethnically homogenous population and lastly its very large sample size. Among the 4616 ovarian cancer patients that received any form of adjuvant chemotherapy Johnatty et al. demonstrate that none of the three common coding SNPs tagging either C1236T (rs1128503), G2677T/A (rs2032582), or C3435T (rs1045642) was associated with progression-free or overall survival. Similarly, no association was seen in a subset of 1882 patients known to have received at least 4 cycles of paclitaxel carboplatin che- motherapy. One of the three coding SNPs, C1236T (rs1128503), which has recently been described to be functionally relevant though silent [16], however, was found to be marginally associated with improved overall survival, but only in those patients that were found to have no residual disease following debulking surgery regardless of chemothera- py. Analysis of an additional 1562 SNPs ﬂanking ABCB1 in ~3000 pa- tients yielded no new signals. This large scale pharmacogenomic study has evidently been designed and conducted very carefully. Nevertheless, I think that