Genetic polymorphisms affecting clinical outcomes in epithelial ovarian cancer patients treated with taxanes and platinum compounds: A Korean population-based study

https://doi.org/10.1016/j.ygyno.2009.01.002Get rights and content

Abstract

Objective

We sought to evaluate the affect of genetic polymorphisms on clinical outcomes in patients with epithelial ovarian cancer (EOC).

Methods

Clinical data of 118 patients between March 2001 and November 2006 were reviewed. They underwent staging laparotomy followed by adjuvant chemotherapy using taxanes and platinum compounds. We investigated ERCC1 N118N, ERCC1 8092C>A, ERCC2 K751Q, XRCC1 R399Q, XRCC1 R194W, ABCB1 3435C>T, ABCB1 2677G>T/A, GSTP1 I105V, GSTM1 and GSTT1 polymorphisms with single base primer assay.

Results

The multivariate logistic regression analysis revealed that non-null genotype in GSTT1 polymorphism was a poor prognostic factors for overall response (adjusted OR, 0.29; 95% CI, 0.17–0.67), and A/A genotype in GSTP1 I105V polymorphism and T/T or T/A or A/A genotype in ABCB1 2677G>T/A polymorphism were significant risk factors for grade 3 or 4 hematological (adjusted OR, 3.08; 95% CI, 1.12–8.43) and gastrointestinal toxicities (adjusted OR, 9.74; 95% CI, 1.59–15.85), respectively. Moreover, The multivariate Cox's proportional hazard regression analysis showed that C/A or A/A genotype in ERCC1 8092C>A polymorphism and non-null genotype in GSTT1 polymorphism were prognostic factors for poor progression-free survival (adjusted HR, 1.94; 95% CI, 1.07–3.51) and poor overall survival (adjusted HR, 1.65; 95% CI, 1.79–3.42), respectively.

Conclusion

Genetic polymorphisms such as ERCC1 8092C>A, ABCB1 2677G>T/A, GSTP1 I105V and GSTT1 polymorphisms may affect drug response, toxicity and survival in patient with EOC who received taxane- and platinum-based chemotherapy after surgery. However, large-scale, prospective clinical studies are required for evaluating the role of genetic polymorphisms.

Introduction

The primary standard treatment of epithelial ovarian cancer (EOC) consists of a maximal cytoreductive surgery and adjuvant taxane- and platinum-based chemotherapy [1]. However, clinical outcomes by taxane- and platinum-based chemotherapy are different in patients with EOC. Recent studies suggested that there are significant differences in drug resistance, toxicity and survival for individuals with different genetic polymorphisms in the patients because they can change the function of enzymes related with metabolisms of taxanes and platinum compounds [2], [3].

For example, ATP-binding cassette transporter B1 (ABCB1, Multidrug resistance 1) polymorphism may change the function of P-glycoprotein, by which taxanes can be extruded through the cell membranes [4], [5]. Besides, drug resistance to platinum compounds may be shown by increased tolerance to DNA damage by Excision repair cross-complementation group 1 (ERCC1) [6], [7], Excision repair cross-complementation group 2 (ERCC2, Xeroderma pigmentosum group D) [8], [9], and X-ray repair cross-complementing group 1 (XRCC1) polymorphisms [10], [11], and by increased detoxification thorough the conjugation with glutathione by glutathione-S-transferase (GST) polymorphism [12], [13].

Thus, the current study was designed to determine the affect of genetic polymorphisms on drug response, toxicity and survival in patients with EOC who received taxane- and platinum-based chemotherapy after surgery.

Section snippets

Study population

Clinical data were retrieved from a database of patients diagnosed with EOC between March 2001 and November 2006. Approval by the Institutional Review Board of Seoul National University Hospital was obtained in advance for the current study. The eligibility criteria were as follows: patients with a histological confirmation of EOC; those treated with maximal cytoreductive surgery followed by adjuvant taxane- and platinum-based chemotherapy; those with Eastern Cooperative Oncology Group

Patients' characteristics

A total of 118 patients with a median age of 50 years (range, 24–74 years) were enrolled in the current study. Among all patients, 60 (50.8%) were in menopause, According to the FIGO criteria, 28 (23.7%) patients were in stage I, 9 (7.6%) in stage II, 74 (62.8%) in stage III and 7 (5.9%) in stage IV. Tumor grade was G1 in 33 (28%), G2 in 21 (17.8%) and G3 in 64 (54.2%) of all patients. Histologically, 75 (63.6%) tumors were diagnosed as serous carcinoma, 22 (18.6%) as endometrioid carcinoma, 15

Discussion

Previous studies have shown that many different genes were associated with the metabolism of taxane (ABCB1, ABCC1, ABCC2, ABCG2, CDKN1A, CYP1B1, CYP2C8, CYP3A4, CYP3A5, MAPT, TP53, etc) and platinum compound (ABCC2, ABCG2, ERCC1, ERCC2, GSTP1, MPO, XRCC1, etc) [16]. However, we selected the 10 genetic polymorphisms associated with taxane- and platinum-based chemotherapy because the role of them has been focused on EOC in many studies [16], [17], [18], and the distribution of mutated alleles in

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

The authors wish to thank the Medical Research Collaborating Center (MRCC) in Seoul National University Hospital for statistical analysis. This study was supported by a grant (CRI-06-3) from the Cancer Research Institute, Seoul National University Research Fund. Moreover, we deeply appreciate the committee of the 39th Annual Meeting of the Society of Gynecologic Oncologists for giving us the opportunity to present in a Focused Plenary Session IV—Translational Research (Abstr. 34).

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