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ABCB1 (MDR 1) Polymorphisms and Progression-Free Survival among Women with Ovarian Cancer following Paclitaxel/Carboplatin Chemotherapy

Authors' Affiliations: ¹ Queensland Institute of Medical Research, Brisbane, Queensland, Australia; ² Cancer Research UK, Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; ³ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; ⁴ Westmead Millennium Institute; ⁵ Westmead Institute for Cancer Research, University of Sydney at the Westmead Millennium Institute; ⁶ Department of Medical Oncology and Palliative Care; ⁷ Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia; ⁸ Division of Oncology, Washington University in St. Louis, St. Louis, Missouri; ⁹ UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, North Carolina; and ¹⁰ Imperial College London, Hammersmith Hospital Campus, London, United Kingdom

Requests for reprints: Georgia Chenevix-Trench, Cancer and Cell Biology, Queensland Institute of Medical Research, Royal Brisbane Hospital Post Office, Herston, Queensland 4029, Australia. Phone: 61-7-3362-0390; Fax: 61-7-3362-0105; E-mail: georgiaT{at}qimr.edu.au.

Purpose: The human ABCB1 gene encodes P-glycoprotein, which transports a broad range of anticancer drugs, including paclitaxel. Although the functional consequences of ABCB1 polymorphisms have been the subject of numerous studies, few have assessed the association with clinical outcome.

Experimental Design: We assessed the association between the 2677G>T/A, 3435C>T, and 1236C>T ABCB1 polymorphisms and progression-free and overall survival in 309 patients from the Australian Ovarian Cancer Study treated with paclitaxel/carboplatin and subsequently tested significant observations in an independent validation set.

Results: Women who carried the minor T/A alleles at the 2677G>T/A polymorphism were significantly less likely to relapse following treatment compared with homozygote GG carriers (P_Log-rank = 0.001) in the Australian Ovarian Cancer Study cohort. Subgroup analyses showed that this effect was limited to cases with residual disease 1 cm (P_Log-rank = 0.0004), not for those with residual disease >1 cm (P_Log-rank = 0.3). This effect was not confirmed in an independent validation set of carboplatin/paclitaxel-treated patients (n = 278) using a higher residual disease cut point (2 cm). However, analysis of the unrestricted data set expanded to include docetaxel-treated patients (n = 914) did support an effect of the 2677T/A allele in patients with no macroscopic residual disease (hazard ratio, 0.70; 95% confidence interval, 0.46-1.04; P_one-sided = 0.039).

Conclusion: Our findings indicate that there is an effect of the 2677G>T/A polymorphism on progression-free survival in ovarian cancer patients who are treated with a taxane/carboplatin, which is dependent on the extent of residual disease, with a better prognosis for patients with the 2677T/A allele and minimal residual disease.