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Pharmacogenetic Assessment of Toxicity and Outcome After Platinum Plus Taxane Chemotherapy in Ovarian Cancer: The Scottish Randomised Trial in Ovarian Cancer

Sharon Marsh, Jim Paul, Cristi R. King, Gillian Gifford, Howard L. McLeod, Robert Brown

From the Washington University School of Medicine, Division of Oncology, St Louis, MO; UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC; University of Glasgow, Centre for Oncology and Applied Pharmacology; and Cancer Research UK Beatson Laboratories, University of Glasgow, Glasgow, United Kingdom

Address for reprint requests to Sharon Marsh, PhD, Washington University School of Medicine, Campus Box 8069, 660 S Euclid Ave, St. Louis, MO 63110; e-mail: smarsh{at}im.wustl.edu

Purpose Standard therapy for advanced ovarian cancer consists of a platinum agent in combination with a taxane, which has a 5-year survival rate of approximately 45%. The large individual variability for ovarian cancer patients in both outcome and toxicity risk from chemotherapy makes the identification of pharmacogenetic markers that can be used to screen patients before therapy selection an attractive prospect.

Patients and Methods We assessed 27 selected polymorphisms based on previously described associations or putative functional effects in 16 key genes from pathways that may influence cellular sensitivity to taxanes (ABCB1, ABCC1, ABCC2, ABCG2, CDKN1A, CYP1B1, CYP2C8, CYP3A4, CYP3A5, MAPT, and TP53) and platinum (ABCC2, ABCG2, ERCC1, ERCC2, GSTP1, MPO, and XRCC1) using polymerase chain reaction and Pyrosequencing in 914 ovarian cancer patients from the Scottish Randomised Trial in Ovarian Cancer phase III trial who were treated at presentation with carboplatin and taxane regimens after cytoreductive surgery.

Results No reproducible significant associations between genotype and outcome or toxicity were found for any of the genes analyzed. Previously reported genotype associations could not be replicated in this large study of a well-defined patient population within one specific clinical trial.

Conclusion There are no clear candidates for taxane/platinum pharmacogenetic markers. This study highlights the need for validation of putative genetic markers in large, well-defined clinical sample sets.

Supported by Grant No. R21 CA113491 (St Louis and Glasgow), Cancer Research UK programme Grant No. C536/A2662 (Glasgow), the Pharmacogenetics Research Network Grant No. U01 GM63340 (St Louis), and the National Cancer Institute/National Institutes of Health.

S.M. and J.P. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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