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Relationship Between ERCC1 Polymorphisms, Disease Progression, and Survival in the Gynecologic Oncology Group Phase III Trial of Intraperitoneal Versus Intravenous Cisplatin and Paclitaxel for Stage III Epithelial Ovarian Cancer

Thomas C. Krivak, Kathleen M. Darcy, Chunqiao Tian, Deborah Armstrong, Bora E. Baysal, Holly Gallion, Christine B. Ambrosone, Julie A. DeLoia

From the University of Pittsburgh Magee-Women's Hospital; Precision Therapeutics/PTI, Pittsburgh, PA; Gynecologic Oncology Group Statistical and Data Center and Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY; and John Hopkins Kimmel Cancer Center, Baltimore, MD

Corresponding author: Thomas C. Krivak, MD, Magee-Womens Hospital, Division of Gynecologic Oncology, Pittsburgh, PA 15213; e-mail: tkrivak{at}mail.magee.edu

Purpose We hypothesized that common polymorphisms in excision repair cross-complementation group 1 (ERCC1), involved in nucleotide excision repair of platinum-induced damage, would be associated with progression-free survival (PFS) and overall survival (OS) in women with optimally resected, stage III epithelial ovarian cancer (EOC) treated with cisplatin and paclitaxel (C+P).

Patients and Methods Single nucleotide polymorphism analysis was carried out by direct pyrosequencing at two sites (codon 118 and C8092A) in ERCC1 in leukocyte DNA from women who participated in the Gynecologic Oncology Group (GOG) phase III protocol-172 and were randomly assigned to intraperitoneal or intravenous C+P.

Results ERCC1 genotyping was performed in 233 of the 429 women who participated in GOG-172. The genotype distribution at codon 118 was 17% with C/C, 43% with C/T, and 40% with T/T, and the genotype distribution at C8092A was 56% with C/C, 37% with C/A, and 7% with A/A. Adjusted Cox regression analysis revealed that the codon 118 polymorphism in ERCC1 was not significantly associated with disease progression or death. Women with the C8092A C/A or A/A genotypes compared with the C/C genotype had an increased risk of disease progression (hazard ratio [HR] = 1.44; 95% CI, 1.06 to 1.94; P = .018) and death (HR = 1.50; 95% CI, 1.07 to 2.09; P = .018). Median PFS and OS were 6 and 17 months shorter for women with the C8092A C/A or A/A genotypes versus the C/C genotype, respectively.

Conclusion Although the ERCC1 codon 118 polymorphism does not seem to be associated with clinical outcome, the C8092A polymorphism was an independent predictor of PFS and OS in women with optimally resected EOC.

Supported by National Cancer Institute Grant No. CA 27469 to the Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank and Grant No. CA 37517 to the GOG Statistical and Data Center, as well as by grants from the Gynecologic Oncology Group/Ovarian Cancer Research Fund New Investigator Award (T.C.K.), The Jennie K. Scaife Foundation (J.A.D.), and The Pittsburgh Foundation (J.A.D.).

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL; at the 38th Annual Meeting of the Society of Gynecologic Oncologists, March 3-7, 2007, San Diego, CA; and the 39th Annual Meeting of the Society of Gynecologic Oncologists, March 9-12, 2008, Tampa, FL.

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

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