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.
OBJECTIVE
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).


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.


CONCLUSIONS
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.
Krivak
Thomas C
TC
University of Pittsburgh Magee-Women's Hospital; Precision Therapeutics/PTI, Pittsburgh, PA 15213, USA. tkrivak@mail.magee.edu
Darcy
Kathleen M
KM
Tian
Chunqiao
C
Armstrong
Deborah
D
Baysal
Bora E
BE
Gallion
Holly
H
Ambrosone
Christine B
CB
DeLoia
Julie A
JA
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D017239:Paclitaxel / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide
D004268:DNA-Binding Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; D017239:Paclitaxel; D002945:Cisplatin