Abstract
TPS340 Background: Platinum-based chemotherapy (CT) remains the cornerstone for treatment of many gynecologic tumors including ovarian, cervical, and endometrial cancer. Although response rates to platinum-based regimens are greater than 70%, a relevant clinical problem is the development of resistance. The nucleotide excision repair (NER), which removes cisplatin-induced DNA adducts, appears to be the principal pathway involved with platinum resistance. Single nucleotide polymorphisms (SNPs) of the genes involved in the NER may modulate repair capacity and contribute to individual variations in platinum response. The metabolic inactivation of gemcitabine is catalyzed by cytidine deaminase (CDA) but few studies have evaluated the pharmacogenetics of this enzyme with controversial results. For the objectives of this study, we selected SNPs of key genes (ERCC1, XPA, XPD, XPG, RRM1, CDA, and p53) involved in the mechanism of action or metabolism of platinum and gemcitabine 1) to evaluate the prognostic role of each SNP and 2) its possible predictive value in patients (pts) with ovarian, cervical or endometrial cancer, treated with platinum and/or gemcitabine-based CT. Methods: Eligibility criteria includehistologically proven primary gynaecologic malignancy of the ovary, cervix, and uterine corpus, including all stages, grades, and common epithelial cell types. Pts treated with CT need to receive platinum and/or gemcitabine-based CT. The protocol was approved by the local Institutional Ethical Committee. After signed informed consent, peripheral blood samples are obtained from all pts. Genomic DNA is extracted from whole blood samples (5 ml) using the QIAamp DNA estraction kit on Biorobot EZ1 (Qiagen). 8 SNPs of 7 genes (ERCC1 C118T, ERCC1 C8092A, XPA C114T, XPG Asp1104His, XPD Lys751Gln, CDA Lys27Gln, RRM1 C524T, and P53 Arg72Pro) are detected with TaqMan-probe based assays using the 7300 Real-Time PCR System (Applied Biosystems, Foster City, CA). Approximately 400 pts are expected to be enrolled in about 5 years. From March to December 2009, 92 pts (65 ovary, 20 uterine corpus, 7 cervix) were included in the study. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly, Schering-Plough Schering-Plough
Published Version
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