Context Pancreatic adenocarcinoma (PDAC) has the worst prognosis of any major malignancy, and the identification of predictive factors of drug activity is crucial for maximizing therapeutic efficacy and minimizing useless treatments. The Human Genome Project led to the discovery of a number of DNA sequence variants, the majority of them being singlenucleotide polymorphisms (SNPs). These SNPs can affect the susceptibility of patients to anticancer drugs, and a pharmacogenetic approach to customize PDAC treatment according to genetic characteristics represents a modern and intriguing challenge. Objective To evaluate whether common SNPs in genes involved in the mechanism of action/resistance of anticancer drugs were associated with the overall survival (OS) of PDAC patients treated with polychemotherapeutic regimens, including gemcitabine, cisplatin, epirubicin, docetaxel, capecitabine and 5-fluorouracil. Methods We studied by allelic discrimination assays 10 SNPs of 7 genes (ERCC1, XPD, XRCC1, CYP1B1, ABCB1, CDA, and RRM1) in 145 advanced PDAC patients treated in first-line with the PDGX, PEGX or FLEC regimens, in two different Italian institutions (Carrara Civic Hospital and S. Raffaele Scientific Institute), from 2005 to 2009. Associations of genotypes with OS were evaluated by log-rank test and Cox proportional regression models. Results Three SNPs in the DNA repair genes were significantly associated with OS in univariable analysis. In particular, XPD-Lys751Gln and ERCC1-C118T remained significant predictors for OS in multivariate model, including also the clinical factors which resulted significant to the univariate analysis (age, stage, and PS). Patients harboring the XPD Gln751Gln genotype (n=22) had a significantly shorter OS (median 262 days, 95%CI 173-351 days vs. 446 days, 95%CI 359-453 days in Lys751Lys+LysGln patients, with a HR ranging from 1.6 to 8.0, P=0.003). This strong genotype association with OS was observed in all the patients enrolled in the study, as well as in the subgroup of gemcitabine-treated patients (n=123), epirubicin-treated patients (n=112) and docetaxel-treated patients (n=33). Further studies on the relationship between SNPs and OS in the different regimens are ongoing, enrolling patients treated with gemcitabine-alone. Conclusions SNPs of DNA repair genes have a potential value as prognostic markers for OS in patients with advanced PDAC.
Giovannetti E, Pacetti P, Reni M, Alecci C, Giancola F, Ghidini M, et al. (2009). Significant association of dna repair polymorphisms with survival in pancreatic cancer patients treated with polychemotherapeutic regimens. JOP. JOURNAL OF THE PANCREAS, 10, 599-599.
Significant association of dna repair polymorphisms with survival in pancreatic cancer patients treated with polychemotherapeutic regimens
GIOVANNETTI, ELISA;GIANCOLA, FIORELLA;
2009
Abstract
Context Pancreatic adenocarcinoma (PDAC) has the worst prognosis of any major malignancy, and the identification of predictive factors of drug activity is crucial for maximizing therapeutic efficacy and minimizing useless treatments. The Human Genome Project led to the discovery of a number of DNA sequence variants, the majority of them being singlenucleotide polymorphisms (SNPs). These SNPs can affect the susceptibility of patients to anticancer drugs, and a pharmacogenetic approach to customize PDAC treatment according to genetic characteristics represents a modern and intriguing challenge. Objective To evaluate whether common SNPs in genes involved in the mechanism of action/resistance of anticancer drugs were associated with the overall survival (OS) of PDAC patients treated with polychemotherapeutic regimens, including gemcitabine, cisplatin, epirubicin, docetaxel, capecitabine and 5-fluorouracil. Methods We studied by allelic discrimination assays 10 SNPs of 7 genes (ERCC1, XPD, XRCC1, CYP1B1, ABCB1, CDA, and RRM1) in 145 advanced PDAC patients treated in first-line with the PDGX, PEGX or FLEC regimens, in two different Italian institutions (Carrara Civic Hospital and S. Raffaele Scientific Institute), from 2005 to 2009. Associations of genotypes with OS were evaluated by log-rank test and Cox proportional regression models. Results Three SNPs in the DNA repair genes were significantly associated with OS in univariable analysis. In particular, XPD-Lys751Gln and ERCC1-C118T remained significant predictors for OS in multivariate model, including also the clinical factors which resulted significant to the univariate analysis (age, stage, and PS). Patients harboring the XPD Gln751Gln genotype (n=22) had a significantly shorter OS (median 262 days, 95%CI 173-351 days vs. 446 days, 95%CI 359-453 days in Lys751Lys+LysGln patients, with a HR ranging from 1.6 to 8.0, P=0.003). This strong genotype association with OS was observed in all the patients enrolled in the study, as well as in the subgroup of gemcitabine-treated patients (n=123), epirubicin-treated patients (n=112) and docetaxel-treated patients (n=33). Further studies on the relationship between SNPs and OS in the different regimens are ongoing, enrolling patients treated with gemcitabine-alone. Conclusions SNPs of DNA repair genes have a potential value as prognostic markers for OS in patients with advanced PDAC.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
