Abstract C26: The polymorphism in GSTP1 codon 105 might be associated with biochemical recurrence in Argentine localized prostate cancer patients treated with radical prostatectomy

Abstract Background: Prostate cancer (PCa) is the second most commonly diagnosed cancer among men and the sixth cause of cancer-related deaths worldwide. In Argentina, the PCa incidence and mortality rates were 58.8 and 15.6 per 100,000 men, respectively (GLOBOCAN, 2008); making it the second cause of cancer-related deaths. Earlier detection of PCa is possible due to the use of Prostate-Specific Antigen (PSA) as a biomarker for PCa. However, the ability to determine whether a primary localized tumor is likely to recur or metastasize after treatment has been difficult to achieve. None of the markers currently used have shown sufficient predictive value or sensitivity to foresee PCa progression. Aim: the goal of the study was to characterize a cohort of Argentine men with localized PCa and to identify new genetic markers that could be used as additional tools to better predict PCa progression. Methods: We retrospectively recruited 122 patients diagnosed with localized PCa at the Hospital de Clinicas Jose San Martin, in Buenos Aires, Argentina. The study protocol was approved by the Ethic Committee and follows the ethical principles enunciated by the Declaration of Helsinki. All patients underwent radical prostatectomy (RP) as therapeutic strategy and signed an informed consent before blood donation for DNA analyses. We genotyped five polymorphisms in enzymes involved in: i) drug metabolism and protection against oxidative stress (GSTP1 codon 105 A>G (Ile>Val), GSTT1 null and GSTM1 null), ii) xenobiotic efflux (MDR1 c.3435C>T), and iii) DNA synthesis (MTHFR c.677C>T). GSTP1, MDR1 and MTHFR polymorphisms were genotyped by PCR-RFLP; the other two (GSTT1 and GSTM1) were genotyped by multiplex-PCR. We performed univariate and multivariate Cox regression models to study the association between these polymorphisms and PCa biochemical recurrences (BR) after RP and to estimate Hazard Ratios (HR) and 95% confidence intervals (95%CI). BR was defined as an increase in serum PSA after RP of 0.2 ng/ml. Survival analyses were performed by Kaplan-Meier curves and the comparison between genotypes was done using the log-rank test. Results: Sixteen patients (13%) showed persistently elevated PSA levels after RP and were therefore excluded from final analyses. We observed a positive association between the GSTP1 codon 105 Val/Val genotype and BR when compared to carriers of the Ile/Ile variant (HR=3.19; 95%CI= 1.27-8.03; p=0.014). This association remained statistically significant after adjustment for Gleason score and PSA at diagnosis (HR=2.49; 95%CI=1.03-6.00; p=0.037). Heterozygote Ile/Val patients showed a non-significant positive association (HR=1.14; 95%CI=0.53-2.46). Carriers of the Val/Val genotype had lower biochemical recurrence-free survival (BRFS) compared to the other genotypes (log-rank p=0.023). The 10-year BRFS after RP for homozygote Val patients was 30% compared to 72% for Ile/Val, and 70% for Ile/Ile patients. We did not find statistically significant associations between the other polymorphisms and BR. Discussion: We found that the polymorphism GSTP1 codon 105 A>G (Ile>Val) was predictive of the risk of BR after RP. These results might help predict PCa recurrences in the Argentine population and, in turn, determine which therapeutic schema is best suited for each patient. Citation Format: Javier Cotignola, Ahva Shahabi, Daiana B. Leonardi, Mariana C. Stern, Nora Navone, Carlos Scorticati, Adriana De Siervi, Osvaldo Mazza, Elba S. Vazquez. The polymorphism in GSTP1 codon 105 might be associated with biochemical recurrence in Argentine localized prostate cancer patients treated with radical prostatectomy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C26.