N and survival. Indeed, studies have shown the impact of variations in CYP19A1, HSD3B1, HSD17B4, SLCO2B1, and SLCO1B3 on time to progression during ADT [7,8], but there is still a lack of markers better defining lethal prostate cancer. In the present study, we sought to investigate the prognostic significance of common variants in sex hormone pathway genes on disease progression, prostate cancer-specific mortality (PCSM), and all-cause mortality (ACM) in a cohort of 645 prostate cancer patients receiving ADT.Biomarkers Predict the Efficacy of ADTPatients and Methods Patient Recruitment and Data CollectionSix hundred and forty-five advanced prostate cancer patients were recruited between 1995 and 2009 from three medical centers in Taiwan: Kaohsiung Medical University AKT inhibitor 2 biological activity Hospital, Kaohsiung Veterans General Hospital, and National Taiwan University Hospital, as previously described [9?4]. All patients were treated with ADT (orchiectomy or luteinizing hormone-releasing hormone agonist, with or without antiandrogen) and followed up prospectively to evaluate the efficacy of ADT. Data were collected on patients with disease baseline and clinicopathologic characteristics, as well as three treatment outcomes: time to progression, PCSM, and ACM. The prostate-specific antigen (PSA) nadir was defined as the lowest PSA value achieved during ADT treatment [15,16]. Time to PSA nadir was defined as the duration of time it took for the PSA value to reach nadir after ADT initiation [17]. Disease progression was defined as a serial rise in PSA, at least two rises in PSA (.1 week apart), greater than the PSA nadir [7]. Initiation of secondary hormone treatment for rising PSA was also considered as a progression event. Time to progression was defined as the interval in months between the initiation of ADT and progression. In general, patients were followed every month with PSA tests at 3-monthly intervals. The cause of death was obtained by matching patients’ personal identification number with the official cause of death registry provided by the Department of Health, Executive Yuan, Taiwan. PCSM was defined as the interval from the initiation of ADT to death from prostate cancer. The ACM was defined as the period from the initiation of ADT to death from any cause. As the median PCSM and ACM had not been reached, the mean times to PCSM and ACM were estimated by Kaplan-Meier curves. This study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital, Kaohsiung Veterans General Hospital, and National Taiwan University Hospital, and written ML 281 site informed consent was obtained from each participant.aa+Aa genotype versus AA genotype, recessive: aa genotype versus Aa+AA genotype, and additive: aa versus Aa versus AA) were tested. Multivariate analyses to determine the interdependency of polymorphisms and known prognostic factors, such as age at diagnosis, clinical stage, Gleason score, PSA at ADT initiation, PSA nadir, time to PSA nadir, and treatment modality, were carried out using Cox proportional hazards regression model. Higher order SNP-SNP interactions were evaluated using survival tree analysis by STREE software (http://c2s2.yale.edu/software/ stree/), which uses recursive partitioning to identify subgroups of individuals with similar risk [19]. As we were testing 18 polymorphisms, false-discovery rates (q values) were calculated to determine the degree to which the tests for association were prone to false-positives [20]. q values w.N and survival. Indeed, studies have shown the impact of variations in CYP19A1, HSD3B1, HSD17B4, SLCO2B1, and SLCO1B3 on time to progression during ADT [7,8], but there is still a lack of markers better defining lethal prostate cancer. In the present study, we sought to investigate the prognostic significance of common variants in sex hormone pathway genes on disease progression, prostate cancer-specific mortality (PCSM), and all-cause mortality (ACM) in a cohort of 645 prostate cancer patients receiving ADT.Biomarkers Predict the Efficacy of ADTPatients and Methods Patient Recruitment and Data CollectionSix hundred and forty-five advanced prostate cancer patients were recruited between 1995 and 2009 from three medical centers in Taiwan: Kaohsiung Medical University Hospital, Kaohsiung Veterans General Hospital, and National Taiwan University Hospital, as previously described [9?4]. All patients were treated with ADT (orchiectomy or luteinizing hormone-releasing hormone agonist, with or without antiandrogen) and followed up prospectively to evaluate the efficacy of ADT. Data were collected on patients with disease baseline and clinicopathologic characteristics, as well as three treatment outcomes: time to progression, PCSM, and ACM. The prostate-specific antigen (PSA) nadir was defined as the lowest PSA value achieved during ADT treatment [15,16]. Time to PSA nadir was defined as the duration of time it took for the PSA value to reach nadir after ADT initiation [17]. Disease progression was defined as a serial rise in PSA, at least two rises in PSA (.1 week apart), greater than the PSA nadir [7]. Initiation of secondary hormone treatment for rising PSA was also considered as a progression event. Time to progression was defined as the interval in months between the initiation of ADT and progression. In general, patients were followed every month with PSA tests at 3-monthly intervals. The cause of death was obtained by matching patients’ personal identification number with the official cause of death registry provided by the Department of Health, Executive Yuan, Taiwan. PCSM was defined as the interval from the initiation of ADT to death from prostate cancer. The ACM was defined as the period from the initiation of ADT to death from any cause. As the median PCSM and ACM had not been reached, the mean times to PCSM and ACM were estimated by Kaplan-Meier curves. This study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital, Kaohsiung Veterans General Hospital, and National Taiwan University Hospital, and written informed consent was obtained from each participant.aa+Aa genotype versus AA genotype, recessive: aa genotype versus Aa+AA genotype, and additive: aa versus Aa versus AA) were tested. Multivariate analyses to determine the interdependency of polymorphisms and known prognostic factors, such as age at diagnosis, clinical stage, Gleason score, PSA at ADT initiation, PSA nadir, time to PSA nadir, and treatment modality, were carried out using Cox proportional hazards regression model. Higher order SNP-SNP interactions were evaluated using survival tree analysis by STREE software (http://c2s2.yale.edu/software/ stree/), which uses recursive partitioning to identify subgroups of individuals with similar risk [19]. As we were testing 18 polymorphisms, false-discovery rates (q values) were calculated to determine the degree to which the tests for association were prone to false-positives [20]. q values w.