A correlative biomarker study and integrative prognostic model in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with enzalutamide

There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort. Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort. TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers

RESEARCH ARTICLE Polymorphisms in Endothelin System Genes, Arsenic Levels and

Background/Objectives Obesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be in-volved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipo-cytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situ-ations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity. Subjects/Methods We analyzed two samples of general-population-based studies from two different regions of Spain: the VALCAR Study, 468 subjects from the area of Valencia, and the Hortega Study, 1502 subjects from the area of Valladolid. Eighteen SNPs throughout five genes were ana-lyzed using SNPlex

Polymorphisms in endothelin system genes, arsenic levels and obesity risk.

BACKGROUND/OBJECTIVES:; Obesity has been linked to morbidity and mortality through increased risk for many chronic diseases. Endothelin (EDN) system has been related to endothelial function but it can be involved in lipid metabolism regulation: Receptor type A (EDNRA) activates lipolysis in adipocytes, the two endothelin receptors mediate arsenic-stimulated adipocyte dysfunction, and endothelin system can regulate adiposity by modulating adiponectin activity in different situations and, therefore, influence obesity development. The aim of the present study was to analyze if single nucleotide polymorphisms (SNPs) in the EDN system could be associated with human obesity. SUBJECTS/METHODS:; We analyzed two samples of general-population-based studies from two different regions of Spain: the VALCAR Study, 468 subjects from the area of Valencia, and the Hortega Study, 1502 subjects from the area of Valladolid. Eighteen SNPs throughout five genes were analyzed using SNPlex. RESULTS:; We found associations for two polymorphisms of the EDNRB gene which codifies for EDN receptor type B. Genotypes AG and AA of the rs5351 were associated with a lower risk for obesity in the VALCAR sample (p=0.048, OR=0.63) and in the Hortega sample (p=0.001, OR=0.62). Moreover, in the rs3759475 polymorphism, genotypes CT and TT were also associated with lower risk for obesity in the Hortega sample (p=0.0037, OR=0.66) and in the VALCAR sample we found the same tendency (p=0.12, OR=0.70). Furthermore, upon studying the pooled population, we found a stronger association with obesity (p=0.0001, OR=0.61 and p=0.0008, OR=0.66 for rs5351 and rs3759475, respectively). Regarding plasma arsenic levels, we have found a positive association for the two SNPs studied with obesity risk in individuals with higher arsenic levels in plasma: rs5351 (p=0.0054, OR=0.51) and rs3759475 (p=0.009, OR=0.53). CONCLUSIONS:; Our results support the hypothesis that polymorphisms of the EDNRB gene may influence the susceptibility to obesity and can interact with plasma arsenic levels.This work was supported by the funds for research in health sciences from Carlos III Health Institute (PI07/0497 and PI11/00726), by CIBER de Diabetes y Enfermedades Metabólicas Relacionadas (CIBERDEM); CIBERDEM is an initiative by Carlos III Health Institute in Madrid and the Spanish Health Ministry, by PROMETEO/2009/029, AP-091/11, and ACOMP/2013/039 from the Valencian Government, and by GRS 279/a/08 research project from JUNTA DE CASTILLA Y LEON Government.Ye

Characteristics of selected Polymorphisms.

<p>HGN, The HUGO Gene Nomenclature.</p><p>^¥:Tag-SNP by Hapmap in Caucasian patients. Ensemble ID: Ensemble human release 53. SNP name: dbSNP129 (NCBI´s build 36, version 3)</p><p>Characteristics of selected Polymorphisms.</p

General characteristics of the population.

<p>Values are mean ± standard deviation. For qualitative variables, data are expressed as (n, %)</p><p>* <i>p-value < 0</i>.<i>0001</i></p><p>General characteristics of the population.</p

Association between obesity and BMI and SNPs of EDNRB genes adjusted by age and sex in: A-Valcar Study / B-Hortega Study / C-Both.

<p>HWE, Hardy—Weinberg equilibrium; MAF, minor allele frequency; SNP, single-nucleotide polymorphism; OR, odds ratio. Values are mean ± standard error. Bold indicates significance.</p><p>*dbSNP 129.</p><p>Association between obesity and BMI and SNPs of EDNRB genes adjusted by age and sex in: A-Valcar Study / B-Hortega Study / C-Both.</p

Linkage Disequilibrium (LD) plot of studied EDNRB SNPs. a) D´ b) R².

<p>Linkage Disequilibrium (LD) plot of studied EDNRB SNPs. a) D´ b) R².</p

Relation with Arsenic serum levels.

<p>Association between obesity and BMI and SNPs of EDNRB genes adjusted by age and sex. OR, odds ratio. Values are mean ± standard error. Bold indicates significance.</p><p>Relation with Arsenic serum levels.</p

Haplotype association analysis of rs5351 and rs3759475 of EDNRB gene with BMI and obesity risk adjusted by age and sex in relation with Arsenic serum levels.

<p>Single nucleotide polymorphisms used in the haplotype construction: rs5351, rs3759475.</p><p>Haplotype association analysis of rs5351 and rs3759475 of EDNRB gene with BMI and obesity risk adjusted by age and sex in relation with Arsenic serum levels.</p