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Estrogen receptor ? and aromatase polymorphisms affect risk, prognosis, and therapeutic outcome in men with castration-resistant prostate cancer treated with docetaxel-based therapy.

ABSTRACT: Reactive estrogen species cause genotoxicity and interfere with docetaxel-mediated tubulin polymerization resulting in shortened survival in men with castrate-resistant prostate cancer (CRPC).We hypothesized that polymorphisms in estrogen synthesis and estrogen targets (i.e., CYP19 and ER?) would be linked to interindividual variation in CRPC risk, docetaxel response, and overall survival in men with CRPC.Patients with CRPC (n=115) treated with docetaxel, single-agent thalidomide (n=42), or healthy controls (n=289) were genotyped for the CYP19 R264C (rs700519) and the ER? PvuII T>C (rs2234693) and XbaI A>G (rs9340799) polymorphisms.Patients carrying two copies of ER? polymorphisms had shorter progression-free survival on docetaxel than other patients (median survival difference ? 3.1 months; P ? 0.036). When the analysis was limited to nonobese patients, the relationship between the ER? XbaI A>G polymorphism and PFS improved (median survival difference = 3.5 months; P = 0.0078). The CYP19 R264C variant was related to the duration of survival after docetaxel in patients who were >70 years old (median survival difference =10.6 months; P=0.041). Both ER? polymorphisms were also associated with increases in CRPC risk [P ? 0.032; double variants vs. wild-type odds ratio ? 2.6], and the association with the ER? PvuII T>C also improved in those men who were <70 years old (P = 0.0073; odds ratio = 3.0).This study demonstrates that estrogen-related genetic variation affects docetaxel clinical response and that this relationship is dependent on age and body-type in men with CRPC. Moreover, this study suggests ER? polymorphisms confer risk of developing prostate cancer, especially in men under 70 years of age.

SUBMITTER: Sissung TM

PROVIDER: S-EPMC3048329 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Estrogen receptor α and aromatase polymorphisms affect risk, prognosis, and therapeutic outcome in men with castration-resistant prostate cancer treated with docetaxel-based therapy.

Sissung Tristan M TM Danesi Romano R Kirkland C Tyler CT Baum Caitlin E CE Ockers Sandra B SB Stein Erica V EV Venzon David D Price Douglas K DK Figg William D WD

The Journal of clinical endocrinology and metabolism 20101124 2

<h4>Context</h4>Reactive estrogen species cause genotoxicity and interfere with docetaxel-mediated tubulin polymerization resulting in shortened survival in men with castrate-resistant prostate cancer (CRPC).<h4>Objective</h4>We hypothesized that polymorphisms in estrogen synthesis and estrogen targets (i.e., CYP19 and ERα) would be linked to interindividual variation in CRPC risk, docetaxel response, and overall survival in men with CRPC.<h4>Materials and methods</h4>Patients with CRPC (n=115) ...[more]

PMID: 21106711

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Project description:BackgroundIn men with metastatic castration-resistant prostate cancer (mCRPC) with primarily bone metastases, radium-223 (223 Ra) improves overall survival (OS). However, the selection of 223 Ra is not guided by specific validated clinicopathologic factors, and thus outcomes are heterogeneous.Patients and methodsThis retrospective survival analysis was performed in men with mCRPC treated with 223 Ra at our cancer center. Demographics and disease characteristics were collected. OS was calculated using the Kaplan-Meier method (log-rank). The potential prognostic factors were determined using both univariable (UVA) and multivariable analysis (MVA) (Cox-regression) methods.ResultsIn total, 150 patients with a median age of 74 years (52-93) received 223 Ra between May 2015 and July 2018, and 58% had 6-20 bone metastases. Ninety-four (63%) patients received >4 223 Ra doses, and 56 (37%) received ≤4. The following pre-treatment factors were analyzed (median [range]): eastern cooperative oncology group performance status (ECOG PS), (1 [0-3]); Albumin (ALB), (39 g/L [24-47]); alkaline phosphatase (ALP), (110 U/L [35-1633]); and prostate-specific antigen (PSA), (49 µg/L [0.83-7238]). The median OS for all patients was 14.5 months (95% CI: 11.2-18). These factors were associated with poor survival outcomes in UVA and MVA: ALB <35 g/L, ALP >150 U/L, ECOG PS 2-3, and PSA >80 µg/L. By assigning one point for each of these factors, a prognostic model was developed, wherein three distinct risk groups were identified: good, 0-1 (n = 103); intermediate, 2 (n = 30); and poor risk, 3-4 points (n = 17). The median OS was 19.4, 10.0, and 3.1 months, respectively (p < 0.001).ConclusionsPre-treatment ALB, ALP, ECOG, and PSA, were significantly correlated with OS and could guide treatment selection for men with mCRPC by identifying those who are most or least likely to benefit from 223 Ra. Validation in an independent dataset is required prior to widespread clinical utilization.

Project description:BackgroundIn the AFFIRM trial, enzalutamide significantly increased overall survival (OS) for men with metastatic castration-resistant prostate cancer (mCRPC) after chemotherapy versus placebo and significantly decreased prostate-specific antigen (PSA) levels. The goal of this post hoc analysis was to associate levels of PSA decline from baseline after enzalutamide with clinical outcomes in the postchemotherapy mCRPC setting.MethodsMen in the AFFIRM trial (n = 1199) were grouped by maximal PSA decline in the first 90 days of treatment. Kaplan-Meier estimates evaluated the association of defined PSA changes from baseline with OS, progression-free survival (PFS), radiographic PFS (rPFS), and pain response. Each PSA decline category was assessed for OS surrogacy using Prentice criteria, proportion of treatment effect explained (PTE), and proportion of variation explained.ResultsMen treated with enzalutamide had improved OS (hazard ratio, 0.63; P < .001) and higher rates of PSA decline (odds ratio, >19.0; P < .001) versus placebo. PSA declines of any, ≥30%, ≥50%, and ≥90% with enzalutamide were strongly associated with greater OS, PSA PFS, rPFS (P < .001), and pain response (P < .026) versus PSA increase/no decline. Any, ≥30%, and ≥50% declines in PSA resulted in the PTE range of 1.07-1.29, where treatment was no longer significant after adjustment for decline measures (P > .20).ConclusionsPSA declines of any, ≥30%, and ≥50% following enzalutamide were associated with greater clinical and pain response and improvements in PFS and OS. Surrogacy of PSA decline for OS was not fully established, possibly due to lack of PSA declines with placebo, and discordant results between PSA and imaging responses over time, and because some declines were not durable due to rapid resistance development. However, a lack of PSA decline by 90 days following enzalutamide treatment was a poor prognosis indicator in this setting. Conclusions from sensitivity analyses of maximal PSA decline from baseline over the entire treatment period are consistent with PSA declines restricted to the first 90 days. Cancer 2017;123:2303-2311. © 2017 American Cancer Society.

Dataset Information

Estrogen receptor ? and aromatase polymorphisms affect risk, prognosis, and therapeutic outcome in men with castration-resistant prostate cancer treated with docetaxel-based therapy.

Publications

Estrogen receptor α and aromatase polymorphisms affect risk, prognosis, and therapeutic outcome in men with castration-resistant prostate cancer treated with docetaxel-based therapy.

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