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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PROVIDER: S-EPMC5417300 | biostudies-literature | 2011 Jan
REPOSITORIES: biostudies-literature
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Project description:ContextReactive estrogen species cause genotoxicity and interfere with docetaxel-mediated tubulin polymerization resulting in shortened survival in men with castrate-resistant prostate cancer (CRPC).ObjectiveWe 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.Materials and methodsPatients 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 ERα PvuII T>C (rs2234693) and XbaI A>G (rs9340799) polymorphisms.ResultsPatients carrying two copies of ERα 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 ERα 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 ERα 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 ERα PvuII T>C also improved in those men who were <70 years old (P = 0.0073; odds ratio = 3.0).ConclusionsThis 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 ERα polymorphisms confer risk of developing prostate cancer, especially in men under 70 years of age.
| S-EPMC3048329 | biostudies-literature
Project description:There are few data regarding disparities in overall survival (OS) between Asian and white men with metastatic castration-resistant prostate cancer (mCRPC). We compared OS of Asian and white mCRPC men treated in phase III clinical trials with docetaxel and prednisone (DP) or a DP-containing regimen. Individual participant data from 8820 men with mCRPC randomly assigned on nine phase III trials to receive DP or a DP-containing regimen were combined. Men enrolled in these trials had a diagnosis of prostate adenocarcinoma. The median overall survival was 18.8 months (95% confidence interval [CI] = 17.4 to 22.1 months) and 21.2 months (95% CI = 20.8 to 21.7 months) for Asian and white men, respectively. The pooled hazard ratio for death for Asian men compared with white men, adjusted for baseline prognostic factors, was 0.95 (95% CI = 0.84 to 1.09), indicating that Asian men were not at increased risk of death. This large analysis showed that Asian men did not have shorter OS duration than white men treated with docetaxel.
| S-EPMC7190204 | biostudies-literature
Project description:PurposeSeveral studies have reported that among patients with localized prostate cancer, black men have a shorter overall survival (OS) time than white men, but few data exist for men with advanced prostate cancer. The primary goal of this analysis was to compare the OS in black and white men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in phase III clinical trials with docetaxel plus prednisone (DP) or a DP-containing regimen.MethodsIndividual participant data from 8,820 men with mCRPC randomly assigned in nine phase III trials to DP or a DP-containing regimen were combined. Race was based on self-report. The primary end point was OS. The Cox proportional hazards regression model was used to assess the prognostic importance of race (black v white) adjusted for established risk factors common across the trials (age, prostate-specific antigen, performance status, alkaline phosphatase, hemoglobin, and sites of metastases).ResultsOf 8,820 men, 7,528 (85%) were white, 500 (6%) were black, 424 (5%) were Asian, and 368 (4%) were of unknown race. Black men were younger and had worse performance status, higher testosterone and prostate-specific antigen, and lower hemoglobin than white men. Despite these differences, the median OS was 21.0 months (95% CI, 19.4 to 22.5 months) versus 21.2 months (95% CI, 20.8 to 21.7 months) in black and white men, respectively. The pooled multivariable hazard ratio of 0.81 (95% CI, 0.72 to 0.91) demonstrates that overall, black men have a statistically significant decreased risk of death compared with white men ( P < .001).ConclusionWhen adjusted for known prognostic factors, we observed a statistically significant increased OS in black versus white men with mCRPC who were enrolled in these clinical trials. The mechanism for these differences is not known.
| S-EPMC6804881 | biostudies-literature
Project description:In the present study, we aimed to evaluate the association of circulating AR copy number (CN) and outcome in a cohort of patients with advanced castration-resistant prostate cancer (CRPC) treated with enzalutamide after docetaxel. Fifty-nine CRPC patients were evaluated. AR CN was analyzed with real-time and digital PCR in the serum collected at starting of treatment. Progressive disease was defined on the basis of Prostate Cancer Working Group 2 criteria. AR CN gain was found in 21 of 59 (36%) patients. Median baseline PSA, alkaline phosphatase and lactate dehydrogenase levels were higher in the AR CN gained group (p = 0.007, p = 0.003, p = 0.0009, respectively). Median PFS of patients with AR CN gain was 2.4 (95%CI: 1.9-3.2) vs. 4.0 months (95%CI: 3.0-6.5) of those with no gain (p = 0.0004). Median OS of patients with AR CN gain was 6.1 (95%CI: 3.4-8.6) vs. 14.1 months (95%CI: 8.2-20.5) of those with no gain (p = 0.0003). At multivariate analysis, PSA decline ≥ 50% and AR CN showed a significant association with PFS (p = 0.008 and p = 0.002, respectively) and OS (p = 0.009 and p = 0.001, respectively). These findings indicate that the detection of circulating AR CN gain is a promising non-invasive biomarker for outcome prediction to enzalutamide treatment in CRPC patients.
| S-EPMC5122353 | biostudies-literature
Project description:CTCs have extensively been used for the monitoring and characterization of metastatic prostate cancer, but their application in the clinic is still very scarce. Besides, the resistance mechanisms linked to prostate cancer treatment remain unclear. Liquid biopsies represent the most promising alternative due to the complexity of biopsying bone metastasis and the duration of the disease. We performed a prospective longitudinal study in CTCs from 20 castration-resistant prostate cancer patients treated with docetaxel. For that, we used CellSearch® technology and a custom gene expression panel with qRT-PCR using a CTCs negative enrichment approach. We found that CTCs showed a hybrid phenotype during the disease, where epithelial features were associated with the presence of ≥ 5 CTCs/7.5 mL of blood, while high relative expression of the gene MYCL was observed preferentially in the set of samples with < 5 CTCs/7.5 mL of blood. At baseline, patients whose CTCs had stem or hybrid features showed a later progression. After 1 cycle of docetaxel, high relative expression of ZEB1 indicated worse outcome, while KRT19 and KLK3 high expression could predisposed the patients to a worse prognosis at clinical progression. In the present work we describe biomarkers with clinical relevance for the prediction of early response or resistance in castration-resistant prostate cancer patients. Besides, we question the utility of targeted isolated CTCs and the use of a limited number of markers to define the CTCs population.
| S-EPMC7987626 | biostudies-literature
Project description:Experimental and animal studies suggested that estrogens play an important role in the development of systemic lupus erythematosus (SLE) through a variety of mechanisms involved in the regulation of the immune system. The objective of this study was to investigate the association between genetic variations in estrogen metabolic pathway genes, including estrogen receptor alpha (ESR1), estrogen receptor beta (ESR2), and aromatase (CYP19A1), and risk of SLE. We performed a genetic study of SLE among 46 medical record-confirmed female SLE cases and 102 female controls participating in an Internet-based case-control study of SLE. Polymorphisms analysed included: ESR1 PvuII, XbaI, and GT repeat; ESR2 RsaI, AluI, and CA repeat; and CYP19A1 RsaI, SfaN1, and TTTA repeat. We found significant association of the ESR1 PvuII (PP vs. pp, odds ratio (OR): 3.1, 95% confidence interval (CI): 1.1-9.3) and XbaI (XX vs. xx, adjusted OR: 3.4, 95% CI: 1.1-10.5) with SLE. Carrying the PPXX genotype conferred the highest risk (PPXX vs. ppxx, OR: 4.6, 95% CI: 1.3-15.9). We also found an association of SLE with the ESR2 CA repeat (SS vs. LL, OR: 2.8, 95% CI: 1.0-8.0). Our results support a role of estrogen in pathogenesis of SLE and suggested that genetic variants in the estrogen receptor genes might influence susceptibility.
| S-EPMC3653634 | biostudies-literature
Project description:BackgroundDocetaxel is the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, response rates are ∼50% and determined quite late in the treatment schedule, thus non-responders are subjected to unnecessary toxicity. The potential of circulating microRNAs as early biomarkers of docetaxel response in CRPC patients was investigated in this study.MethodsGlobal microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients.ResultsFourteen microRNAs were associated with serum prostate-specific antigen (PSA) response or overall survival, according to Mann-Whitney U or log-rank tests. Non-responders to docetaxel and patients with shorter survival generally had high pre-docetaxel levels of miR-200 family members or decreased/unchanged post-docetaxel levels of miR-17 family members. Multivariate Cox regression with bootstrapping validation showed that pre-docetaxel miR-200b levels, post-docetaxel change in miR-20a levels, pre-docetaxel haemoglobin levels and visceral metastasis were independent predictors of overall survival when modelled together.ConclusionsOur study suggests that circulating microRNAs are potential early predictors of docetaxel chemotherapy outcome, and warrant further investigation in clinical trials.
| S-EPMC4021524 | biostudies-literature
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.
| S-EPMC8419779 | biostudies-literature
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.
| S-EPMC5484320 | biostudies-literature
Project description:BackgroundSarcopenia is a geriatric syndrome that is characterized by the gradual muscle loss and frailty in the elderly. Meanwhile, the prevalence of prostate cancer is on the rise worldwide. Mainstay treatments for metastatic prostate cancer are androgen-deprivation therapy and taxane-based chemotherapy. Owing to the indolent nature of prostate cancer, these treatments tend to be long-lasting, giving rise to the problem of tolerance to the treatments. Especially given the fact that long-term chemotherapy is closely associated with muscle loss, we aimed to elucidate the correlation between chemotherapy and sarcopenia in the clinical setting.Materials and methodsThis study was a retrospective study. Participants with castration-resistant prostate cancer were recruited from November 2009 to September 2015.Participants were recruited at two hospitals, Juntendo and Teikyo University Hospital, Tokyo, Japan.Participants were 77 Japanese males with castration-resistant prostate cancer who underwent docetaxel chemotherapy.Sarcopenia was defined as L3-psoas muscle index < 5.7 cm2/m2. We statistically investigated whether the existence of sarcopenia has an impact on the survival time, and identified potential covariates that affect it.ResultsOut of 77 patients, 26 patients (34%) were diagnosed as sarcopenia. Analysis showed that sarcopenia is independently associated with mortality risk (hazards ratio = 2.74, P = 0.0055). Sarcopenic patients showed significant decrease in body mass index, pretreatment hemoglobin, C-related protein, and L3-psoas muscle index as compared with nonsarcopenic patients. The median observation period was 499 days (330-790). Thirty-five patients (45%) died of prostate cancer during that period. Sarcopenic patients showed significantly shorter survival time after the initiation of docetaxel treatments (P = 0.0055).ConclusionSarcopenia is an independent predictive factor for a poor tolerance to docetaxel treatment. Given that cessation of the treatment leads to death from the disease, our study identified sarcopenia as an independent factor that raises mortality risk.
| S-EPMC6424678 | biostudies-literature