Castration-refractory Prostate Cancer Research Articles

Prognostic value of circulating tumor cell enumeration for castration refractory prostate cancer

Objective To investigating the prognostic value of the CellSearch CTC enumeration system for the castration resistant prostate cancer (CRPC) patients. Methods From January 2013 to June 2014, 92 CRPC patients' peripheral blood were collected and tested by CellSearch CTC detection system. The median age was 69 (range 53-85) years old and the median PSA was 19.1(range 2.6-273.0) ng/ml. The median serum hemoglobin was 124(69-156)g/L, the serum alkaline phosphatase was 87.0(29.0-2778.5)U/L, the serum lactate dehydrogenase was 207(114-2467)U/ L and the serum albumin was 44.0(32.3-52.2)g/L respectively. Among all the patients, 39.1%(36/92) was Gleason score below 8, 32.6% (30/92)was 8 and 28.3%(26/92) was over 8. 93.5% (86/92) of the patients were diagnosed as bone metastasis and 31.5%(29/92)as lymph node metastasis. Another 5 healthy volunteers with no evidence of tumor history were also tested as the control group. During the follow up, 42 patients were treated with docetaxel plus prednisone as their first-line therapeutic regimen, and the remaining 50 patients who were intolerant to or refused chemotherapy were treated with ketoconazole, estrogen or traditional Chinese medicine. For the survival analysis, Kaplan-Meier plots were generated based on CTC enumeration at baseline and Log-rank test was conducted for calculating the survival difference between the groups. The independent prognostic factors were analyzed by the univariate and multivariate Cox analysis. Results At the time of follow-up, 41 patients had died of prostate cancer with the median follow up of 16.2 months (range: 7.0-26.0 months). All the five patients were detected with no CTC. Ninety-two patients were divided into two groups based on CTC enumeration. Fifty-six patients were defined as favorable CTC counts group (CTC<5) with median follow up of 25 months and 36 as unfavorable CTC counts group(CTC≥5) with median follow up of 18 months. Unfavorable CTC enumerations were predictive of shorter overall survival (Log-rank P=0.00). In the univariate analysis, lactate dehydrogenase(P=0.02), hemoglobin(P=0.00), alkaline phosphatase(P=0.00), serum albumin(P=0.01), ECOG performance status(P=0.00) and CTC enumeration(P=0.00) were associated with prognosis of CRPC patients. A multivariate analysis indicated that only baseline serum alumin (P=0.01), ECOG performance status(P=0.01) and CTC enumeration(P=0.00) were independent prognostic factors for overall survival. Subgroup analysis still support the notion that CTC≥5 are indicative of poor prognosis regardless of receiving docetaxel plus prednisone as their first-line therapeutic regimen or not(P<0.05). Conclusions In the current study, we validated that CTC enumeration could provide a useful prognostic determinant for CRPC patients. Key words: Castration resistant prostate cancer; Circulating tumor cell; Prognosis

TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer

Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent. Patients were randomised to receive six cycles of docetaxel plus prednisolone: alone, with ZA, with a single Sr-89 dose after cycle 6, or with both. Primary outcomes were clinical progression-free survival (CPFS: time to pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE-free interval (SREFI), total SREs, overall survival (OS) and quality of life (QoL). Log-rank test and Cox regression modelling were used to determine clinical effectiveness. Cost-effectiveness was assessed from the NHS perspective and expressed as cost per additional quality-adjusted life-year (QALY). An additional analysis was carried out for ZA to reflect the availability of generic ZA. 757 randomised (median age 68.7 years; Eastern Cooperative Oncology Group scale score 0, 40%; 1, 52%; 2, 8%; prior radiotherapy, 45%); median prostate-specific antigen 143.78 ng/ml (interquartile range 50.8-353.9 ng/ml). Stratified log-rank analysis of CPFS was statistically non-significant for either agent (Sr-89, p = 0.11; ZA, p = 0.45). Cox regression analysis adjusted for stratification variables showed CPFS benefit for Sr-89 [hazard ratio (HR) 0.845, 95% confidence interval (CI) 0.72 to 0.99; p = 0.036] and confirmed no effect of ZA (p = 0.46). ZA showed a significant SREFI effect (HR 0.76; 95% CI 0.63 to 0.93; p = 0.008). Neither agent affected OS (Sr-89, p = 0.74; ZA, p = 0.91), but both increased total cost (vs. no ZA and no Sr-89, respectively); decreased post-trial therapies partly offset costs [net difference: Sr-89 £1341; proprietary ZA (Zometa(®), East Hanover, NJ, USA) £1319; generic ZA £251]. QoL was maintained in all trial arms; Sr-89 (0.08 additional QALYs) and ZA (0.03 additional QALYs) showed slight improvements. The resulting incremental cost-effectiveness ratio (ICER) for Sr-89 was £16,590, with £42,047 per QALY for Zometa and £8005 per QALY for generic ZA. Strontium-89 improved CPFS, but not OS. ZA did not improve CPFS or OS but significantly improved SREFI, mostly post progression, suggesting a role as post-chemotherapy maintenance therapy. QoL was well maintained in all treatment arms, with differing patterns of care resulting from the effects of Sr-89 on time to progression and ZA on SREFI and total SREs. The addition of Sr-89 resulted in additional cost and a small positive increase in QALYs, with an ICER below the £20,000 ceiling per QALY. The additional costs and small positive QALY changes in favour of ZA resulted in ICERs of £42,047 (Zometa) and £8005 for the generic alternative; thus, generic ZA represents a cost-effective option. Additional analyses on the basis of data from the Hospital Episode Statistics data set would allow corroborating the findings of this study. Further research into the use of ZA (and other bone-targeting therapies) with newer prostate cancer therapies would be desirable. Current Controlled Trials ISRCTN12808747. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 53. See the NIHR Journals Library website for further project information.

Association of single nucleotide polymorphisms (SNPs) in TPD52 gene with response to treatment with enzalutamide (ENZA) in men with metastatic castration refractory prostate cancer (mCRPC).

5066Background: Germline variations in genes encoding proteins that contribute to androgen receptor (AR)’s transcriptional output may be associated with response to AR antagonists in men with mCRPC...

Inherited Variants in SULT1E1 and Response to Abiraterone Acetate by Men with Metastatic Castration Refractory Prostate Cancer

Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict the response to abiraterone acetate in men with metastatic, castration refractory prostate cancer. The variations may serve as prognostic and predictive biomarkers to allow for more individualized therapy. We evaluated 832 single nucleotide polymorphisms from the OmniExpress genotyping platform (Illumina®) in the boundaries of 61 candidate genes reported to be involved in the androgen metabolic pathway. The purpose was to investigate them for an association with time to treatment failure in 68 white men with metastatic, castration refractory prostate cancer undergoing treatment with abiraterone acetate. Cox proportional hazard analysis was used with Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation as covariates. Each single nucleotide polymorphism was assessed using an allele carriage genetic model in which carriage of 1 or more minor alleles contributes to increased risk. Subset analyses were done to determine whether metastasis site, or prior treatment with ketoconazole or docetaxel would interact with the single nucleotide polymorphisms investigated. Six single nucleotide polymorphisms in the estrogen sulfotransferase gene SULT1E1 were associated with time to treatment failure on abiraterone acetate therapy after false discovery rate (q value) correction for multiple testing while controlling for Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation (q <0.05). Single nucleotide polymorphisms in SULT1E1 were significantly associated with time to treatment failure in men on abiraterone acetate therapy. The single nucleotide polymorphisms may serve as predictive markers for treatment with abiraterone acetate.

Association of single nucleotide polymorphisms (SNPs) in SULT1E1 with response to treatment with abiraterone acetate (AA) in men with metastatic castration refractory prostate cancer (mCRPC).

222 Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict response to AA in men with mCRPC, serve as prognostic and predictive biomarkers, and guide towards more individualized therapy. Methods: 836 single nucleotide polymorphisms (SNPs) from the Illumina OmniExpress genotyping platform within the boundaries of 61 genes reported to be involved in the androgen metabolic pathway were investigated for association with time to treatment failure (TTF) in 68 Caucasian men with mCRPC undergoing treatment with AA. Cox proportional hazard analysis was employed using Gleason score as a covariate and assessing each SNP under an additive genetic model in which the number of minor alleles contributes increasing risk (or protection). Results: Three SNPs in SULT1E1 were associated with TTF on AA therapy after correcting for multiple testing (p &lt; .00007) while controlling for Gleason Score (Table). Conclusions: SNPs in SULT1E1(estrogen sulfotransferase gene) were significantly associated with TTF on AA therapy, and may serve as predictive markers to treatment with AA. Further validation is being performed in a larger cohort of men with mCRPC. [Table: see text]

Role of the Immune System and Possibilities of Immunotherapy in Prostate Cancer

In recent years, thanks to new advances in tumor immunology, immunotherapy became a part of intensive research as a novel strategy in cancer treatment. Sipuleucel T is the first and only medicinal product approved by the regulatory agencies in the USA and Europe for the treatment of asymptomatic or minimal symptomatic castrate re-fractory prostate cancer. It represents the first product of autologous cell therapy. This article gives a brief overview of new approaches in cancer immunotherapy in clinical development.

Abstract C91: Reversible lysine specific demethylase-1 inhibition is synergistic with docetaxel in castrate refractory prostate cancer

Abstract Lysine specific demethylase-1 (LSD-1) expression correlates with poor survival in prostate cancer. LSD-1 is also key in androgen receptor signaling in androgen sensitive and castration refractory prostate cancer. LSD-1 is a chromatin modifying enzyme that in conjunction with its binding partners functions as an ‘erasor’ in the Epigenetic code process and demethylates lysine 4 and 9 residues on H3 protein resulting in gene repression or activation. Specifically in prostate cancer it demethylates H3k9me2 playing an important role in androgen receptor signaling promoting myc expression. Docetaxel chemotherapy is effective in prostate cancer but limited by toxicity and development of resistance. In this study we demonstrate synergy between LSD-1 inhibition and docetaxel in castrate refractory cell lines. We further demonstrate that LSD-1 inhibition is effective in docetaxel resistant cell lines. Cell survival assays were performed with HCI2509 on castrate refractory and docetaxel resistant prostate cancer cell lines. Histone methylation and myc expression were assessed. Colony formation assays, cell cycle analysis, xenograft studies were performed. Synergy studies were performed to assess the combination of 2509 and docetaxel. HCI2509 is cytotoxic to castrate refractory and docetaxel resistant prostate cancer cell lines in low micromolar doses. Treatment with HCI2509 resulted in dose dependent increase in H3K4me2, H3K4me3, H3K9me2 levels and decrease in myc protein. RT-PCR showed a significant decrease in MYC expression upon treatment with HCI2509. Cell cycle progression was arrested at G0/G1 upon treatment with 2509 with inhibition of colony formation at 10 to 100 fold lower concentrations. PC3 xenografts in mice showed significant reduction in tumor burden upon treatment with 2509 with increased H3K9me2 marks and reduced myc protein levels. LSD-1 inhibition with HCI2509 has therapeutic potential in castrate refractory and docetaxel resistant prostate cancer. It inhibits myc expression and sensitizes castrate refractory prostate cancer to docetaxel. Citation Format: Sumati Gupta, Alexis Weston, Jared Bearss, Sunil Sharma. Reversible lysine specific demethylase-1 inhibition is synergistic with docetaxel in castrate refractory prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C91.

The first experience in using abiraterone acetate in patients with castration-refractory prostate cancer

Even in the mid-twentieth century, Huggins and Hodges proved the susceptibility of prostate cancer cells to hormonal manipulations, by using surgical castration as an example. An average of 18–36 months after initiation of first-line hormonal therapy, patients develop the castration resistance in prostate cancer, one of the causes of which was hyperproduction of the tumor receptors of prostate cancer cells and their hypersusceptibility to the castration levels of testosterone. Long-term treatment in patients with castration-refractory prostate cancer was extremely symptomatic and quality of life and overall survival were low. In the 2000s, investigations aimed at designing drugs to treat this category of patients were underway, which have culminated in the advent of three drugs (two of which belong to chemotherapy) that are now used in the Russian Federation. The second-line hormonal agent abiraterone acetate (Zytiga) is one of these drugs, which was officially registered in 2011. Its mechanism of action is due to inhibition of the enzyme CYP17, leading to the blocked synthesis of testosterone at all levels, including at the intracrine level, and achieving testosterone levels below the postcastration ones. The paper reviews the literature regarding abiraterone acetate and the first experience in using second-line hormonal therapy in three patients.

Chemotherapy in the treatment of metastatic prostate cancer: the present state of the problem

The paper reviews the current possibilities of cytostatic chemotherapy in patients with metastatic prostate cancer. It gives the data of studies dealing with the early use of docetaxel in patents with hormone-susceptible tumors and analyzes approaches to sequential therapy with docetaxel, cabazitaxel, and antiandrogens (abiraterone, enzalutamide) in patients with castration-refractory prostate cancer. Assessment of the prognostic role of different clinical and biological factors could provide an algorithm for the choice of first- and second-line therapy in patients with castration resistance.

Association of single nucleotide polymorphisms (SNPs) in ESR1 and PRMT8 and response to treatment with abiraterone acetate (AA) in men with metastatic castration refractory prostate cancer (mCRPC).

5048 Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict response to AA in men with mCRPC, serve as prognostic and predictive biomarkers, a...

Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer. (ISRCTN 12808747) TRAPEZE.

e16108 Background: Bony metastatic CRPC has a poor prognosis and high morbidity. TRAPEZE is a factorial RCT using 3 agents, docetaxel (D), zoledronic acid (ZA) and strontium-89 (Sr89). All have pal...

THERAPY WITH SOMATOSTATIN ANALOGUES IN PATIENTS WITH CASTRATION-REFRACTORY PROSTATE CANCER

Prostate cancer remains an actual problem in daily practice of oncourology because of the ongoing high incidence of this pathology. The main method of treatment in patients with metastatic PC is palliative hormonal therapy. In case of disease progression and development of castration-refractory prostate cancer it is possible to provide the second line chemotherapy or hormonal therapy, as well as to treat with drugs aimed at inhibiting the so-called ligand-independent pathway of activation of androgenous receptors. The article presents an overview of the results of a recent study that evaluated the efficacy of inhibitors of insulin-like growth factor, the analogue of somatostatin - octreotide - depot.

Actualités dans le cancer de la prostate lors de l'Asco 2010

In urologic oncology, prostate cancer represented, even this year, a wide part during the ASCO 2010 meeting. In the non metastatic diseases, two phase III trials confirmed the benefit of radiotherapy combined with hormonotherapy in locally advanced stage. For patients with metastatic hormonoresistant cancer, two randomized trials will probably change the daily practice in the next months. On the one hand, denosumab versus zoledronate decreased significantly the risk of skeletal-related events in bone metastases. On the other hand, compared with mitoxantrone, cabazitaxel in docetaxel pretreated patients improved overall survival. On the contrary, docetaxel in monotherapy remains the standard of care in first line chemotherapy in castration refractory metastatic prostate cancer. Indeed, in two trials, combination of bevacizumab or calcitriol with docetaxel showed no benefit for patients with more toxicities. Finally, docetaxel-based chemotherapy was again evaluated in two other situations: biological recurrence, and hormono-sensitive metastatic stage. Preliminary results of tolerance were presented this year. No doubt that communications during future ASCO meetings would reported definitive results of efficiency of these phase III studies.

Pretreatment neutrophil/lymphocyte ratio (NLR) prior to steroids as a prognostic factor in metastatic castrate refractory prostate cancer (mCRPC) patients treated with taxanes.

273 Background: The neutrophil/lymphocyte ratio (NLR) has been demonstrated to be a prognostic factor in multiple malignancies. Prior analyses have demonstrated conflicting results in correlation between NLR and overall survival (OS) in mCRPC. Prednisone and dexamethasone, commonly used in chemotherapy regimens for prostate cancer, have been demonstrated to affect neutrophils and hence NLR. We investigated the correlation between pre-dexamethasone NLR and OS in patients with mCRPC. Methods: We performed a retrospective single-center study of patients with mCRPC who received taxane-based chemotherapy (docetaxel or cabazitaxel) between 9/2005 and 12/2012. Patients were included if blood test results were available between 3 and 28 days prior to commencement of chemotherapy. Baseline demographics and NLR were correlated with OS using a Cox proportional hazards model. Results: 42 patients were included, 9 of whom were still alive, with median age 70 and median follow-up 23.1 months. Median OS was 24.1 months. 36 were commenced on docetaxel-based chemotherapy and 6 on cabazitaxel-based chemotherapy. Considering NLR as a categorical variable, OS was significantly better in patients with NLR&lt;5 (n=28) compared to those with NLR&gt;5 (n=14), with median OS 32mo vs 15.4mo and HR 2.155 (95% CI 1.072-4.332, p=0.0007 by log-rank test). In multivariate analyses, NLR (p=0.008) and age (p=0.048) were independent predictors of overall survival. In sensitivity analyses, when including NLRs within 48 hours of chemotherapy initiation, the correlation between NLR and OS was only marginally significant (p=0.048). Conclusions: HighNLR is an adverse prognostic marker for decreased overall survival in mCRPC patients undergoing taxane-based chemotherapy. Previous conflicting results regarding its value may be related to the effect of steroids on NLR.

Effect of cabazitaxel on the growth of human castration-refractory prostate cancer cells in vitro compared to docetaxel and on the anti-tumor properties of the angio-inhibitor PEDF in vivo.

205 Background: Docetaxel/DTX and cabazitaxel/CBZ have shown promise in the treatment of metastatic Castration-Refractory Prostate Cancer/mCPRC however, comparative studies are missing. Toxicities of these drugs are significant, urging the need to modify taxane regimens. Recently, low-dose metronomic/LDM treatments using conventional chemotherapeutic drugs have shown benefits in CPRC in improving the effect of anti-angiogenic agents. Previously, we have demonstrated that LDM-DTX in combination with PEDF curbs significantly CRPC growth, limits metastases formation and prolongs survival in vivo. In this study, we intended to compare the cytotoxic effect of CBZ and DTX on CRPC cells in vitro and CL1 tumors in vivo. Methods: PC3, DU145 cell lines were from ATCC.CL1 cells were obtained from androgen-deprived LNCaP cells. Cell proliferation was assessed by crystal violet staining and cell cycle analyses. In vitro cytotoxicity assays were performed on CL1 cells/RAW264.7 macrophages co-cultures treated with PEDF and increasing doses of taxanes. For the in vivo studies, CL1 cells were engineered to stably express the DsRed Express protein +/- PEDF. PEDF anti-tumor effects were assessed on s.c. xenografts treated with DTX (5mg/kg ip ev. 4 day) as reference, CBZ (5mg/kg ip ev. 4 days, 1mg/kg for 10 days, 0.5mg/kg q.a.d. and 0.1mg/kg daily) or placebo. Results: CBZ limits cell proliferation with a greater efficacy than DTX in all CRPC cell lines tested. DU145 presented the largest difference. High doses of taxane blocked tumor cells in mitosis, whereas LDM increased the SubG1 population. This effect was significantly higher in DU145 cells treated with CBZ. In vivo, 5mg/kg CBZ delayed tumor growth more efficiently than 5mg/kg DTX. PEDF/5mg/kg CBZ markedly delayed tumor growth compared to all treatments. Finally, engulfment of tumor cells by macrophages was higher in combined treatments suggesting an inflammation-related process. Conclusions: CBZ is more efficient than DTX both in vitro and in vivo.The data also reinforce PEDF as a promising anti-neoplasic agent in combination with LDM taxane chemotherapies.

Ipilimumab in the treatment of prostate cancer.

Ipilimumab (Yervoy(®); Bristol-Myers Squibb, NY, USA) is a fully human monoclonal antibody targeting CTLA-4 and is approved for the treatment of metastatic melanoma. Preclinical and clinical studies have shown its activity in a number of different cancer types, including prostate cancer. Recently, the results from a Phase III study of ipilimumab in prostate cancer patients with prior docetaxel therapy were reported. Although the study did not meet the primary end point of improved overall survival, prespecified subset analyses suggested that ipilimumab may be more active in men with lower disease burden, which suggests that immunotherapy should be tested early in men with castration-refractory prostate cancer. Immune-related adverse events are common and most can be well managed with standard immunosuppressive algorithms.

Therapy using somatostatin analogs in patients with castration-refractory prostate cancer

Therapy using somatostatin analogs in patients with castration-refractory prostate cancer

Liver Metastases in Prostate Carcinoma Represent a Relatively Aggressive Subtype Refractory to Hormonal Therapy and Short-Duration Response to Docetaxel Monotherapy.

BackgroundWe report a single institution’s experience from a small series of patients suggesting that liver metastasis in metastatic castration-refractory prostate cancer (mCRPC) represents a relatively aggressive subtype that is refractory to hormonal manipulation treatment, including luteinizing hormone-releasing hormone agonist (LA) and abiraterone (Ab) therapy, although docetaxel is briefly effective.MethodsBetween 2007 and 2013, six patients with prostate cancer with liver metastases were analyzed. Biochemical response was defined as > 50% decrease in prostate-specific antigen (PSA) value.ResultsTwo patients who presented with liver metastases died in less than 3 months after LA therapy. Two out of three patients (one died while receiving chemotherapy) received Ab after chemotherapy did not show any response and died while on therapy. One patient who presented with lung metastases initially received LA therapy and progressed on it with liver metastases in < 6 months. Thus, five of six patients did not respond to hormone therapy including LA and Ab. Three patients who received docetaxel after LA therapy had more than 50% objective PSA response with a mean survival of 4 months.ConclusionsNo literature addresses the response to hormone treatment in hepatic metastasis in prostate carcinoma. This small series suggests that liver metastases in prostate carcinoma represent a relatively aggressive subset against which hormonal therapy, including the LA and Ab, appears to be ineffective. Although our patients responded to docetaxel chemotherapy, their responses were of short duration. A further clinical trial involving more patients will be necessary to substantiate our findings.

The association of 5-alpha reductase type 2 (SRD5A2) gene polymorphisms with prostate cancer in a Korean population

PurposeSteroid 5-alpha reductase type 2 (SRD5A2) modifies testosterone to dihydrotestosterone (DHT) in the prostate. Single-nucleotide polymorphisms (SNPs) of the SRD5A2 gene might affect DHT. We sought to understand the relationship of SRD5A2 SNPs to prostate cancer in the Korean population.Materials and MethodsTwenty-six common SNPs in the SRD5A2 gene were assessed in 272 prostate cancer cases and 173 controls. Single-locus analyses were conducted by using conditional logistic regression. Additionally, we performed a haplotype analysis for the SRD5A2 SNPs tested.ResultsAmong the 20 SNPs and 4 haplotypes, there were no statistically significant results in the prostate cancer patients and the controls. In the logistic analysis of SRD5A2 polymorphisms with prostate-specific antigen (PSA) criteria, two SNPs (rs508562, rs11675297) and haplotype 1 displayed significant results (odds ratio [OR], 1.76; p=0.05; OR, 1.88-2.02; p=0.01-0.04; OR, 0.59; p=0.02, respectively). rs508562, rs11675297, rs2208532, and haplotype 1 (OR, 1.49; p=0.05; OR, 2.02; p=0.05; OR, 2.01; p=0.04; OR, 0.56-0.64, p=0.03-0.04, respectively) had significant associations with Gleason score. rs508562, rs11675297, and haplotype 1 (OR, 1.41-2.34; p=0.004-0.05; OR, 1.74-1.82; p=0.03-0.05; OR, 0.42-0.67; p=0.0005-0.03, respectively) were significantly associated with clinical stage.ConclusionsWe conclude that there was no significant association between SRD5A2 SNPs and the risk of prostate cancer in the Korean population. However, we found that some SNPs and 1 haplotype influenced PSA level, Gleason score, and clinical stage.

Diethylstilboestrol (1 mg) in the Management of Castration-Resistant Prostate Cancer

Objective: To investigate the efficacy of diethylstilboestrol (DES) in patients with advanced prostate cancer refractory to androgen suppression. Methods: This retrospective study comprises 194 patients with prostate cancer treated with DES (1 mg daily) between 1976 and 2010. Study outcome parameters included demographic data, tumour characteristics, treatment history, prostate-specific antigen (PSA) responses, radiologic studies, adverse events and overall survival. Results: At initiation of oestrogen therapy the mean patient age was 69 years (range: 48-89) and the median PSA was 96 ng/ml (range: 1.9-9,500). The median duration of prior prostate cancer treatment was 29 months (range: 1-365). DES was the second-line treatment in 58 patients and the third/fourth-line therapy in 136 men. A formal (≥50%) PSA response was observed in 95 patients (48.9%) and the median time to progression (TTP) was 250 days (95% CI, 180-360) for this group. An additional 62 patients (31.9%) had a partial PSA response with a median TTP of 150 days (95% CI, 92-180). Thirty-seven patients (19.1%) did not have a PSA response and the median TTP was 90 days (95% CI, 90-97). The median overall survival from the start of oestrogen therapy for the entire cohort was 576 days (95% CI, 482-690). The median overall survival of patients who had a formal (≥50%), partial (<50%) and no PSA response was 756 (95% CI, 670-1,429), 428 (95% CI, 340-630) and 329 (95% CI, 287-510) days, respectively. Thirty-nine patients (20.1%) were still alive at the end of the study. No treatment-related deaths occurred. Conclusions: In the age of chemotherapy this study highlights the efficacy of oestrogen therapy in castration-refractory prostate cancer. The optimal point in the therapeutic pathway at which DES should be prescribed remains to be established.