Abiraterone Acetate/therapeutic use* ; Androstenes/therapeutic use* ; Dexamethasone/therapeutic use* ; Humans ; Male ; Prostatic Neoplasms, Castration-Resistant/pathology*

PURPOSE: Cytochrome P450 17alpha-hydroxylase/17,20-lyase (CYP17A1) is a key enzyme in the androgen biosynthesis pathway. CYP17A1 has been focused on because of the promising results of a potent CYP17A1 inhibitor in the treatment of castration-resistant prostate cancer (CRPC). A hypothesis that intratumoral androgenesis may play a role in the progression of CRPC has recently been postulated. Thus, we evaluated whether commonly used prostate cancer cell lines express CYP17A1. MATERIALS AND METHODS: Androgen-sensitive LNCaP and androgen-insensitive PC-3 and DU145 cells were used. To evaluate the expression of CYP17A1 protein and RNA, we performed Western blotting and RT-PCR, respectively. RESULTS: We were unable to detect either CYP17A1 protein or RNA in any of the cell lines tested. We failed to detect any expression of CYP17A1, despite several repetitions of these techniques under different conditions. CONCLUSIONS: The expression of CYP17A1 protein and RNA in LNCaP, PC-3, and DU145 cells appears to be either absent or too low for detection. The mechanism of action of abiraterone acetate, a CYP17A1 inhibitor, may be related more to adrenal androgen blockade than to intratumoral androgenesis.
Androgens ; Androstadienes ; Blotting, Western ; Cell Line ; Cytochrome P-450 Enzyme System ; Cytochromes ; Prostate ; Prostatic Neoplasms ; RNA ; Steroid 17-alpha-Hydroxylase ; Abiraterone Acetate

Individualized treatment of prostate cancer depends on an accurate stratification of patients who are sensitive to various treatments. Interleukin-23 (IL-23) was reported to play a significant role in prostate cancer. Here, we aimed to explore the clinical value of IL-23-secreting (IL-23+) cells in prostate cancer patients. We evaluated interleukin-23A (IL-23A) expression in The Cancer Genome Atlas database and retrospectively enrolled 179 treatment-naïve metastatic prostate cancer patients diagnosed in our institute between June 2012 and December 2014. IL-23⁺ cells were stained and evaluated via immunohistochemistry. Further, survival and multivariate Cox regression analyses were conducted to explore the prognostic value of IL-23⁺ cells. We found that IL-23A expression correlated with disease progression, while IL-23⁺ cells were clearly stained within prostate cancer tissue. Patients with higher Gleason scores and multiple metastatic lesions tended to have more IL-23⁺ cell infiltration. Further analyses showed that patients with higher levels of IL-23⁺ cells had significantly worse overall survival (hazard ratio [HR] = 2.996, 95% confidence interval [95% CI]: 1.812-4.955; P = 0.001) and a higher risk of developing castration resistance (HR = 2.725, 95% CI: 1.865-3.981; P = 0.001). Moreover, subgroup analyses showed that when patients progressed to a castration-resistant status, the prognostic value of IL-23⁺ cells was observed only in patients treated with abiraterone instead of docetaxel. Therefore, we showed that high IL-23⁺ cell infiltration is an independent prognosticator in patients with metastatic prostate cancer. IL-23⁺ cell infiltration may correlate with abiraterone effectiveness in castration-resistant prostate cancer patients.
Abiraterone Acetate/therapeutic use* ; Androstenes ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Disease-Free Survival ; Humans ; Interleukin-23/metabolism* ; Male ; Prostatic Neoplasms, Castration-Resistant/pathology* ; Retrospective Studies ; Treatment Outcome

Corticosteroid switching can reverse abiraterone resistance in some patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we investigated the potential biomarkers for predicting the efficacy of corticosteroid switching during treatment with abiraterone acetate (AA). We retrospectively analyzed 101 mCRPC patients receiving corticosteroid switching from West China Hospital and Sun Yat-Sen University Cancer Center between January 2016 and December 2018. All cases received AA plus prednisone as first-line therapy during mCRPC. Primary end points were biochemical progression-free survival (bPFS) and overall survival (OS). The risk groups were defined based on multivariate analysis. A total of 42 (41.6%) and 25 (24.8%) patients achieved 30% and 50% decline in prostate-specific antigen (PSA), respectively, after corticosteroid switching. The median bPFS and median OS on AA plus dexamethasone were 4.9 (95% confidence interval [CI]: 3.7-6.0) months and 18.8 (95% CI: 16.2-30.2) months, respectively. Aldo-keto reductase family 1 member C3 (AKR1C3) expression (hazard ratio [HR]: 2.15, 95% Cl: 1.22-3.80, P = 0.008) and baseline serum alkaline phosphatase (ALP; HR: 4.95, 95% Cl: 2.40-10.19, P < 0.001) were independent predictors of efficacy before corticosteroid switching in the multivariate analysis of bPFS. Only baseline serum ALP >160 IU l^-1 (HR: 3.41, 95% Cl: 1.57-7.38, P = 0.002) together with PSA level at switch ≥50 ng ml^-1 (HR: 2.59, 95% Cl: 1.22-5.47, P = 0.013) independently predicted poorer OS. Based on the predictive factors in multivariate analysis, we developed two risk stratification tools to select candidates for corticosteroid switching. Detection of serum ALP level, PSA level, and tissue AKR1C3 expression in mCRPC patients could help make clinical decisions for corticosteroid switching.
Abiraterone Acetate/therapeutic use* ; Adrenal Cortex Hormones/therapeutic use* ; Androstenes ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Dexamethasone/therapeutic use* ; Disease-Free Survival ; Humans ; Male ; Prednisone/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms, Castration-Resistant/pathology* ; Retrospective Studies ; Treatment Outcome

PURPOSE: Few data are available concerning the clinical outcome of abiraterone acetate treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) in terms of the duration of androgen deprivation therapy (ADT) before diagnosis of CRPC. We investigated the clinical efficacy of abiraterone acetate according to the duration of ADT. MATERIALS AND METHODS: We reviewed the medical records of 20 patients with mCRPC who received abiraterone acetate after failure of docetaxel chemotherapy from May 2012 to March 2014 at Seoul National University Bundang Hospital. Clinical factors including prostate-specific antigen (PSA) nadir level, time to PSA nadir, PSA doubling time, PSA response, and modes of progression (PSA, radiologic, clinical) were analyzed. Disease progression was classified according to the Prostate Cancer Working Group 2 criteria. RESULTS: The mean age and PSA value of the entire cohort were 76.0+/-7.2 years and 158.8+/-237.9 ng/mL, respectively. The median follow-up duration was 13.4+/-6.7 months. There were no statistically significant differences in clinical characteristics between patients who received abiraterone acetate with ADT duration<35 months and those who received abiraterone acetate with ADT duration> or =35 months. There were also no significant differences in terms of PSA progression-free survival, radiologic progression-free survival, and clinical progression-free survival between patients with ADT duration<35 months and those with ADT duration > or =35 months. CONCLUSIONS: Although this was a retrospective study with a small sample size, we did not observe any statistically significant differences in the clinical response to abiraterone acetate between mCRPC patients with long ADT duration and those with short ADT duration in terms of disease progression-free survival.
Abiraterone Acetate/administration & dosage ; Aged ; Aged, 80 and over ; Androgen Receptor Antagonists/administration & dosage ; Antineoplastic Agents/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Disease Progression ; Drug Administration Schedule ; Humans ; Kallikreins/blood ; Male ; Neoplasm Metastasis ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms, Castration-Resistant/*drug therapy ; Retrospective Studies ; Taxoids/administration & dosage ; Treatment Outcome

Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer (CRPC); however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival (OS). We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 (53.6%), 34 (30.9%), and 17 (15.5%) in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C-index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations (<110 g l^-1), liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation (<36 months) as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 (95% CI, 0.678-0.836). In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters.
Abiraterone Acetate/therapeutic use* ; Adenocarcinoma/secondary* ; Aged ; Aged, 80 and over ; Alkaline Phosphatase/blood* ; Androgen Antagonists/therapeutic use* ; Antineoplastic Agents/therapeutic use* ; Bone Neoplasms/secondary* ; Cohort Studies ; Humans ; Kaplan-Meier Estimate ; L-Lactate Dehydrogenase/blood* ; Liver Neoplasms/secondary* ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Metastasis ; Nomograms ; Prognosis ; Proportional Hazards Models ; Prostatic Neoplasms, Castration-Resistant/pathology* ; Retrospective Studies ; Serum Albumin/metabolism* ; Survival Rate ; Time Factors

Even in the era of novel targeted agents, switching to a second-line nonsteroidal antiandrogen (NSAA) is still widely used in treating metastatic castration-resistant prostate cancer (mCRPC), especially in undeveloped countries. However, whether prior treatment with a second-line NSAA would impact the efficacy of abiraterone acetate (Abi) remains uncertain. In the current study, 87 mCRPC patients treated with Abi were analyzed. Among them, 21 were treated with a second-line NSAA (from bicalutamide to flutamide) before receiving abiraterone, while the remaining 66 received Abi directly. Therapeutic efficacy of Abi was compared between those with and without prior second-line NSAA using Kaplan-Meier curves, log-rank test, and Cox regression models. The therapeutic efficacy of Abi was similar between those with or without the prior switching treatment of flutamide, in terms of either prostate-specific antigen progression-free survival (PSA-PFS, 5.5 vs 5.6 months, P = 0.967), radiographic progression-free survival (rPFS, 12.8 vs 13.4 months, P = 0.508), overall survival (OS, not reached vs 30.6 months, P = 0.606), or PSA-response rate (71.4% [15/21] vs 60.6% [40/66], P = 0.370). This is the first time that the impact of prior switching of treatment to a second-line NSAA on the efficacy of Abi in mCRPC patients has been addressed. Our data support that, use of prior sequential bicalutamide and flutamide does not seem to preclude response to abiraterone, although larger cohort studies and, ideally, a randomized controlled trial are needed. These findings will facilitate doctors' decision-making in the treatment of mCRPC patients, especially for those with previous experience of switching NSAA second-line treatments in the clinic.
Abiraterone Acetate/therapeutic use* ; Aged ; Aged, 80 and over ; Androgen Antagonists/therapeutic use* ; Anilides/therapeutic use* ; Antineoplastic Agents, Hormonal/therapeutic use* ; Disease-Free Survival ; Female ; Flutamide/therapeutic use* ; Humans ; Kaplan-Meier Estimate ; Male ; Nitriles/therapeutic use* ; Nonsteroidal Anti-Androgens/therapeutic use* ; Prostate-Specific Antigen/analysis* ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Retrospective Studies ; Survival Analysis ; Tosyl Compounds/therapeutic use* ; Treatment Outcome