Germline variant in SLCO2B1 and response to abiraterone acetate plus prednisone (AA) in new onset metastatic castration-resistant prostate cancer (mCRPC)
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PROVIDER: PRJNA509610 | ENA |
REPOSITORIES: ENA
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Project description:There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently available. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate (AA) for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line AA in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah. Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line AA in men with mCRPC. We performed a pre-specified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on AA. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line AA for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared to the homozygous wild-type group (8.9 months vs. 6.3 months, HR 0.46, 95% CI 0.23-0.94, p=0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line AA In men with mCRPC.
2018-12-13 | GSE123695 | GEO
Project description:Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC). However, its efficacy varies among individuals, thus the identification of biomarkers to predict and follow treatment response is required. In this pilot study, we explored the potential of circulating miRNAs (c-miRNAs) to stratify patients based on their responsiveness to AA. We conducted a miRNA candidate analysis on 9 responders versus 9 non-responders mCRPC patients via Exiqon qPCR panels The patients were considered responders to AA if they either achieved a radiological response without PSA progression and performance status deterioration, or in the presence of PSA reduction ≥ 50% compared to the baseline values without radiological progression and performance status deterioration.
2024-06-20 | GSE262550 | GEO
Project description:Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20-40% of the patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance. Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients. Results: Thirty cytosines showed significant modification differences (FDR q < 0.05) between the AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, the AA-sensitive patients, but not AA-resistant patients, lost interindividual variation of cfDNA modification shortly after starting AA-treatment, but such variation returned to initial levels in the later phases of treatment. Conclusions: Our findings provide a list of potential biomarkers for prediction of AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients.
2018-03-20 | GSE108462 | GEO
Project description:BackgroundAlthough the benefit of androgen deprivation therapy (ADT) continuation in metastatic castration-resistant prostate cancer (mCRPC) remains controversial, clinical evidence is lacking. Recent results indicated that treatment with abiraterone acetate (AA) plus prednisone (P) further suppresses serum testosterone levels over ADT alone, suggesting that continuation of ADT in the treatment of mCRPC may not be necessary.MethodsIn this exploratory phase 2 study, mCRPC patients were randomized with a 1:1 ratio to receive either continued ADT plus AA + P (Arm A) or AA + P alone (Arm B). The primary endpoint was the rate of radiographic progression-free survival (rPFS) at month 12. Secondary endpoints included PSA-response rate, objective response, time to PSA progression and safety.ResultsA total of 68 patients were equally randomized between the two study arms. Median testosterone-levels remained below castrate-levels throughout treatment in all patients. According to the intention-to-treat analysis the rPFS rate was 0.84 in Arm A and 0.89 in Arm B. Moderate and severe treatment-emergent adverse events were reported for 72% of the patients in Arm A and for 85% of the patients in Arm B.ConclusionsAA + P treatment without ADT may be effective in mCRPC patients and ADT may not be necessary in patients receiving AA + P.
| S-EPMC9705242 | biostudies-literature
Project description:IntroductionAbiraterone acetate plus prednisone (AA+P) has shown to significantly improve survival. COSMiC, a Canadian Observational Study in Metastatic Cancer of the Prostate, set out to prospectively amass real-world data on metastatic castration-resistant prostate cancer (mCRPC) patients managed with AA+P in Canada. Herein, we report their patient-reported outcomes (PROs).MethodsAfter a median followup of 67.1 weeks, 254 patients were enrolled across 39 sites. Functional Assessment of Cancer Therapy-Prostate (FACT-P), Montreal Cognitive Assessment (MoCA), Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), and Current Health Satisfaction in Prostate Cancer (CHS-PCa) were evaluated at baseline, as well as at weeks 12, 24, 48, and 72 after AA+P initiation. Descriptive analysis was used with continuous variables. Changes from baseline were summarized using mean (standard deviation [SD]).ResultsAt a median age of 76.6 (8.94), baseline FACT-P total score was 111.3 (19.56) with no significant change in their functional status observed from baseline over time. The median baseline MoCA score was 25.2 (4.52), yet subsequent assessments showed an absence of cognitive decline while under treatment. Similarly, no meaningful changes were detected in BPI, BFI, and CHS-PCa during the 72-week study period, thus suggesting that patients' PROs were well-maintained throughout AA+P treatment. Prostate-specific antigen (PSA) response with >50% decline was 66.4%. Safety profile was consistent with the known side effect of AA+P.ConclusionsCOSMiC represents the largest Canadian mCRPC cohort treated with AA+P with real-world, prospective evaluation of PROs. This data demonstrated the maintenance in quality of life and cognitive status over the course of the study and underscores the importance of PRO use in this complex patient population.
| S-EPMC7704085 | biostudies-literature
Project description:Informed consent was obtained to collect human mCRPC tissues and generate the patient-derived xenograft tumors as described previously (Labrecque et al., 2019; Nguyen et al., 2017). The study was approved by the University of Washington Human Subjects Division institutional review board (no. 39053). All animal studies were approved by University of Washington IACUC and performed according to NIH guidelines. Molecular characterization of AR+ mCRPC LuCaP PDXs 70CR, 78CR, 81CR, 96CR, 105CR, 136CR and 147CR was previously described (Labrecque et al., 2019; Nguyen et al., 2017). LuCaP PDX 167CR was established from a liver metastasis of 77-year-old Caucasian male who died of abiraterone-, carboplatin- and docetaxel-resistant CRPC. LuCaP 167CR expresses AR, responds to castration and is negative for synaptophysin. PDX cellular morphology recapitulates the original liver metastasis (Supplementary Figure S8A).
2022-04-06 | GSE163220 | GEO
Project description:To identify the molecular signature associated with abiraterone acetate (AA) response and mechanisms underlying AA resistance in castration-resistant prostate cancer patient-derived xenografts (PDXs).
2016-12-22 | GSE85672 | GEO
Project description:The goal of this study was to determine the effects of a well-characterized anti-androgen, abiraterone acetate, and a suspected human anti-androgen, di-n-butyl phthalate (DBP) on the androgenic function of human fetal testis. Human fetal testis was xenografted into the renal subcapsular space of castrated male athymic nude mice. Hosts were treated with hCG to stimulate testosterone production in the xenografts, and were concurrently treated with either abiraterone acetate or DBP. While abiraterone acetate (14 d, 75 mg/kg/d p.o.) dramatically reduced testosterone and the weights of androgen-sensitive host organs, DBP (14 d, 500 mg/kg/d p.o.) had no effect on androgenic endpoints. Three paired analyses were performed using the LIMMA package in R (commands lmfit and eBayes), with the Benjamini-Hochberg correction for multiple comparisons (Smyth 2005): vehicle-treated xenografts vs. unimplanted testis (n=5), abiraterone-treated xenografts vs. matched control xenografts (n=3), and DBP-treated xenografts vs. matched control xenografts (n=3). There were significant differences in gene expression between grafted and ungrafted samples, including dramatic upregulation of microRNAs. Gene expression analysis also showed that abiraterone decreased expression of genes related to cell differentiation, while DBP induced expression of oxidative stress response genes and decreased expression of factors related to embryonic development. 17 xenograft samples were analyzed, including 5 unimplanted samples, 6 vehicle treated xenografts, 3 abiraterone acetate-treated xenografts, and 3 DBP-treated xenografts. Samples were paired (derived from the same donor tissue) for each comparison: vehicle vs. unimplanted (n=5), abiraterone vs. vehicle (n=3), and DBP vs. vehicle (n=3).
2013-10-31 | E-GEOD-49244 | biostudies-arrayexpress
Project description: Not available
| S-EPMC9377412 | biostudies-literature
Project description:Lessons learnedThe safety and activity findings of abiraterone acetate plus prednisone treatment in black men with mCRPC were similar to results from previously conducted studies with largely white populations.Poor trial accrual continues to be a challenge in black men with mCRPC and further efforts are needed to address such underrepresentation.BackgroundSelf-identified black men have higher incidence and mortality from prostate cancer in the United States compared with white men but are dramatically underrepresented in clinical trials exploring novel therapies for metastatic castration-resistant prostate cancer (mCRPC).MethodsBlack men with mCRPC were treated with abiraterone acetate (AA), 1,000 mg daily, and prednisone (P), 5 mg twice daily. The primary objective was to determine antitumor activity (defined by a ≥30% decline in prostate-specific antigen [PSA] level) and to correlate germline polymorphisms in androgen metabolism genes with antitumor activity. Secondary objectives included determining safety, post-treatment changes in measurable disease, and time to disease progression.ResultsFrom April 2013 to March 2016, a total of 11 black men were enrolled and received AA plus P (AA+P); 7 of 10 evaluable patients were docetaxel naive. Post-treatment declines in PSA level of ≥30% were achieved in 90% of patients. The side effect profile was consistent with prior clinical trials exploring AA+P in mCRPC. Due to poor accrual, the study was closed prematurely with insufficient sample size for the planned pharmacogenetic analyses.ConclusionIn this small prospective study terminated for poor accrual, the safety and activity of AA+P in black men with mCRPC was similar to that reported in prior studies exploring AA in largely white populations. Further efforts are needed to address underrepresentation of black men in mCRPC trials.
| S-EPMC5153336 | biostudies-literature