Enhancer of zeste-homolog 2 (EZH2) expression and clinical outcomes in metastatic castrate resistant prostate cancer (mCRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 350-350
Author(s):  
Karthik Giridhar ◽  
Brian Addis Costello ◽  
Carlos Sosa ◽  
Haojie Huang ◽  
Manish Kohli
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Clinical Outcomes ◽  
Prognostic Significance ◽  
Disease Recurrence ◽  
Abiraterone Acetate ◽  
Rna Seq ◽  
Exact Test ◽  
P Gene ◽  
Ezh2 Expression

350 Background: In prostate cancer, overexpression of EZH2 is associated with disease recurrence, androgen independent growth, cell invasion, and metastases. We evaluated the prognostic significance of EZH2 gene expression in metastatic biopsies from men with CRPC. Methods: EZH2 (RNA) expression was evaluated in two serial metastatic site biopsies in patients (pts) prior to treatment with abiraterone acetate and prednisone (pre-AA/P) and after 12 weeks of treatment (post-AA/P). All pts were enrolled and prospectively followed for clinical outcomes. The primary endpoint was overall survival (OS), defined as the time from CRPC to death or last follow-up. Cox proportional hazard regression analysis was performed on EZH2 expression using normalized fragments per kilobase million (FPKM) > 1 for association with OS and time to treatment failure (TTF). Results: Of 92 enrolled pts, 59 pts had (pre-AA/P) gene expression using RNA-seq, 45 had paired pre and post-AA/P RNA-seq available for analysis. In pre-AA/P samples, the median EZH2 expression was 4.82 FPKMs (range 1.05-38.8). Elevated expression of EZH2 was associated with shorter OS [hazard ratio (HR) 2.58, p = 0.016]. Radiographic progression at 12 weeks was more frequent in high EZH2 tumors compared to low EZH2 tumors (48% vs 20%, p = 0.03, Fisher’s exact test) No statistically significant associations were identified between EZH2 expression and TTF. In paired post-AA/P biopsies, EZH2 expression increased in 13/45 tumors and decreased in 32/45 tumors. The median log2 fold change in EZH2 expression was -1.38 (range -6.7 to 3.1). In post-AA/P biopsies, no associations were identified between an increase in EZH2 expression and OS or TTF. Conclusions: EZH2 expression represents a potential novel prognostic biomarker in mCRPC and warrants further exploration. Clinical trial information: 01953640.

scholarly journals Prognostic significance of the evaluation of expression of the gene PCA3 in urine in patients with localized prostate cancer and histomorphological changes in the peritumoral zone

2018 ◽  
Vol 8 (3) ◽  
pp. 11-19
Author(s):  
Philip S. Bova
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Biochemical Recurrence ◽  
Prognostic Significance ◽  
Intraepithelial Neoplasia ◽  
Disease Recurrence ◽  
Localized Prostate Cancer ◽  
Urine Sediment ◽  
Increased Risk ◽  
Urine Exosomes

Aim. To determine the prognostic significance PCA3 gene expression in urine sediment and exosomes in patients with localized prostate cancer (PC) and associated histologic changes in the peritumoral zone as a predictor of biochemical recurrence after radical prostatectomy (RPE). Materials and methods. Of 148 patients with localized PC, 96 (65%) had high-grade prostatic intraepithelial neoplasia (PIN-2) in the peritumoral zone. The other 52 (35%) had no pathologic tissue of the peritumoral zone. PDA3 expression in urine sediment and exosomes was determined with real-time PCR with respect to the reference gene KLK3. Results. The PCA3 gene expression level in urine exosomes in patients with PIN-2 in the prostatic peritumoral zone and synchronous pancreatic adenocarcinoma was higher among patients with subsequent disease recurrence. Increased PCA3 gene expression in the urine sediment was also predictive of the risk of recurrence of a prostatic tumor with PIN-2 in the peritumoral zone, although to a lesser degree than the results with urine exosomes. When the ∆Ct РСА3-KLK3 was ≥1,86 in the urine sediment, biochemical recurrence of PC and PIN-2 developed more frequently in the peritumoral zone (84% versus 51%, p = 0,013). Conclusions. Increased PCA3 gene expression in urine sediment and exosomes is a predictor of increased risk of biochemical recurrence after RPE in patients with localized PC and PIN-2 in the peritumoral zone.

Multi-institutional evaluation of the clinical outcomes and genomic correlates of African Americans with metastatic castration-sensitive prostate cancer (mCSPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 17-17
Author(s):  
Meredith MI Freeman ◽  
Ellen Jaeger ◽  
Jason Zhu ◽  
Audrey Phone ◽  
Roberto Nussenzveig ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Retrospective Analysis ◽  
Clinical Outcomes ◽  
De Novo ◽  
High Volume ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Treatment Intensification ◽  
Radium 223 ◽  
Incidence And Mortality

17 Background: Prostate cancer incidence and mortality is higher in African American (AA) as compared with non-AA men. The outcomes of mCSPC have significantly improved through treatment intensification yet, AA representation in those studies was suboptimal. We aimed to report the clinical, treatment outcomes and genomic data of AA men with mCSPC. Methods: Retrospective analysis of consecutive AA men with mCSPC at six Academic Institutions. The primary objective was to report the baseline characteristics and treatment patterns of mCSPC AA patients. The secondary objectives included the germline and somatic data and the clinical outcomes including PSA response, progression-free survival and subsequent treatments. Results: A total of 71 patients, median age 63 years (range, 41-84) with 58% Gleason 8-10, initial PSA of 69.8 ng/mL (0.02-7650), 59% with de-novo and 55% with high-volume (CHAARTED criteria; 20% visceral) disease, were included in this analysis. Twenty-two patients (31%) were treated with androgen deprivation therapy (ADT; 67% prior to year 2017), while 24%, 45% and 3% received docetaxel (median 6 cycles), abiraterone acetate and enzalutamide, respectively. Two patients received triplet therapy with ADT/docetaxel plus abiraterone or enzalutamide. Undetectable PSA was achieved in 35% after a median of 8.9 months (1.8-22.3). Among patients with mCSPC who received radiation therapy to prostate (n = 8), 89% had low volume disease. At time of cut off, thirty-two patients developed CRPC and the estimated median time to CRPC was 2.9 years (95% CI, 1.6-4.2). Subsequent therapies (n = 29) included abiraterone acetate (41%), enzalutamide (24%), bicalutamide (10%), radium-223 (7%), chemotherapy (7%), sipuleucel-T (3%) and others (7%). Five patients (8%) had pathogenic germline alterations (n = 2 BRCA1; n = 1 HOXB13, PALB2 and PMS2). Additionally, the most common somatic alterations among tested patients (n = 27) included CDK12, SPOP, TMPRSS2-ERG fusion, and TP53, all in 11% frequency. Of note, n = 2 BRCA1 and n = 1 high MSI/TMB. Conclusions: In one of the largest reported cohorts to our knowledge, mCSPC AA presented with a high number of de-novo and high-volume disease and might harbor a different germline and somatic genomic profile. The outcomes were comparable to contemporary phase III trials with treatment intensification, yet 31% were treated with ADT. Despite the known limitations associated with retrospective analysis, these data support prior observations where AA might have better initial PSA responses to ADT-based strategies compared with Caucasians, requiring further validation.

scholarly journals A prognostic model for stratifying clinical outcomes in chemotherapy-naive metastatic castration-resistant prostate cancer patients treated with abiraterone acetate

2017 ◽  
Vol 12 (2) ◽  
pp. E47-52 ◽  
Author(s):  
Daniel Joseph Khalaf ◽  
Claudia M. Avilés ◽  
Arun A. Azad ◽  
Katherine Sunderland ◽  
Tilman Todenhöfer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Outcomes ◽  
Group Performance ◽  
Eastern Cooperative Oncology Group ◽  
Specific Antigen ◽  
Prognostic Index ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Psa Progression

Introduction: Recently, a prognostic index including six risk factors (RFs) (unfavourable Eastern Cooperative Oncology Group performance status [ECOG PS], presence of liver metastases, short response to luteinizing hormone-releasing hormone [LHRH] agonists/ antagonists, low albumin, increased alkaline phosphatase [ALP] and lactate dehydrogenase [LDH]) was developed from the COUAA- 301 trial in post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate. Our primary objective was to evaluate this model in a cohort of chemotherapy-naive mCRPC patients receiving abiraterone.Methods: We identified 197 chemotherapy-naive patients who received abiraterone at six BC Cancer Agency centres and who had complete information on all six RFs. Study endpoints were prostate-specific antigen (PSA) response rate (RR), time to PSA progression, time on treatment, and overall survival (OS). PSA RR and survival outcomes were compared using Χ2 test and log-rank test. Multivariable Cox proportional hazard analysis was performed to identify RFs independently associated with OS.Results: Patients were classified into good (0‒1 RFs), intermediate (2‒3 RFs), and poor (4‒6 RFs) prognostic groups (33%, 52%, and 15%, respectively). For good-, intermediate-, and poor-risk patients, PSA RR (≥50% decline) was 60% vs. 42% vs. 40% (p=0.05); median time to PSA progression was 7.3 vs. 5.3 vs. 5.0 months (p=0.02); and median OS was 29.4 vs. 13.8 vs. 8.7 months (p<0.0001).Conclusions: The six-factor prognostic index model stratifies clinical outcomes in chemotherapy-naive mCRPC patients treated with abiraterone. Identifying patients at risk of poor outcome is important for informing clinical practice and clinical trial design.

Association of CTC detection by AdnaTest with outcome on enzalutamide in chemotherapy-naïve castration-resistant prostate cancer: Exploratory results from PREMIERE—A SOGUG trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5052-5052 ◽  
Author(s):  
Albert Font Pous ◽  
Sergio Vazquez-Estevez ◽  
Aranzazu Gonzalez del Alba ◽  
Begoña Mellado ◽  
Ovidio Fernandez Calvo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Clinical Outcome ◽  
Cox Regression ◽  
Castration Resistant Prostate Cancer ◽  
Exact Test ◽  
Castration Resistant ◽  
Expression Studies ◽  
Psa Response ◽  
Gene Expression Studies

5052 Background: Circulating tumor cells (CTCs) enumeration using CellSearch correlates with clinical outcome in prostate cancer, but is limited for gene expression analysis. AdnaTest ProstateCancer is a commercially available CTC immune-enrichment and PCR-related detection method that allows gene expression studies (Antonarakis E, NEJM 2014). It has demonstrated incremental detection of CTCs in patients with no CTCs identified by CellSearch (Samoila A, ASCO 2013) but needs to be clinically qualified. There is a strong need for studies to assess the association with the clinical outcome in CRPC. Methods: Between February and November 2015, 98 asymptomatic or oligo-symptomatic chemotherapy-naïve mCRPC pts were recruited in 16 institutions. Although initially designed to study the predictive value of TMPRSS2-ETS, data emerging after the trial was initiated led the group to prioritize alternative predefined exploratory biomarkers, including plasma AR (Grande E, ASC0 2017 #) and CTC characterization (Grande E, ESMO 2016). Outcome measures included PSA-PFS (sPFS), radiographic PFS (rPFS) and OS. Cox regression was used for survival analyses and Fisher’s exact test for PSA response. Results: Ninety-eight patients had CTC blood samples available. CTCs were detected at baseline, 12 weeks and progression in 36% (35/98), 27% (26/95) and 78% (32/41), respectively. The CTC conversion rate (positive to negative after 12 w) was 43% (15/35). All CTC conversions had ≥50% decline in PSA (15/15) whereas only 35% (7/20) of pts with persistent CTCs. At first interim analysis, with a median follow-up of 10.6 months, detection of CTCs at baseline was associated with worse sPFS (median, 7.59 m versus NR, HR, 3.67; 95% CI 1.90-7.10; P < 0.001), rPFS (median, 12.9 m versus NR; HR, 7.61; 95% CI, 2.80-20.64; P < 0.001) and OS (medians NR, HR, 9.51; 95% CI, 1.11-81.52; P = 0.0398). CTC positive pts were less likely to have a ≥90% decline in PSA (OR, 2.88; 95% CI, 1.13-7.72; P = 0.02). Conclusions: CTC detection using AdnaTest is associated with an adverse outcome in chemotherapy-naïve asymptomatic or oligo-symptomatic mCRPC pts. Clinical trial information: NCT02288936.

Characterization of PSMA and 18F-fluciclovine transporter gene expression in localized prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 295-295
Author(s):  
Carissa Chu ◽  
Mohammed Alshalalfa ◽  
Martin Sjöström ◽  
Shuang Zhao ◽  
Annika Herlemann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Clinical Outcomes ◽  
Molecular Subtypes ◽  
Localized Prostate Cancer ◽  
Transporter Gene ◽  
Psma Pet ◽  
Pet Ct ◽  
Genomic Risk ◽  
Psma Expression

295 Background: While 18F-fluciclovine PET/CT is approved in the US and recommended by the NCCN, prostate-specific membrane antigen (PSMA) PET/CT is more common in Europe/Australia and recommended by the EAU. Less is known about the biology of lesions detected by either modality. 18F-fluciclovine PET relies on radiotracer uptake by amino acid transporters LAT1-4 and ASCT1-2. PSMA PET is dependent on surface expression of PSMA. We compared relative expression of PSMA and fluciclovine transporter genes in radical prostatectomy (RP) samples to determine their distribution across subtypes and correlation with outcomes. Methods: Gene expression data of 19,102 RP samples were analyzed using the Affymetrix Human Exon 1.0 ST microarray. 1,135 patients had long term follow up. Associations between expression of PSMA and fluciclovine transporter genes (LAT1-4 and ASCT1-2) and pathologic variables, molecular subtypes, and clinical outcomes were conducted. Results: All fluciclovine transporter genes (LAT 1-4, ASCT1-2) were expressed at lower levels than PSMA (p <0.0001). PSMA expression was positively correlated with genomic risk score and pathologic Gleason score (p<0.0001), but LAT2-3 and ASCT2 were inversely correlated with genomic risk in primary tumors (p<0.0001) and less expressed in GS 9-10 tumors (p<0.0001). PSMA expression was associated with worse metastasis-free survival (MFS) (HR 1.45, p=0.001) and lymph node involvement (HR 2.14, p<0.0001). Expression of LAT2, LAT3, ASCT2 expression was associated with better MFS (HR 0.85, 0.63, 0.74, p<0.0001-0.04). After multivariable adjustment, PSMA expression remained independently prognostic of poorer MFS (HR 1.3, p=0.028). Luminal B subtype was notable for PSMA overexpression; Luminal A was enriched in ASCT2 and LAT2 (p<0.0001). PSMA expression did not correlate with ERG fusion prostate cancers, but LAT2, ASCT1, and ASCT2 were overexpressed in ERG fusion negative tumors (p<0.0001). Conclusions: PSMA expression is associated with more aggressive disease and poorer clinical outcomes than fluciclovine transporter genes in localized prostate cancer. Molecular subtypes of prostate cancer vary in PSMA and fluciclovine transporter gene expression.

scholarly journals Down-regulation of Human DAB2IP Gene Expression Mediated by Polycomb Ezh2 Complex and Histone Deacetylase in Prostate Cancer

2005 ◽  
Vol 280 (23) ◽  
pp. 22437-22444 ◽  
Author(s):  
Hong Chen ◽  
Szu-wei Tu ◽  
Jer-Tsong Hsieh
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Epithelial Cells ◽  
Histone Deacetylase ◽  
Promoter Region ◽  
Small Interfering Rna ◽  
Gene Promoter ◽  
Down Regulation ◽  
Ezh2 Expression ◽  
Interfering Rna

Human DAB2IP (hDAB2IP), a novel GTPase-activating protein modulating the Ras-mediated signaling and tumor necrosis factor-mediated apoptosis, is a potent growth inhibitor in human prostate cancer (PCa). Loss of hDAB2IP expression in PCa is due to altered epigenetic regulation (i.e. DNA methylation and histone modification) of its promoter region. The elevated polycomb Ezh2, a histone methyltransferase, has been associated with PCa progression. In this study, we have demonstrated that an increased Ezh2 expression in normal prostatic epithelial cells can suppress hDAB2IP gene expression. In contrast, knocking down the endogenous Ezh2 levels in PCa by a specific small interfering RNA can increase hDAB2IP expression. The association of Ezh2 complex (including Eed and Suz12) with hDAB2IP gene promoter is also detected in PCa cells but not in normal prostatic epithelial cells. Increased Ezh2 expression in normal prostatic epithelial cells by cDNA transfection facilitates the recruitment of other components of Ezh2 complex to the hDAB2IP promoter region accompanied with the increased levels of methyl histone H3 (H3) and histone deacetylase (HDAC1). Consistently, data from PCa cells transfected with Ezh2 small interfering RNA demonstrated that reduced Ezh2 levels resulted in the dissociation of Ezh2 complex accompanied with decreased levels of both methyl H3 and HDAC1 from hDAB2IP gene promoter. We further unveiled that the methylation status of Lys-27 but not Lys-9 of H3 in hDAB2IP promoter region is consistent with the hDAB2IP levels in both normal prostatic epithelial cells and PCa cells. Together, we conclude that hDAB2IP gene is a target gene of Ezh2 in prostatic epithelium, which provides an underlying mechanism of the down-regulation of hDAB2IP gene in PCa.

An elevated body mass (BMI) index predicts for better clinical outcomes in men with metastatic hormone refractory prostate cancer (HRPC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4556-4556
Author(s):  
S. Halabi ◽  
S. Ou ◽  
N. J. Vogelzang ◽  
E. J. Small
Keyword(s):  
Prostate Cancer ◽  
Clinical Outcomes ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Performance Status ◽  
Prognostic Significance ◽  
P Value ◽  
Ecog Performance Status ◽  
Increased Risk ◽  
Severely Obese

4556 Background: Previous articles have reported that an elevated BMI was associated with an increased risk of biochemical failure in hormone sensitive patients. We asked the question as to whether an elevated BMI predicts for worst clinical outcomes, namely overall survival (OS) and prostate-cancer survival (PCS), among 1,216 men with HRPC. Methods: Patients were enrolled on eight clinical trials conducted by the Cancer and Leukemia Group B (CALGB). Eligible patients had progressive prostate cancer during androgen deprivation therapy (with documented castrate levels of testosterone), an ECOG performance status of 0–2, adequate hematologic, renal and hepatic function. We used the NIH definition to classify patients as: normal (<25 kg/m2), overweight (25–29 kg/m2 ), mildly obese (30–34 kg/m2), and moderately to severely obese (≥35 kg/m2). PCS was defined as the time from study entry to the time of death due to prostate cancer. The proportional hazards model was used to explore the prognostic significance of BMI in predicting OS and PCS. Results: The median BMI was 27.7 kg/m2 (inter-quartile range = 25.2–31.0 kg/m2 ). Twenty three percent (285/1216) of the patients had normal BMI, 46% (555/1216) were overweight, 23% (280/1216) were mildly obese, and 8% (96/1216) were moderately to severely obese. In multivariate analysis, adjusting for age, race, performance status, hemoglobin, PSA, LDH, alkaline phosphatase, testosterone, years since diagnosis, presence of visceral disease and Gleason scores, BMI was a statistically significant predictor of OS and PCS. Compared to normal men, the hazard ratios (HR) of overweight patients was 0.80 (95% CI = 0.69–0.93, p-value = 0.003), for mildly obese patients was 0.86 (95% CI = 0.72–1.02, p-value = 0.087) and for moderately to severely obese men it was 0.60 (95% CI = 0.47–0.78, p-value < 0.001). In addition, the HRs for PCS for overweight patients was 0.83 (95% CI = 0.70–0.97, p-value = 0.023), was 0.88 (95% CI = 0.72–1.06, p-value = 0.179) for mildly obese and for moderately to severely obese was 0.62 (95% CI = 0.47–0.81, p-value = 0.001) compared to men with normal BMI. Conclusions: Contrary to what was reported, these findings demonstrate an inverse relationship between BMI and clinical outcomes in men with HRPC. [Table: see text]

Association between cancer stem-like cell gene expression and clinical outcome in localized prostate cancer: A nested case-control study.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 31-31
Author(s):  
Adrian Stuart Fairey ◽  
Dongyun Yang ◽  
Susan G. Groshen ◽  
Philip Kim ◽  
Navneet Virk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
Case Control Study ◽  
Risk Group ◽  
Recursive Partitioning ◽  
Disease Recurrence ◽  
Chi Square ◽  
Nested Case Control ◽  
Control Study

31 Background: New biomarkers are needed to better predict outcome after radical prostatectomy for clinically localized prostate cancer. Recent data suggest that subpopulations of cancer stem-like cells (CSC) are present in prostate cancer, and the CSC phenotype has been associated with high tumorigenicity, drug resistance, and disease progression. We sought to determine whether the expression of genes associated with the CSC phenotype are associated with disease recurrence. Methods: A nested case-control study was performed. Cases were men who underwent radical prostatectomy and had disease recurrence (n=147). Controls were men who underwent radical prostatectomy and did not have disease recurrence (n=59). Cases and controls were matched based on D’Amico risk stratification group. Laser capture microdissection with mRNA extraction and quantitative RT-PCR were used to measure the expression of 9 novel candidate CSC-associated genes (Axin2, Bmi1, CD133, CD44a, CTNNB1, ITGA2, Nkx3-1, Notch1, TACSTD2) in formalin-fixed, paraffin-embedded radical prostatectomy specimens. The Wilcoxon test was used to examine the association between CSC-associated gene expression and D’Amico risk stratification group. The optimal chi-square approach and recursive partitioning analysis were used to determine the association between CSC-associated gene expression and disease recurrence. Results: Complete gene expression data were evaluable for 206 out of 261 patients (79%). The median age was 64 years (range, 42-78 years). High expression of TACSTD2 (p=0.04) and CD44a (p=0.05) were associated with D’Amico low risk group. The optimal chi-square approach showed that Axin2 was associated with disease recurrence (recurrence rate: Axin2 ≤ 3.83 = 80% versus Axin2 > 3.83 = 43%, p=0.0015). Recursive partitioning analysis confirmed an association between Axin2 and disease recurrence. Conclusions: A novel finding of the current study was that a low gene expression level of Axin2 was associated with disease recurrence. High gene expression levels of TACSTD2 and CD44a were associated with D’Amico low risk group. Further analysis of the Wnt/beta-catenin pathway is ongoing in this cohort.

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