Publications by authors named "Eric A Klein"

440 Publications

Factors Associated with Time to Conversion from Active Surveillance to Treatment for Prostate Cancer in a Multi-Institutional Cohort.

J Urol 2021 Aug 16:101097JU0000000000001937. Epub 2021 Aug 16.

Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer.

Materials And Methods: A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses.

Results: Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry.

Conclusions: A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JU.0000000000001937DOI Listing
August 2021

Prospective Multicenter Comparison of Open and Robotic Radical Prostatectomy: The PROST-QA/RP2 Consortium.

J Urol 2021 Aug 26:101097JU0000000000002176. Epub 2021 Aug 26.

Department of Urology, Emory University School of Medicine, Atlanta, Georgia.

Purpose: To evaluate the comparative effectiveness of robot-assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) in a multicenter study.

Materials And Methods: We evaluated men with localized prostate cancer at eleven high-volume academic medical centers in the United States from the PROST-QA (2003-2006) and the PROST-QA/RP2 cohorts (2010-2013) with a pre-specified goal of comparing RALP (N=549) and ORP (N=545). We measured longitudinal patient-reported health related quality of life (HRQOL) at pre-treatment, 2, 6, 12, and 24 months, and pathologic and peri-operative outcomes/complications.

Results: Demographics, cancer characteristics, and margin status were similar between surgical approaches. ORP subjects were more likely to undergo lymphadenectomy (89% vs 47%; p <0.01) and nerve sparing (94% vs 89%; p <0.01). RALP vs ORP subjects experienced less mean intraoperative blood loss (192 vs 805 mL, p <0.01), shorter mean hospital stay (1.6 vs 2.1 days; p <0.01), and fewer blood transfusions (1% vs 4%; p <0.01), wound infections (2% vs 4%; p=0.02), other infections (1% vs 4%; p <0.01), deep vein thromboses (0.5% vs 2%; p=0.04), and bladder neck contractures requiring dilation (1.6% vs 8.3%; p <0.01). RALP subjects reported less pain (p=0.04), less activity interference (p <0.01) and higher incision satisfaction (p <0.01). Surgical approach (RALP vs ORP) was not a significant predictor of longitudinal HRQOL change in any HRQOL domain.

Conclusions: In high-volume academic centers, RALP and ORP patients may expect similar long-term HRQOL outcomes. Overall, RALP patients have less pain, shorter hospital stays, and fewer post-surgical complications such as blood transfusions, infections, DVTs, and bladder neck contractures.

Trial Registration: NCT01325506: Effectiveness of Open and Robotic Prostatectomy (PROSTQA- RP2).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JU.0000000000002176DOI Listing
August 2021

5α-Reductase Inhibitors are Associated with Reduced Risk of SARS-COV-2 Infection: A Matched-Pair, Registry-Based Analysis.

J Urol 2021 Aug 26:101097JU0000000000002180. Epub 2021 Aug 26.

Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic.

Purpose: SARS-CoV-2 has a disproportionately severe effect on men, suggesting that the androgen pathway plays a role in the disease. Studies on the effect of castration and androgen receptor (AR) blockade have been mixed, while 5α-reductase inhibitor (5ARI) use in men with COVID-19 have shown potential benefits. We assessed the association of 5ARI use on risk of community acquired SARS-CoV-2 infection.

Materials And Methods: 60,474 males in a prospective registry of people tested for SARS-CoV-2 between March 8, 2020-February 15, 2021 were included. Using a matched cohort design, men using 5ARIs were matched 1:1 to non-5ARI users. Independent analysis using unconditional multivariable logistic regression on the entire unmatched dataset was completed for validation. Primary outcome measures were the association of 5ARI use on rates of SARS-Cov-2 positivity and disease severity.

Results: 1079 men (1.8%) reported 5ARI use, and 55,100 were available for matching. The final matched cohorts included 944 men each. Mean duration of use was 60.4 months (IQR 17-84 months). Absolute risk for infection was significantly lower in 5ARI users compared to nonusers, 42.3% (399/944) vs. 47.2% (446/944), respectively (absolute risk reduction (ARR) 4.9%, OR 0.81, 95% CI 0.67-0.97, p=0.026). Unconditional multivariable logistic regression analysis of the entire study cohort of 55,100 men confirmed the protective association of 5ARI use (ARR 5.3%, OR=0.877, 95% CI 0.774-0.995, p=0.042). Use of 5ARIs was not associated with disease severity.

Conclusions: Use of 5ARIs in men without prostate cancer was associated with a reduction in community acquired SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JU.0000000000002180DOI Listing
August 2021

The PATHFINDER Study: Assessment of the Implementation of an Investigational Multi-Cancer Early Detection Test into Clinical Practice.

Cancers (Basel) 2021 Jul 13;13(14). Epub 2021 Jul 13.

Department of Medical Oncology, Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

To examine the extent of the evaluation required to achieve diagnostic resolution and the test performance characteristics of a targeted methylation cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test, ~6200 participants ≥50 years with (cohort A) or without (cohort B) ≥1 of 3 additional specific cancer risk factors will be enrolled in PATHFINDER (NCT04241796), a prospective, longitudinal, interventional, multi-center study. Plasma cfDNA from blood samples will be analyzed to detect abnormally methylated DNA associated with cancer (i.e., cancer "signal") and a cancer signal origin (i.e., tissue of origin). Participants with a "signal detected" will undergo further diagnostic evaluation per guiding physician discretion; those with a "signal not detected" will be advised to continue guideline-recommended screening. The primary objective will be to assess the number and types of subsequent diagnostic tests needed for diagnostic resolution. Based on microsimulations (using estimates of cancer incidence and dwell times) of the typical risk profiles of anticipated participants, the median (95% CI) number of participants with a "signal detected" result is expected to be 106 (87-128). Subsequent diagnostic evaluation is expected to detect 52 (39-67) cancers. The positive predictive value of the MCED test is expected to be 49% (39-58%). PATHFINDER will evaluate the integration of a cfDNA-based MCED test into existing clinical cancer diagnostic pathways. The study design of PATHFINDER is described here.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13143501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304888PMC
July 2021

Influence of 5-Alpha Reductase Inhibitors on Prostate Cancer Detection with Magnetic Resonance Imaging: A Matched Cohort Study.

J Urol 2021 Jul 6:101097JU0000000000001932. Epub 2021 Jul 6.

Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.

Purpose: We evaluated the influence of 5-alpha reductase inhibitors (5-ARIs) on the performance of magnetic resonance imaging (MRI) for detection of Gleason grade group (GG) ≥2 prostate cancer, and on apparent diffusion coefficient (ADC) maps.

Materials And Methods: This single center, retrospective study included men who had MRI for initial detection or active surveillance of prostate cancer. The study group included 59 men who used for 5-ARIs for ≥12 months, and the control group included 59 men who were matched for both MRI indication and biopsy results. DeLong's test was used to compare the area under the receiver operating curve (AUC) for detection of GG ≥2 cancer between the groups. Wilcoxon rank sum test was used for comparison of lesions apparent diffusion coefficient (ADC) metrics between the groups.

Results: MRI accuracy in the study group (AUC=0.778) was not significantly different compared to the control group (AUC=0.821; 95% CI for difference 0.22-0.13; p=0.636). In the control group, all ADC metrics were lower in lesions with GG ≥2 cancer on biopsy than in those with GG 1 cancer or negative results (p=0.001-0.01). In the study group, this difference was significant only when the mean ADC of the lesions was normalized by the ADC of urine (p=0.044).

Conclusions: Long-term exposure to 5-ARIs does not seem to impair the detection of significant cancer on MRI but may affect the ability of ADC metrics to discriminate between lesions that harbor significant cancer and those that harbor insignificant cancer or benign tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JU.0000000000001932DOI Listing
July 2021

Comparison of Multimodal Therapies and Outcomes Among Patients With High-Risk Prostate Cancer With Adverse Clinicopathologic Features.

JAMA Netw Open 2021 Jul 1;4(7):e2115312. Epub 2021 Jul 1.

Department of Urology, Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland.

Importance: The optimal management strategy for high-risk prostate cancer and additional adverse clinicopathologic features remains unknown.

Objective: To compare clinical outcomes among patients with high-risk prostate cancer after definitive treatment.

Design, Setting, And Participants: This retrospective cohort study included patients with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network [NCCN]) and at least 1 adverse clinicopathologic feature (defined as any primary Gleason pattern 5 on biopsy, clinical T3b-4 disease, ≥50% cores with biopsy results positive for prostate cancer, or NCCN ≥2 high-risk features) treated between 2000 and 2014 at 16 tertiary centers. Data were analyzed in November 2020.

Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT), or EBRT plus brachytherapy boost (BT) with ADT. Guideline-concordant multimodal treatment was defined as RP with appropriate use of multimodal therapy (optimal RP), EBRT with at least 2 years of ADT (optimal EBRT), or EBRT with BT with at least 1 year ADT (optimal EBRT with BT).

Main Outcomes And Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis was a secondary outcome. Differences were evaluated using inverse probability of treatment weight-adjusted Fine-Gray competing risk regression models.

Results: A total of 6004 men (median [interquartile range] age, 66.4 [60.9-71.8] years) with high-risk prostate cancer were analyzed, including 3175 patients (52.9%) who underwent RP, 1830 patients (30.5%) who underwent EBRT alone, and 999 patients (16.6%) who underwent EBRT with BT. Compared with RP, treatment with EBRT with BT (subdistribution hazard ratio [sHR] 0.78, [95% CI, 0.63-0.97]; P = .03) or with EBRT alone (sHR, 0.70 [95% CI, 0.53-0.92]; P = .01) was associated with significantly improved prostate cancer-specific mortality; there was no difference in prostate cancer-specific mortality between EBRT with BT and EBRT alone (sHR, 0.89 [95% CI, 0.67-1.18]; P = .43). No significant differences in prostate cancer-specific mortality were found across treatment cohorts among 2940 patients who received guideline-concordant multimodality treatment (eg, optimal EBRT alone vs optimal RP: sHR, 0.76 [95% CI, 0.52-1.09]; P = .14). However, treatment with EBRT alone or EBRT with BT was consistently associated with lower rates of distant metastasis compared with treatment with RP (eg, EBRT vs RP: sHR, 0.50 [95% CI, 0.44-0.58]; P < .001).

Conclusions And Relevance: These findings suggest that among patients with high-risk prostate cancer and additional unfavorable clinicopathologic features receiving guideline-concordant multimodal therapy, prostate cancer-specific mortality outcomes were equivalent among those treated with RP, EBRT, and EBRT with BT, although distant metastasis outcomes were more favorable among patients treated with EBRT and EBRT with BT. Optimal multimodality treatment is critical for improving outcomes in patients with high-risk prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2021.15312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251338PMC
July 2021

Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA.

Clin Cancer Res 2021 Aug 4;27(15):4221-4229. Epub 2021 Jun 4.

Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota.

Purpose: We recently reported the development of a cell-free DNA (cfDNA) targeted methylation (TM)-based sequencing approach for a multi-cancer early detection (MCED) test that includes cancer signal origin prediction. Here, we evaluated the prognostic significance of cancer detection by the MCED test using longitudinal follow-up data.

Experimental Design: As part of a Circulating Cell-free Genome Atlas (CCGA) substudy, plasma cfDNA samples were sequenced using a TM approach, and machine learning classifiers predicted cancer status and cancer signal origin. Overall survival (OS) of cancer participants in the first 3 years of follow-up was evaluated in relation to cancer detection by the MCED test and clinical characteristics.

Results: Cancers not detected by the MCED test had significantly better OS ( < 0.0001) than cancers detected, even after accounting for other covariates, including clinical stage and method of clinical diagnosis (i.e., standard-of-care screening or clinical presentation with signs/symptoms). Additionally, cancers not detected by the MCED test had better OS than was expected when data were adjusted for age, stage, and cancer type from the Surveillance, Epidemiology, and End Results (SEER) program. In cancers with current screening options, the MCED test also differentiated more aggressive cancers from less aggressive cancers ( < 0.0001).

Conclusions: Cancer detection by the MCED test was prognostic beyond clinical stage and method of diagnosis. Cancers not detected by the MCED test had better prognosis than cancers detected and SEER-based expected survival. Cancer detection and prognosis may be linked by the underlying biological factor of tumor fraction in cfDNA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-21-0417DOI Listing
August 2021

Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes.

Sci Rep 2021 05 27;11(1):11130. Epub 2021 May 27.

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.

The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-90491-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159988PMC
May 2021

Hexose-6-phosphate dehydrogenase blockade reverses prostate cancer drug resistance in xenograft models by glucocorticoid inactivation.

Sci Transl Med 2021 05;13(595)

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Prostate cancer resistance to next-generation hormonal treatment with enzalutamide is a major problem and eventuates into disease lethality. Biologically active glucocorticoids that stimulate glucocorticoid receptor (GR) have an 11β-OH moiety, and resistant tumors exhibit loss of 11β-HSD2, the oxidative (11β-OH → 11-keto) enzyme that normally inactivates glucocorticoids, allowing elevated tumor glucocorticoids to drive resistance by stimulating GR. Here, we show that up-regulation of hexose-6-phosphate dehydrogenase (H6PD) protein occurs in prostate cancer tissues of men treated with enzalutamide, human-derived cell lines, and patient-derived prostate tissues treated ex vivo with enzalutamide. Genetically silencing H6PD blocks NADPH generation, which inhibits the usual reductive directionality of 11β-HSD1, to effectively replace 11β-HSD2 function in human-derived cell line models, suppress the concentration of biologically active glucocorticoids in prostate cancer, and reverse enzalutamide resistance in mouse xenograft models. Similarly, pharmacologic blockade of H6PD with rucaparib normalizes tumor glucocorticoid metabolism in human cell lines and reinstates responsiveness to enzalutamide in mouse xenograft models. Our data show that blockade of H6PD, which is essential for glucocorticoid synthesis in humans, normalizes glucocorticoid metabolism and reverses enzalutamide resistance in mouse xenograft models. We credential H6PD as a pharmacologic vulnerability for treatment of next-generation androgen receptor antagonist-resistant prostate cancer by depleting tumor glucocorticoids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.abe8226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319670PMC
May 2021

GPS Assay Association With Long-Term Cancer Outcomes: Twenty-Year Risk of Distant Metastasis and Prostate Cancer-Specific Mortality.

JCO Precis Oncol 2021 24;5. Epub 2021 Feb 24.

Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH.

Purpose: To assess the association between the Oncotype DX Genomic Prostate Score (GPS) result and long-term oncological outcomes following radical prostatectomy (RP).

Methods: We evaluated the association of the GPS result assayed from the index lesion from RP tissue with the risk of distant metastases (DM) and prostate cancer-specific mortality (PCSM) over the 20 years following RP in a stratified cohort sample of 428 patients from 2,641 treated between 1987 and 2004. Cox regression of cause-specific hazards was used to estimate the absolute risk of both end points, with death from other causes treated as a competing risk. A correction for regression to the mean (RM) was applied since the GPS test was developed using this cohort. Exploratory analysis using presurgical parameters and the GPS test as prognostic variables was performed to assess the additional value of the GPS test on 20-year risk of DM and PCSM. Model discrimination was measured using the area under the receiver operating characteristic curve.

Results: The GPS test appears to be independently associated with both 20-year risk of DM and PCSM with a low false discovery rate. Per 20-unit increase in GPS, multivariable analysis with RM correction estimated hazard ratios of 2.24 (95% CI, 1.49 to 3.53) and 2.30 (95% CI, 1.45 to 4.36) for DM and PCSM, respectively. Accuracy of models including clinical risk factors alone appeared to improve when including the GPS test in assessing risk of both end points.

Conclusion: The results suggest that the GPS test provides information on the risk for the meaningful long-term outcomes of DM and PCSM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.20.00325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140813PMC
February 2021

Androgen Deprivation Therapy in Men with Prostate Cancer Does Not Affect Risk of Infection with SARS-CoV-2. Reply.

Authors:
Eric A Klein

J Urol 2021 09 17;206(3):785. Epub 2021 May 17.

Cleveland Clinic Foundation, Cleveland, Ohio.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JU.0000000000001884DOI Listing
September 2021

Tumor subtype defines distinct pathways of molecular and clinical progression in primary prostate cancer.

J Clin Invest 2021 05;131(10)

Sandra and Edward Meyer Cancer Center and.

BACKGROUNDMolecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.METHODSWe explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.RESULTSWe identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERG-overexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSIONThese findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.FUNDINGProstate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI147878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121518PMC
May 2021

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer.

Eur Urol 2021 Aug 10;80(2):142-146. Epub 2021 May 10.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. PATIENT SUMMARY: High-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eururo.2021.04.035DOI Listing
August 2021

Prostate cancer in young men represents a distinct clinical phenotype: gene expression signature to predict early metastases.

J Transl Genet Genom 2021 9;5:50-61. Epub 2021 Mar 9.

Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, CA 91010, USA.

Aim: Several genomic signatures are available to predict Prostate Cancer (CaP) outcomes based on gene expression in prostate tissue. However, no signature was tailored to predict aggressive CaP in younger men. We attempted to develop a gene signature to predict the development of metastatic CaP in young men.

Methods: We measured genome-wide gene expression for 119 tumor and matched benign tissues from prostatectomies of men diagnosed at ≤ 50 years and > 70 years and identified age-related differentially expressed genes (DEGs) for tissue type and Gleason score. Age-related DEGs were selected using the improved Prediction Analysis of Microarray method (iPAM) to construct and validate a classifier to predict metastasis using gene expression data from 1,232 prostatectomies. Accuracy in predicting early metastasis was quantified by the area under the curve (AUC) of receiver operating characteristic (ROC), and abundance of immune cells in the tissue microenvironment was estimated using gene expression data.

Results: Thirty-six age-related DEGs were selected for the iPAM classifier. The AUC of five-year survival ROC for the iPAM classifier was 0.87 (95%CI: 0.78-0.94) in young (≤ 55 years), 0.82 (95%CI: 0.76-0.88) in middle-aged (56-70 years), and 0.69 (95%CI: 0.55-0.69) in old (> 70 years) patients. Metastasis-associated immune responses in the tumor microenvironment were more pronounced in young and middle-aged patients than in old ones, potentially explaining the difference in accuracy of prediction among the groups.

Conclusion: We developed a genomic classifier with high precision to predict early metastasis for younger CaP patients and identified age-related differences in immune response to metastasis development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.20517/jtgg.2021.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081383PMC
March 2021

Oncologic outcomes among Black and White men with grade group 4 or 5 (Gleason score 8-10) prostate cancer treated primarily by radical prostatectomy.

Cancer 2021 May 15;127(9):1425-1431. Epub 2021 Mar 15.

Department of Urology, University of Washington, Seattle, Washington.

Background: The aim of this study was to describe pathologic and short-term oncologic outcomes among Black and White men with grade group 4 or 5 prostate cancer managed primarily by radical prostatectomy.

Methods: This was a multi-institutional, observational study (2005-2015) evaluating radical prostatectomy outcomes by self-identified race. Descriptive analysis was performed via nonparametric statistical testing to compare baseline clinicopathologic data. Univariable and multivariable time-to-event analyses were performed to assess biochemical recurrence (BCR), metastasis, cancer-specific mortality (CSM), and overall survival between Black and White men.

Results: In total, 1662 men were identified with grade group 4 or 5 prostate cancer initially managed by radical prostatectomy. Black men represented 11.3% of the cohort (n = 188). Black men were younger, demonstrated a longer time from diagnosis to surgery, and were at a lower clinical stage (all P < .05). Black men had lower rates of pT3/4 disease (49.5% vs 63.5%; P < .05) but higher rates of positive surgical margins (31.6% vs 26.5%; P = .14) on pathologic evaluation. There was no difference in BCR, CSM, or overall survival over a median follow-up of 40.7 months. Black men had a lower 5-year cumulative incidence of metastasis-free survival (93.6%; 95% confidence interval [CI], 86.5%-97.0%) in comparison with White men (85.8%; 95% CI, 83.1%-88.0%), which did not persist in an age-adjusted analysis.

Conclusions: Black and White men with high-grade prostate cancer at diagnosis demonstrated similar oncologic outcomes when they were managed by primary radical prostatectomy. Our findings suggest that racial disparities in prostate cancer mortality are not related to differences in the efficacy of extirpative therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33419DOI Listing
May 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Management of a Prostate Cancer Patient With Inherited Germline BRCA1 and BRCA2 Mutations: A Case Report.

Urology 2021 Jul 6;153:129-131. Epub 2021 Feb 6.

Department of Urology, Glickman Urologic and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH.

The Breast Cancer Gene (BRCA) confers an 8.6-fold higher risk of developing prostate cancer in men ≤ 65 years of age and portends a worse prognosis as compared to noncarriers even in patients with low volume, localized disease. The BRCA2 gene, in particular, imparts a more biologically aggressive form of prostate cancer and a higher prostate cancer specific mortality. From a treatment standpoint, this translates to worse overall clinical outcomes for such patients. The most appropriate screening and management strategy for germline BRCA mutation carriers with prostate cancer is not known. Herein, we present an incidentally discovered prostate cancer in a 61-year-old BRCA1 and BRCA2 germline mutation carrier who was screened and managed using an individualized treatment approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2020.11.076DOI Listing
July 2021

A comparative study of PCS and PAM50 prostate cancer classification schemes.

Prostate Cancer Prostatic Dis 2021 Sep 2;24(3):733-742. Epub 2021 Feb 2.

Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Two prostate cancer (PC) classification methods based on transcriptome profiles, a de novo method referred to as the "Prostate Cancer Classification System" (PCS) and a variation of the established PAM50 breast cancer algorithm, were recently proposed. Both studies concluded that most human PC can be assigned to one of three tumor subtypes, two categorized as luminal and one as basal, suggesting the two methods reflect consistency in underlying biology. Despite the similarity, differences and commonalities between the two classification methods have not yet been reported.

Methods: Here, we describe a comparison of the PCS and PAM50 classification systems. PCS and PAM50 signatures consisting of 37 (PCS37) and 50 genes, respectively, were used to categorize 9,947 PC patients into PCS and PAM50 classes. Enrichment of hallmark gene sets and luminal and basal marker gene expression were assessed in the same datasets. Finally, survival analysis was performed to compare PCS and PAM50 subtypes in terms of clinical outcomes.

Results: PCS and PAM50 subtypes show clear differential expression of PCS37 and PAM50 genes. While only three genes are shared in common between the two systems, there is some consensus between three subtype pairs (PCS1 versus Luminal B, PCS2 versus Luminal A, and PCS3 versus Basal) with respect to gene expression, cellular processes, and clinical outcomes. PCS categories displayed better separation of cellular processes and luminal and basal marker gene expression compared to PAM50. Although both PCS1 and Luminal B tumors exhibited the worst clinical outcomes, outcomes between aggressive and less aggressive subtypes were better defined in the PCS system, based on larger hazard ratios observed.

Conclusion: The PCS and PAM50 classification systems are similar in terms of molecular profiles and clinical outcomes. However, the PCS system exhibits greater separation in multiple clinical outcomes and provides better separation of prostate luminal and basal characteristics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41391-021-00325-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326303PMC
September 2021

Multicenter Comparison of 17-Gene Genomic Prostate Score as a Predictor of Outcomes in African American and Caucasian American Men with Clinically Localized Prostate Cancer.

J Urol 2021 Apr 1;205(4):1047-1054. Epub 2020 Dec 1.

Genomic Health Inc., an Exact Sciences corporation, Redwood City, California.

Purpose: Adoption of prognostic molecular assays for prostate cancer requires evidence of robust performance in different racial groups. Retrospective analysis was conducted to assess the performance of the Oncotype DX Genomic Prostate Score test in African American and Caucasian American men with surgically treated prostate cancer.

Materials And Methods: We compared the assay results (scale 0-100) and the 4 gene group scores in biopsy specimens from 201 African American and 1,144 Caucasian American men with clinically localized prostate cancer in 6 cohorts. Adverse pathology was defined as high grade (primary Gleason pattern 4 or any pattern 5) and/or nonorgan-confined disease (≥pT3). Binary logistic regression models were used for adverse pathology. Biochemical recurrence was defined as 2 successive prostate specific antigen levels >0.2 ng/ml or initiation of salvage therapy after radical prostatectomy. Cox proportional hazards models evaluated the association of the assay result or racial group with time to biochemical recurrence.

Results: Each cohort had different clinical risk distributions and percentages of African Americans, although median and interquartile ranges of the assay results and gene group scores were similar between both racial groups. In a multivariable model with the assay and pathological/clinical features including race, the assay was significantly associated with adverse pathology (p ≤0.004) and biochemical recurrence (p <0.001). Race was not a significant predictor of either end point.

Conclusions: The assay is similarly predictive of outcomes in African American and Caucasian American patients, and improves risk stratification in men with newly diagnosed prostate cancer from both racial groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JU.0000000000001484DOI Listing
April 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Editorial Comment.

Authors:
Eric A Klein

J Urol 2021 02 26;205(2):460. Epub 2020 Nov 26.

Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JU.0000000000001361.01DOI Listing
February 2021

Surgical management of high-risk, localized prostate cancer.

Nat Rev Urol 2020 Dec 10;17(12):679-690. Epub 2020 Nov 10.

Department of Urology, University of Washington Medical Center, Seattle, WA, USA.

High-risk prostate cancer is a heterogeneous disease that lacks clear consensus on its ideal management. Historically, non-surgical treatment was the preferred strategy, and several studies demonstrated improved survival among men with high-risk disease managed with the combination of radiotherapy and androgen deprivation therapy (ADT) compared with ADT alone. However, practice trends in the past 10-15 years have shown increased use of radical prostatectomy with pelvic lymph node dissection for primary management of high-risk, localized disease. Radical prostatectomy, as a primary monotherapy, offers the potential benefits of avoiding ADT, reducing rates of symptomatic local recurrence, enabling full pathological tumour staging and potentially reducing late adverse effects such as secondary malignancy compared with radiation therapy. Retrospective studies have reported wide variability in short-term (pathological) and long-term (oncological) outcomes of radical prostatectomy. Surgical monotherapy continues to be appropriate for selected patients, whereas in others the best treatment strategy probably involves a multimodal approach. Appropriate risk stratification utilizing clinical, pathological and potentially also genomic risk data is imperative in the initial management of men with prostate cancer. However, data from ongoing and planned prospective trials are needed to identify the optimal management strategy for men with high-risk, localized prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41585-020-00384-7DOI Listing
December 2020

Influence of Enema and Dietary Restrictions on Prostate MR Image Quality: A Multireader Study.

Acad Radiol 2020 Nov 5. Epub 2020 Nov 5.

Imaging institute, Cleveland Clinic, 9500 Euclid Avenue, JB-322, Cleveland, OH 44145.

Purpose: To evaluate the effect of enema and dietary restrictions on prostate MR image quality metrics and to assess inter-reader agreement for these metrics.

Methods: This retrospective study included 195 men divided into groups based on their compliance with preparation instructions before prostate MRI (Enema + Diet, n = 98; Enema, n = 42; Diet, n = 35; Control [no compliance], n = 20). Four readers independently assessed six image quality metrics on a 5-point scale. Between-group comparisons were made using Wilcoxon rank sum test. Inter-reader agreement was calculated using Fleiss' kappa.

Results: Compared with the Control group, image quality with respect to rectal stool/gas, distortion of diffusion-weighted images, overall image quality, and confidence in assessment was higher in the Enema + Diet, Enema, and Diet groups (p  < 0.05 for all comparisons). The Enema + Diet and Enema groups had significantly higher scores than the Diet group for rectal stool/gas (p < 0.001 and 0.005, respectively). The Enema + Diet and Diet groups had higher scores than the Control group for rectal peristalsis (p = 0.027 and 0.009, respectively), but there were no significant differences in motion artifacts on T2-weighted images. Agreement among readers was fair, with kappa values ranging from 0.25 to 0.37.

Conclusion: Enema and dietary restriction can improve the quality of prostate MRI by decreasing rectal distension and distortion of diffusion-weighted images and by increasing reader confidence in image assessment. Inter-reader agreement using subjective criteria for analysis of MRI quality is fair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.acra.2020.10.019DOI Listing
November 2020

Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2.

bioRxiv 2020 Oct 14. Epub 2020 Oct 14.

Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic.

The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide therapy. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.04.21.051201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574256PMC
October 2020

Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer.

Clin Cancer Res 2021 01 9;27(1):320-329. Epub 2020 Oct 9.

Department of Cancer Epidemiology, H Lee Moffitt Cancer Center & Research Institutes, Tampa, Florida.

Purpose: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME).

Experimental Design: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis.

Results: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial-mesenchymal transition. AAM TME has higher total immune content score (ICS) compared with 0 (37.8% vs. 21.9%, = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HR = 2.30; 95% confidence interval (CI), 1.21-4.34; = 0.01] and validation (HR = 2.42; 95% CI, 1.52-3.86; = 0.0001) but not in EAM.

Conclusions: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-2925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042600PMC
January 2021

Androgen Deprivation Therapy in Men with Prostate Cancer Does Not Affect Risk of Infection with SARS-CoV-2.

J Urol 2021 02 8;205(2):441-443. Epub 2020 Sep 8.

Department of Neurology, Neurological Institute Cleveland Clinic and Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.

Purpose: is a host co-receptor for cell entry of SARS-CoV-2. A prior report suggested that use of androgen deprivation therapy, which downregulates , may protect men with prostate cancer from infection.

Materials And Methods: This is a cohort study of a prospective registry of all patients tested for SARS-CoV-2 between March 12 and June 10, 2020 with complete followup until disease recovery or death. The main exposure examined was the use of androgen deprivation therapy, and the outcome measures were the rate of SARS-CoV-2 positivity and disease severity as a function of androgen deprivation therapy use.

Results: The study cohort consisted of 1,779 men with prostate cancer from a total tested population of 74,787, of whom 4,885 (6.5%) were positive for SARS-CoV-2. Of those with prostate cancer 102 (5.7%) were SARS-CoV-2 positive and 304 (17.1%) were on androgen deprivation therapy. Among those on androgen deprivation therapy 5.6% were positive as compared to 5.8% not on androgen deprivation therapy. Men on androgen deprivation therapy were slightly older (75.5 vs 73.8 years, p=0.009), more likely to have smoked (68.1% vs 59.3%, p=0.005) and more likely to report taking steroids (43.8% vs 23.3%, p <0.001). Other factors known to increase risk of infection and disease severity were equally distributed (asthma, diabetes mellitus, hypertension, coronary artery disease, heart failure and immune suppressive disease). Multivariable analysis did not indicate a difference in infection risk for those with prostate cancer on androgen deprivation therapy (OR 0.93, 95% CI 0.54-1.61, p=0.8).

Conclusions: Androgen deprivation therapy does not appear to be protective against SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JU.0000000000001338DOI Listing
February 2021

Quantitative analyses of EGFR localization and trafficking dynamics in the follicular epithelium.

Development 2020 08 14;147(15). Epub 2020 Aug 14.

Center for Computational and Integrative Biology, Rutgers, The State University of New Jersey, Camden, NJ 08103, USA

To bridge the gap between qualitative and quantitative analyses of the epidermal growth factor receptor (EGFR) in tissues, we generated an sfGFP-tagged EGF receptor (EGFR-sfGFP) in The homozygous fly appears similar to wild type with EGFR expression and activation patterns that are consistent with previous reports in the ovary, early embryo, and imaginal discs. Using ELISA, we quantified an average of 1100, 6200 and 2500 receptors per follicle cell (FC) at stages 8/9, 10 and ≥11 of oogenesis, respectively. Interestingly, the spatial localization of the EGFR to the apical side of the FCs at early stages depended on the TGFα-like ligand Gurken. At later stages, EGFR localized to basolateral positions of the FCs. Finally, we followed the endosomal localization of EGFR in the FCs. The EGFR colocalized with the late endosome, but no significant colocalization of the receptor was found with the early endosome. The EGFR-sfGFP fly is an exciting new resource for studying cellular localization and regulation of EGFR in tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/dev.183210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438018PMC
August 2020

A Rational Approach to Managing Prostate Cancer in an Irrational Time.

Authors:
Eric A Klein

Oncology (Williston Park) 2020 May;34(5):163-164

Glickman Urological and Kidney Institute, Cleveland Clinic.

View Article and Find Full Text PDF

Download full-text PDF

Source
May 2020
-->