Publications by authors named "Adam S Kibel"

331 Publications

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

Prostate Cancer Prostatic Dis 2021 Jun 14. Epub 2021 Jun 14.

School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA.

Background: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.

Materials And Methods: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.

Results: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.

Conclusion: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.
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http://dx.doi.org/10.1038/s41391-021-00403-7DOI Listing
June 2021

Domain adaptation for segmentation of critical structures for prostate cancer therapy.

Sci Rep 2021 Jun 1;11(1):11480. Epub 2021 Jun 1.

Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Preoperative assessment of the proximity of critical structures to the tumors is crucial in avoiding unnecessary damage during prostate cancer treatment. A patient-specific 3D anatomical model of those structures, namely the neurovascular bundles (NVB) and the external urethral sphincters (EUS), can enable physicians to perform such assessments intuitively. As a crucial step to generate a patient-specific anatomical model from preoperative MRI in a clinical routine, we propose a multi-class automatic segmentation based on an anisotropic convolutional network. Our specific challenge is to train the network model on a unique source dataset only available at a single clinical site and deploy it to another target site without sharing the original images or labels. As network models trained on data from a single source suffer from quality loss due to the domain shift, we propose a semi-supervised domain adaptation (DA) method to refine the model's performance in the target domain. Our DA method combines transfer learning and uncertainty guided self-learning based on deep ensembles. Experiments on the segmentation of the prostate, NVB, and EUS, show significant performance gain with the combination of those techniques compared to pure TL and the combination of TL with simple self-learning ([Formula: see text] for all structures using a Wilcoxon's signed-rank test). Results on a different task and data (Pancreas CT segmentation) demonstrate our method's generic application capabilities. Our method has the advantage that it does not require any further data from the source domain, unlike the majority of recent domain adaptation strategies. This makes our method suitable for clinical applications, where the sharing of patient data is restricted.
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http://dx.doi.org/10.1038/s41598-021-90294-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169882PMC
June 2021

A Pilot Study of Multidimensional Diffusion MRI for Assessment of Tissue Heterogeneity in Prostate Cancer.

Invest Radiol 2021 May 27. Epub 2021 May 27.

From the Department of Radiology, Brigham and Women's Hospital, Boston, MA University Clinic Magdeburg, Otto von Guericke University, Magdeburg, Germany Harvard Medical School, Boston, MA Clinical Sciences Lund, Lund University, Lund, Sweden Department of Urology, Brigham and Women's Hospital, Boston, MA.

Objectives: The objectives of this exploratory study were to investigate the feasibility of multidimensional diffusion magnetic resonance imaging (MddMRI) in assessing diffusion heterogeneity at both a macroscopic and microscopic level in prostate cancer (PCa).

Materials And Methods: Informed consent was obtained from 46 subjects who underwent 3.0-T prostate multiparametric MRI, complemented with a prototype spin echo-based MddMRI sequence in this institutional review board-approved study. Prostate cancer tumors and comparative normal tissue from each patient were contoured on both apparent diffusion coefficient and MddMRI-derived mean diffusivity (MD) maps (from which microscopic diffusion heterogeneity [MKi] and microscopic diffusion anisotropy were derived) using 3D Slicer. The discriminative ability of MddMRI-derived parameters to differentiate PCa from normal tissue was determined using the Friedman test. To determine if tumor diffusion heterogeneity is similar on macroscopic and microscopic scales, the linear association between SD of MD and mean MKi was estimated using robust regression (bisquare weighting). Hypothesis testing was 2 tailed; P values less than 0.05 were considered statistically significant.

Results: All MddMRI-derived parameters could distinguish tumor from normal tissue in the fixed-effects analysis (P < 0.0001). Tumor MKi was higher (P < 0.05) compared with normal tissue (median, 0.40; interquartile range, 0.29-0.52 vs 0.20-0.18; 0.25), as was tumor microscopic diffusion anisotropy (0.55; 0.36-0.81 vs 0.20-0.15; 0.28). The MKi could not be predicted (no significant association) by SD of MD. There was a significant correlation between tumor volume and SD of MD (R2 = 0.50, slope = 0.008 μm2/ms per millimeter, P < 0.001) but not between tumor volume and MKi.

Conclusions: This explorative study demonstrates that MddMRI provides novel information on MKi and microscopic anisotropy, which differ from measures at the macroscopic level. MddMRI has the potential to characterize tumor tissue heterogeneity at different spatial scales.
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http://dx.doi.org/10.1097/RLI.0000000000000796DOI Listing
May 2021

A Selective Androgen Receptor Modulator (OPK-88004) in Prostate Cancer Survivors: A Randomized Trial.

J Clin Endocrinol Metab 2021 May 21. Epub 2021 May 21.

Research Program in Men's Health: Aging and Metabolism, Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Boston, MA.

Background: Androgen deficiency is common among prostate cancer survivors, but many guidelines consider history of prostate cancer a contraindication for testosterone replacement. We determined the safety and efficacy of a selective androgen receptor modulator (OPK-88004) in symptomatic, testosterone-deficient men who had undergone radical prostatectomy for low grade, organ-confined prostate cancer.

Methods: In this placebo-controlled, randomized, double-blind trial, 114 men, >19 years, who had undergone radical prostatectomy for low grade, organ-localized prostate cancer, undetectable PSA (<0.1 ng/mL) for >2 years after radical prostatectomy and testosterone deficiency were randomized in stages to placebo or 1, 5 or 15 mg OPK-88004 daily for 12-weeks. Outcomes included PSA recurrence, sexual activity, sexual desire, erectile function, body composition, muscle strength and physical function measures, mood, fatigue and bone markers.

Results: Participants were on average 67.5-years and had severe sexual dysfunction (mean erectile function and sexual desire domain scores 7.3, and 14.6, respectively). No participant experienced PSA recurrence or erythrocytosis. OPK-88004 was associated with a dose-related increase in whole body (P<0.001) and appendicular (P<0.001) lean mass and a significantly greater decrease in percent body fat (p<0.001) and serum alkaline phosphatase (p<0.001) than placebo. Changes in sexual activity, sexual desire, erectile function, mood, fatigue, physical performance, and bone markers did not differ among groups (p=0.73).

Conclusions: Administration of OPK-8804 was safe and not associated with PSA recurrence in androgen-deficient men who had undergone radical prostatectomy for organ-confined prostate cancer. OPK-88004 increased lean body mass and decreased fat mass, but did not improve sexual symptoms or physical performance.
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http://dx.doi.org/10.1210/clinem/dgab361DOI Listing
May 2021

One-year urinary and sexual outcome trajectories among prostate cancer patients treated by radical prostatectomy: a prospective study.

BMC Urol 2021 May 17;21(1):81. Epub 2021 May 17.

Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, 600 S. Taylor Ave., 2nd floor, Rm. 208S, Campus Box 8100, St. Louis, MO, 63110, USA.

Background: To examine one-year trajectories of urinary and sexual outcomes, and correlates of these trajectories, among prostate cancer patients treated by radical prostatectomy (RP).

Methods: Study participants were recruited from 2011 to 2014 at two US institutions. Self-reported urinary and sexual outcomes were measured at baseline before surgery, and 5 weeks, 6 months and 12 months after surgery, using the modified Expanded Prostate Cancer Index Composite-50 (EPIC-50). Changes in EPIC-50 scores from baseline were categorized as improved (beyond baseline), maintained, or impaired (below baseline), using previously-reported minimum clinically important differences.

Results: Of the 426 eligible participants who completed the baseline survey, 395 provided data on at least one EPIC-50 sub-scale at 5 weeks and 12 months, and were analyzed. Although all mean EPIC-50 scores declined markedly 5 weeks after surgery and then recovered to near (incontinence-related outcomes) or below (sexual outcomes) baseline levels by 12 months post-surgery, some men experienced improvement beyond their baseline levels on each sub-scale (3.3-51% depending on the sub-scale). Having benign prostatic hyperplasia (BPH) at baseline (prostate size ≥ 40 g; an International Prostate Symptom Index Score ≥ 8; or using BPH medications) was associated with post-surgical improvements in voiding dysfunction-related bother at 5 weeks (OR = 3.9, 95% CI: 2.1-7.2) and 12 months (OR = 3.3, 95% CI: 2.0-5.7); and in sexual bother at 5 weeks (OR = 5.7, 95% CI:1.7-19.3) and 12 months (OR = 3.0, 95% CI: 1.2-7.1).

Conclusions: Our findings provide additional support for considering baseline BPH symptoms when selecting the best therapy for early-stage prostate cancer.
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http://dx.doi.org/10.1186/s12894-021-00845-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130427PMC
May 2021

Effect of Medicaid Expansion on Receipt of Definitive Treatment and Time to Treatment Initiation by Racial and Ethnic Minorities and at Minority-Serving Hospitals: A Patient-Level and Facility-Level Analysis of Breast, Colon, Lung, and Prostate Cancer.

JCO Oncol Pract 2021 May;17(5):e654-e665

Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Purpose: We sought to investigate the association between Medicaid expansion under the Affordable Care Act and access to stage-appropriate definitive treatment for breast, colon, non-small-cell lung, and prostate cancer for underserved racial and ethnic minorities and at minority-serving hospitals (MSHs).

Methods: We conducted a retrospective, difference-in-differences study including minority patients with nonmetastatic breast, colon, non-small-cell lung, and prostate cancer and patients treated at MSHs between the age of 40 and 64, with tumors at stages eligible for definitive treatment from the National Cancer Database. We not only defined non-Hispanic Black and Hispanic cancer patients as racial and ethnic minorities but also report findings for non-Hispanic Black cancer patients separately. We examined the effect of Medicaid expansion on receipt of stage-appropriate definitive therapy, time to treatment initiation (TTI) within 30 days of diagnosis, and TTI within 90 days of diagnosis.

Results: Receipt of definitive treatment for minorities in expansion states did not change compared with minority patients in nonexpansion states. The proportion of racial and ethnic minorities in expansion states receiving treatment within 30 days increased (difference-in-differences: +3.62%; 95% CI, 1.63 to 5.61; < .001) compared with minority patients in nonexpansion states; there was no change for TTI within 90 days. Analysis focused on Black cancer patients yielded similar results. In analyses stratified by MSH status, there was no change in receipt of definitive therapy, TTI within 30 days, and TTI within 90 days when comparing MSHs in expansion states with MSHs in nonexpansion states.

Conclusion: In our cohort of cancer patients with treatment-eligible disease, we found no significant association between Medicaid expansion and changes in receipt of definitive treatment for breast, prostate, lung, and colon cancer for racial and ethnic minorities and at MSHs. Medicaid expansion was associated with improved TTI at the patient level for racial and ethnic minorities, but not at the facility level for MSHs. Targeted interventions addressing the needs of MSHs are still needed to continue mitigating national facility-level disparities in cancer outcomes.
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http://dx.doi.org/10.1200/OP.21.00010DOI Listing
May 2021

KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Sci Rep 2021 Apr 29;11(1):9264. Epub 2021 Apr 29.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10) and 3145 (P < 1 × 10) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.
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http://dx.doi.org/10.1038/s41598-021-85169-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084951PMC
April 2021

EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.

Nat Cancer 2021 Apr 22;2(4):444-456. Epub 2021 Mar 22.

Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Prostate cancers are considered to be immunologically 'cold' tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA-STING-ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8 T cells and increased M1 tumor-associated macrophages, overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. These data suggest EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.
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http://dx.doi.org/10.1038/s43018-021-00185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061902PMC
April 2021

Impact of Pathogenic Germline DNA Damage Repair alterations on Response to Intense Neoadjuvant Androgen Deprivation Therapy in High-risk Localized Prostate Cancer.

Eur Urol 2021 Apr 19. Epub 2021 Apr 19.

Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address:

Background: Intense neoadjuvant androgen deprivation therapy (ADT) before radical prostatectomy (RP) is an investigational approach to reduce recurrence rates in men with high-risk localized prostate cancer (PCa). The impact of germline DNA damage repair (gDDR) gene alterations on response to intense neoadjuvant ADT is not known.

Objective: To evaluate the prevalence of gDDR alterations among men with localized PCa at high risk of recurrence and evaluate their impact on response to intense neoadjuvant ADT.

Design, Setting, And Participants: We performed germline panel sequencing for 201 men with intermediate- and high-risk localized PCa from five randomized multicenter clinical trials of intense neoadjuvant ADT before RP.

Intervention: Intense neoadjuvant ADT followed by RP.

Outcome Measurements And Statistical Analysis: The prevalence of pathogenic gDDR alterations and their association with exceptional pathologic response (complete response or minimal residual disease, defined as residual tumor with the largest cross-section dimension ≤5 mm) to intense neoadjuvant ADT and rates of post-RP biochemical recurrence.

Results And Limitations: Pathogenic gDDR alterations were detected in 19 (9.5%) of the 201 PCa patients. The most frequently altered genes were BRCA2 (n = 6; 3.0%) and ATM (n = 4; 2.0%). Patients with gDDR alterations exhibited similar rates of exceptional pathologic response (26% vs 22%), pT3 disease (42% vs 53%), lymph node involvement (5.3% vs 10%), extraprostatic extension (35% vs 54%), and positive margins (5.3% vs 13%) to patients without gDDR alterations (all p > 0.05). The 3-yr biochemical recurrence-free survival was also similar at 45% (95% confidence interval 7.9-78%) for men with gDDR alterations and 55% (95% confidence interval 44-64%) for men without gDDR alterations.

Conclusions: gDDR alterations are common among men with intermediate- and high-risk localized PCa. Men with gDDR alterations appear to have a comparable response to intense neoadjuvant ADT to that among men without gDDR alterations and should not be excluded from consideration for this treatment approach.

Patient Summary: Intense therapy to inhibit the production of androgen hormones (eg, testosterone) before surgery may minimize the risk of cancer recurrence for men with high-risk localized prostate cancer. Inherited mutations in certain DNA repair genes are associated with particularly high rates of recurrence. We found that men with these mutations respond equally well to this intense androgen inhibition before surgery as men without the mutations.
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http://dx.doi.org/10.1016/j.eururo.2021.03.031DOI Listing
April 2021

Is Medicaid expansion associated with increases in palliative treatments for metastatic cancer?

J Comp Eff Res 2021 Jun 21;10(9):733-741. Epub 2021 Apr 21.

Division of Urological Surgery & Center for Surgery & Public Health, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Medicaid expansion following the 2010 Affordable Care Act has an unknown impact on palliative treatments. This registry-based study of individuals with metastatic cancer from 2010 to 2016 identified men and women with metastatic cancer in expansion and non-expansion states who received palliative treatments. A mixed effects logistic regression compared trends in expansion and non-expansion states and generated risk-adjusted probabilities or receiving palliative treatments each year. Despite lower baseline use of palliative treatments, the rate of change was more rapid in expansion states (odds ratio [OR]: 1.02; 95% CI: 1.01-1.03; p < 0.001). The adjusted probability of receiving palliative treatments rose from 21.3 to 26.0% in non-expansion states, and from 19.7 to 26.9% in expansion states. Use of palliative treatments among metastatic cancer patients increased from 2010 to 2016 with a significantly greater increase in Medicaid expansion states, even when adjusting for demographic differences between states.
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http://dx.doi.org/10.2217/cer-2020-0178DOI Listing
June 2021

Evaluation of a Multiethnic Polygenic Risk Score Model for Prostate Cancer.

J Natl Cancer Inst 2021 Apr 1. Epub 2021 Apr 1.

Urology Division, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Polygenic risk scores (PRS) of common genetic variants have shown promise in prostate cancer risk stratification, but their validity across populations has yet to be confirmed. We evaluated a multiethnic PRS model based on 269 germline genetic risk variants (261 were available for analysis) using an independent population of 13,628 U.S. men. The PRS was strongly associated with prostate cancer, but not with any other disease. Comparing men in the top PRS decile to those at average risk (40%-60%), the odds ratio of prostate cancer was 3.89 (95% confidence interval = 3.24 to 4.68) for men of European ancestry and 3.81 (95% confidence interval = 1.48 to 10.19) for men of African ancestry. By age 85, the cumulative incidence of prostate cancer for European American men was 7.1% in the bottom and 54.1% in the top decile. This suggests that the PRS can be used to identify a substantial proportion of men at high risk for prostate cancer.
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http://dx.doi.org/10.1093/jnci/djab058DOI Listing
April 2021

Impact of high-intensity local treatment on overall survival in stage IV upper tract urothelial carcinoma.

Urol Oncol 2021 Mar 15. Epub 2021 Mar 15.

Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address:

Objectives: To investigate the impact of high-intensity local treatment (LT) on overall survival (OS) in patients with stage IV upper tract urothelial carcinoma (UTUC).

Patients And Methods: Within the National Cancer Database, we identified 7,357 patients diagnosed with stage IV UTUC from 2004 to 2015. Patients who underwent high-intensity LT, defined as radical surgery of the primary tumor, were compared with those who did not. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics. Weighted survival analyses were used to test the association between high-intensity LT and OS. Multivariable Cox model was used to assess for independent predictors of OS. Sensitivity analysis was used to account for possible biases.

Results: Among stage IV patients, 10.6% (n = 779) had locally advanced disease (T4), 32.6% (n = 2,399) had node-positive disease (N+) and 56.8% (N = 4,179) had distant metastases (M+). Fewer than half of the patients underwent high-intensity LT (n = 2,908, 39.5%) while the remainder did not. On IPTW-adjusted survival analysis, high-intensity LT was associated with a prolonged OS (11.17 months [IQR, 5.19 to 24.28] months vs. 6.18 months [IQR, 2.27 to 14.49], P ≤ 0.001). A similar benefit was seen on adjusted survival analyses for each stage IV subgroup, defined according to TNM characteristics. The survival benefit was confirmed at sensitivity analysis.

Conclusion: High-intensity LT in balanced cohorts of patients with stage IV UTUC is associated with prolonged OS including those with locally advanced (T4), node-positive (N+) or distant metastases (M+).
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http://dx.doi.org/10.1016/j.urolonc.2021.01.031DOI Listing
March 2021

Reply by Authors.

J Urol 2021 May 11;205(5):1274. Epub 2021 Mar 11.

Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1097/JU.0000000000001601.02DOI Listing
May 2021

Results of a Randomized Phase II Trial of Intense Androgen Deprivation Therapy prior to Radical Prostatectomy in Men with High-Risk Localized Prostate Cancer.

J Urol 2021 Jul 8;206(1):80-87. Epub 2021 Mar 8.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: This multicenter randomized phase 2 trial investigates the impact of intense androgen deprivation on radical prostatectomy pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368).

Materials And Methods: Eligible patients had a Gleason score ≥4+3=7, prostate specific antigen >20 ng/mL or T3 disease and lymph nodes <20 mm. In Part 1, patients were randomized 1:1 to apalutamide, abiraterone acetate, prednisone and leuprolide (AAPL) or abiraterone, prednisone, leuprolide (APL) for 6 cycles (1 cycle=28 days) followed by radical prostatectomy. Surgical specimens underwent central review. The primary end point was the rate of pathologic complete response or minimum residual disease (minimum residual disease, tumor ≤5 mm). Secondary end points included prostate specific antigen response, positive margin rate and safety. Magnetic resonance imaging and tissue biomarkers of pathologic outcomes were explored.

Results: The study enrolled 118 patients at 4 sites. Median age was 61 years and 94% of patients had high-risk disease. The combined pathologic complete response or minimum residual disease rate was 22% in the AAPL arm and 20% in the APL arm (difference: 1.5%; 1-sided 95% CI -11%, 14%; 1-sided p=0.4). No new safety signals were observed. There was low concordance and correlation between posttherapy magnetic resonance imaging assessed and pathologically assessed tumor volume. PTEN-loss, ERG positivity and presence of intraductal carcinoma were associated with extensive residual tumor.

Conclusions: Intense neoadjuvant hormone therapy in high-risk prostate cancer resulted in favorable pathologic responses (tumor 5 mm) in 21% of patients. Pathologic responses were similar between treatment arms. Part 2 of this study will investigate the impact of adjuvant hormone therapy on biochemical recurrence.
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http://dx.doi.org/10.1097/JU.0000000000001702DOI Listing
July 2021

Videos of Sipuleucel-T Programmed T Cells Lysing Cells That Express Prostate Cancer Target Antigens.

J Natl Cancer Inst 2021 Feb 25. Epub 2021 Feb 25.

Yale Cancer Center, Yale School of Medicine, New Haven, CT.

Sipuleucel-T, an autologous cellular immunotherapy, was approved to treat metastatic castration-resistant prostate cancer in 2010 in the United States. Treatment with sipuleucel-T primes the immune system to target prostate acid phosphatase (PAP), which is expressed by prostate cancer cells, potentially leading to lysis of cancer cell. Expanding upon previously reported indirect evidence of cell killing with sipuleucel-T treatment, we sought to provide direct evidence of cell lysis through visualization. We used advanced video technology and available samples of peripheral blood mononuclear cells from subjects enrolled in the STAMP trial (NCT01487863). Isolated CD8+ T cells were used as effector cells and co-cultured with autologous monocytes pulsed with control or target antigens. Differentially stained effector and target cells were then video-recorded during co-culture. Here, we present video recordings and analyses of T cells from sipuleucel-T-treated subjects showing-for the first time-direct lysis of cells that express prostate cancer target antigens, PAP or prostate-specific antigen.
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http://dx.doi.org/10.1093/jnci/djab025DOI Listing
February 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Outcomes of Post-Neoadjuvant Intense Hormone Therapy and Surgery for High Risk Localized Prostate Cancer: Results of a Pooled Analysis of Contemporary Clinical Trials.

J Urol 2021 Jun 27;205(6):1689-1697. Epub 2021 Jan 27.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: We report on the post-radical prostatectomy outcomes of patients enrolled in 3 randomized, multicenter, clinical trials of intense neoadjuvant androgen deprivation therapy prior radical prostatectomy.

Materials And Methods: All patients included were enrolled in trials evaluating intense androgen deprivation therapy followed by radical prostatectomy. The primary end point was time to biochemical recurrence, defined as the time from radical prostatectomy to prostate specific antigen >0.1 ng/ml or start of first post-radical prostatectomy therapy, stratified by pathological response at radical prostatectomy (presence or absence of exceptional pathological response defined as residual tumor at radical prostatectomy measuring 0-5 mm). Secondary end points included metastasis-free survival, overall survival, and time to testosterone recovery.

Results: Overall, 117 patients were included in the analysis, of whom 78.6% (92) had high risk disease. Following neoadjuvant therapy, 21.4% (25) had 0-5 mm of residual tumor, including 9.4% (11) with a pathological complete response. Overall, 49 patients (41.9%) experienced biochemical recurrence and the 3-year biochemical recurrence-free rate was 59.1% (95% CI 49.0-67.9). Of the 25 patients with an exceptional pathological response, 2 patients (8.0%) developed biochemical recurrence while 51.1% of nonresponders (47/92) developed biochemical recurrence. Testosterone recovery was observed in 93.8% of patients (106/113). PTEN loss and intraductal carcinoma were associated with shorter time to biochemical recurrence.

Conclusions: In this pooled analysis of prospective trials, we demonstrate that exceptional pathological response following neoadjuvant therapy is associated with a favorable impact on biochemical recurrence. PTEN loss and intraductal carcinoma were associated with biochemical recurrence. Additional followup is warranted to evaluate the impact on long-term outcomes.
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http://dx.doi.org/10.1097/JU.0000000000001632DOI Listing
June 2021

Systematic Review of Time to Definitive Treatment for Intermediate Risk and High Risk Prostate Cancer: Are Delays Associated with Worse Outcomes?

J Urol 2021 May 14;205(5):1263-1274. Epub 2021 Jan 14.

Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: Prostate cancer is most commonly an indolent disease, especially when detected at a localized stage. Unlike other tumors that may benefit from timely receipt of definitive therapy, it is generally accepted that treatment delays for localized prostate cancer are acceptable, especially for low risk prostate cancer. Since treatment delay for intermediate risk and high risk disease is more controversial, we sought to determine if delays for these disease states negatively impacted oncological outcomes.

Materials And Methods: We conducted a systematic review of the literature with searches of Medline, EMBASE and the Cochrane Database of Systematic Reviews from inception to June 30, 2020. General study characteristics as well as study population and delay information were collected. The outcomes of interest extracted included biochemical recurrence, pathological features (positive surgical margins, upgrading, extracapsular extension, and other pathological features), cancer specific survival and overall survival.

Results: After identifying 1,793 unique references, 24 manuscripts met criteria for data extraction, 15 of which were published after 2013. Based on our review, delays up to 3 months are safe for all localized prostate cancer and are not associated with worse oncological outcomes. Some studies identified worse oncological outcomes as a result of delays beyond 6 to 9 months. However, these studies are counterbalanced by others finding no statistically significant association with delays up to 12 months. Studies that did find worse outcomes as a result of delays identified a higher risk of biochemical recurrence and worse pathological outcomes but not worse cancer specific or overall survival.

Conclusions: Definitive treatment for intermediate risk and high risk prostate cancer can be delayed up to 3 months without any oncological consequences. Some evidence suggests that there is a higher risk of biochemical recurrence and worse pathological outcomes associated with delays beyond 6 to 9 months. To date, there are no reports of worse cancer specific survival or overall survival as a result of delayed treatment for intermediate risk and high risk prostate cancer.
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http://dx.doi.org/10.1097/JU.0000000000001601DOI Listing
May 2021

Insulinemic and Inflammatory Dietary Patterns and Risk of Prostate Cancer.

Eur Urol 2021 Mar 6;79(3):405-412. Epub 2021 Jan 6.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Background: Hyperinsulinemia and inflammation are inter-related pathways that link diet with the risk of several chronic diseases. Evidence suggests that these pathways may also increase prostate cancer risk.

Objective: To determine whether hyperinsulinemic diet and inflammatory diet are associated with prostate cancer incidence and mortality.

Design, Setting, And Participants: We prospectively followed 41 209 men in the Health Professionals Follow-up Study (1986-2014). Scores for two validated dietary patterns were calculated from food frequency questionnaires at baseline and updated every 4 yr.

Outcome Measurements And Statistical Analysis: Total, advanced, and lethal prostate cancer outcomes were assessed. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for associations between two empirical hypothesis-oriented dietary patterns-empirical dietary index for hyperinsulinemia and empirical dietary inflammatory pattern-and prostate cancer risk estimated using Cox proportional hazard regression.

Results And Limitations: During 28 yr of follow-up, 5929 incident cases of total prostate cancer, including 1019 advanced and 667 fatal, were documented. In multivariable-adjusted models, there was a 7% higher risk of advanced prostate cancer (HR: 1.07; 95% CI: 1.01-1.15) and a 9% higher risk of fatal prostate cancer (HR: 1.09; 95% CI: 1.00-1.18) per standard deviation (SD) increase in the hyperinsulinemic diet. When stratified by age, the hyperinsulinemic diet was associated with only earlier-onset aggressive prostate cancer (men under 65 yr), with per SD HRs of 1.20 (95% CI: 1.06-1.35) for advanced, 1.22 (1.04-1.42) for fatal, and 1.20 (1.04-1.38) for lethal. The inflammatory diet was not associated with prostate cancer risk in the overall study population, but was associated with earlier-onset lethal prostate cancer (per SD increase HR: 1.16; 95% CI: 1.00-1.35).

Conclusions: Hyperinsulinemia and inflammation may be potential mechanisms linking dietary patterns with the risk of aggressive prostate cancer, particularly earlier-onset disease.

Patient Summary: Avoiding inflammatory and hyperinsulinemic dietary patterns may be beneficial for the prevention of clinically relevant prostate cancer, especially among younger men.
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http://dx.doi.org/10.1016/j.eururo.2020.12.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887049PMC
March 2021

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 Jun 8;24(2):532-541. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
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http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157993PMC
June 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.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

The impact of smoking on radical cystectomy complications increases in elderly patients.

Cancer 2021 May 22;127(9):1387-1394. Epub 2020 Dec 22.

Division of Urological Surgery, Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Smoking, the most common risk factor for bladder cancer (BC), is associated with increased complications after radical cystectomy (RC), poorer oncologic outcomes, and higher mortality. The authors hypothesized that the effect of smoking on the probability of major complications increases with increasing age among patients who undergo RC.

Methods: The authors analyzed the American College of Surgeons National Surgical Quality Improvement Program database (2011-2017), identified all patients undergoing RC using Current Procedural Terminology codes, and formed two groups according to smoking status (active smoker and nonsmoker [included former and never-smokers]). Patient characteristics and 30-day postoperative complications using the Clavien-Dindo Classification (CDC) were assessed. A multivariable logistic regression model was constructed that included age, sex, race, body mass index, operative time, comorbidities, chemotherapy status, and type of diversion with major complications (CDC ≥III) as the outcome variable, and explored the interaction between age and smoking status.

Results: A total of 10,528 patients underwent RC, including 22.8% who were active smokers. The authors identified an interaction between age and smoking status (P = .045). Older patients were found to experience a stronger smoking effect than younger patients with regard to the probability of major complications. The risk of a major complication was the same for 50-year-old nonsmokers and smokers, but it increased from 17.8% to 21.7% for 70-year-old nonsmokers and smokers, respectively (P < .001).

Conclusions: Up to 20% of patients who undergo RC are active smokers, and these individuals have an increased risk of major complications. The effect of smoking is stronger with increasing age; the difference with regard to complications for smokers versus nonsmokers was found to increase substantially, wherein older smokers are at an especially high risk of complications.
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http://dx.doi.org/10.1002/cncr.33308DOI Listing
May 2021

Assessment of Time-to-Treatment Initiation and Survival in a Cohort of Patients With Common Cancers.

JAMA Netw Open 2020 12 1;3(12):e2030072. Epub 2020 Dec 1.

Division of Urological Surgery, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Resource limitations because of pandemic or other stresses on infrastructure necessitate the triage of time-sensitive care, including cancer treatments. Optimal time to treatment is underexplored, so recommendations for which cancer treatments can be deferred are often based on expert opinion.

Objective: To evaluate the association between increased time to definitive therapy and mortality as a function of cancer type and stage for the 4 most prevalent cancers in the US.

Design, Setting, And Participants: This cohort study assessed treatment and outcome information from patients with nonmetastatic breast, prostate, non-small cell lung (NSCLC), and colon cancers from 2004 to 2015, with data analyzed January to March 2020. Data on outcomes associated with appropriate curative-intent surgical, radiation, or medical therapy were gathered from the National Cancer Database.

Exposures: Time-to-treatment initiation (TTI), the interval between diagnosis and therapy, using intervals of 8 to 60, 61 to 120, 121 to 180, and greater than 180 days.

Main Outcomes And Measures: 5-year and 10-year predicted all-cause mortality.

Results: This study included 2 241 706 patients (mean [SD] age 63 [11.9] years, 1 268 794 [56.6%] women, 1 880 317 [83.9%] White): 1 165 585 (52.0%) with breast cancer, 853 030 (38.1%) with prostate cancer, 130 597 (5.8%) with NSCLC, and 92 494 (4.1%) with colon cancer. Median (interquartile range) TTI by cancer was 32 (21-48) days for breast, 79 (55-117) days for prostate, 41 (27-62) days for NSCLC, and 26 (16-40) days for colon. Across all cancers, a general increase in the 5-year and 10-year predicted mortality was associated with increasing TTI. The most pronounced mortality association was for colon cancer (eg, 5 y predicted mortality, stage III: TTI 61-120 d, 38.9% vs. 181-365 d, 47.8%), followed by stage I NSCLC (5 y predicted mortality: TTI 61-120 d, 47.4% vs 181-365 d, 47.6%), while survival for prostate cancer was least associated (eg, 5 y predicted mortality, high risk: TTI 61-120 d, 12.8% vs 181-365 d, 14.1%), followed by breast cancer (eg, 5 y predicted mortality, stage I: TTI 61-120 d, 11.0% vs. 181-365 d, 15.2%). A nonsignificant difference in treatment delays and worsened survival was observed for stage II lung cancer patients-who had the highest all-cause mortality for any TTI regardless of treatment timing.

Conclusions And Relevance: In this cohort study, for all studied cancers there was evidence that shorter TTI was associated with lower mortality, suggesting an indirect association between treatment deferral and mortality that may not become evident for years. In contrast to current pandemic-related guidelines, these findings support more timely definitive treatment for intermediate-risk and high-risk prostate cancer.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.30072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737088PMC
December 2020

Recovery from minimally invasive vs. open surgery in kidney cancer patients: Opioid use and workplace absenteeism.

Investig Clin Urol 2021 Jan 13;62(1):56-64. Epub 2020 Nov 13.

Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Purpose: Does surgical approach (minimally invasive vs. open) and type (radical vs. partial nephrectomy) affects opioid use and workplace absenteeism.

Materials And Methods: Retrospective multivariable regression analysis of 2,646 opioid-naïve patients between 18 and 64 undergoing radical or partial nephrectomy via either a minimally invasive vs. open approach for kidney cancer in the United States between 2012 and 2017 drawn from the IBM Watson Health Database was performed. Outcomes included: (1) opioid use in opioid-naïve patients as measured by opioid prescriptions in the post-operative setting at early, intermediate and prolonged time periods and (2) workplace absenteeism after surgery.

Results: Patients undergoing minimally invasive surgery had a lower odds of opioid use in the early and intermediate post-operative periods (early: odds ratio [OR], 0.77; 95% confidence interval [CI], 0.62-0.97; p=0.02, intermediate: OR, 0.60; 95% CI, 0.48-0.75; p<0.01), but not in the prolonged setting (prolonged: OR, 1.00; 95% CI, 0.75-1.34; p=0.98) and had earlier return to work (minimally invasive vs. open: -10.53 days; 95% CI, -17.79 to -3.26; p<0.01). Controlling for approach, patient undergoing partial nephrectomy had lower rates of opioid use across all time periods examined and returned to work earlier than patients undergoing radical nephrectomy (partial vs. radical: -14.41 days; 95% CI, -21.22 to -7.60; p<0.01).

Conclusions: Patients undergoing various forms of surgery for kidney cancer had lower rates of peri-operative opioid use, fewer days of workplace absenteeism, but no difference in long-term rates of opioid use in patients undergoing minimally invasive as compared to open surgery.
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http://dx.doi.org/10.4111/icu.20200194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801161PMC
January 2021

Health care spending in prostate cancer: An assessment of characteristics and health care utilization of high resource-patients.

Urol Oncol 2021 02 9;39(2):130.e17-130.e24. Epub 2020 Dec 9.

Department of Urology, Brigham and Women's Hospital, Boston, MA; Center for Surgery and Public Health, Brigham and Women's Hospital, Boston, MA; Genitourinary Lank Center, Dana-Farber Cancer Institute, Boston, MA. Electronic address:

Background: Prostate cancer ranks among the top 5 cancers in contribution to national expenditures. Previous reports have identified that 5% of the population accounts for 50% of the nation's annual health care spending. To date, the assessment of the top 5% resource-patients among men diagnosed with prostate cancer (PCa) has never been performed. We investigate the determinants and health care utilization of high resource-patients diagnosed with PCa using a population-based cohort using the Surveillance, Epidemiology, and End Results Medicare-linked database.

Methods: Men aged ≥66-year-old with a primary diagnosis of PCa in 2009 were identified. High resource spenders were defined as the top 5% of the sum of the total cost incurred for all services rendered per beneficiary. The spending in each group and predictors of being a high resource-patient were assessed.

Results: The top 5% resource-patients consisted of 646 men who spent a total of $62,474,504, comprising 26% of the total cost incurred for all 12,875 men who were diagnosed with PCa in 2009. Of the top 5% resource-patients, the average amount spent per patient was $96,710 vs. $14,664 among the bottom 95% resource-patients. In adjusted analyses, older (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.00-1.03), Charlson Comorbidity Index ≥2 (OR: 3.78, 95% CI: 3.10-4.60) men, and advanced disease (metastasis OR: 2.29, 95% CI: 1.68-3.11) were predictors of being a top 5% resource-patient. Of these patients, 210 men died within 1 year of PCa diagnosis (32.5%) vs. 606 men of the bottom 95% resource-patients (5.0%, P < 0.001).

Conclusion: Five percent of men diagnosed with PCa bore 26% of the total cost incurred for all men diagnosed with the disease in 2009. Multimorbidity and advanced disease stage represent the primary drivers of being a high-resource PCa patient. Multidisciplinary care and shared decision-making is encouraged for such patients to better manage cost and quality of care.
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http://dx.doi.org/10.1016/j.urolonc.2020.09.033DOI Listing
February 2021

Metabolomics of Prostate Cancer Gleason Score in Tumor Tissue and Serum.

Mol Cancer Res 2021 03 9;19(3):475-484. Epub 2020 Nov 9.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine and the New York Genome Center, New York, New York.

Gleason score, a measure of prostate tumor differentiation, is the strongest predictor of lethal prostate cancer at the time of diagnosis. Metabolomic profiling of tumor and of patient serum could identify biomarkers of aggressive disease and lead to the development of a less-invasive assay to perform active surveillance monitoring. Metabolomic profiling of prostate tissue and serum samples was performed. Metabolite levels and metabolite sets were compared across Gleason scores. Machine learning algorithms were trained and tuned to predict transformation or differentiation status from metabolite data. A total of 135 metabolites were significantly different ( < 0.05) in tumor versus normal tissue, and pathway analysis identified one sugar metabolism pathway ( = 0.03). Machine learning identified profiles that predicted tumor versus normal tissue (AUC of 0.82 ± 0.08). In tumor tissue, 25 metabolites were associated with Gleason score (unadjusted < 0.05), 4 increased in high grade while the remainder were enriched in low grade. While pyroglutamine and 1,5-anhydroglucitol were correlated (0.73 and 0.72, respectively) between tissue and serum from the same patient, no metabolites were consistently associated with Gleason score in serum. Previously reported as well as novel metabolites with differing abundance were identified across tumor tissue. However, a "metabolite signature" for Gleason score was not obtained. This may be due to study design and analytic challenges that future studies should consider. IMPLICATIONS: Metabolic profiling can distinguish benign and neoplastic tissues. A novel unsupervised machine learning method can be utilized to achieve this distinction.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0548DOI Listing
March 2021

The Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
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http://dx.doi.org/10.3390/cancers12113254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694218PMC
November 2020

Racial and Ethnic Variation in PSA Testing and Prostate Cancer Incidence Following the 2012 USPSTF Recommendation.

J Natl Cancer Inst 2021 Jun;113(6):719-726

Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.

Background: The 2012 US Preventive Services Task Force recommendation against routine prostate-specific antigen (PSA) testing led to a decrease in prostate cancer screening, but the heterogeneity of its impact by race and ethnicity remains unclear.

Methods: The proportion of 40- to 74-year-old men who self-reported receiving a routine PSA test in the past year was estimated in the Behavioral Risk Factor Surveillance System (2012-2018). Odds ratios (ORs) of undergoing screening by race and ethnicity were estimated, adjusting for healthcare-related factors. Prostate cancer incidence rates and rate ratios (IRRs) by race and ethnicity were estimated using Surveillance, Epidemiology, and End Results registry data (2004-2017).

Results: PSA testing frequencies were 32.3% (95% confidence interval [CI] = 31.7% to 32.8%) among non-Hispanic White (NHW), 30.3% (95% CI = 28.3% to 32.3%) among non-Hispanic Black (NHB), 21.8% (95% CI = 19.9% to 23.7%) among Hispanic, and 17.7% (95% CI = 14.1% to 21.3%) among Asian and Pacific Islander men in 2012. The absolute screening frequency declined by 9.5% from 2012 to 2018, with a larger decline among NHB (11.6%) than NHW men (9.3%). The relative annual decrease was greater among NHB (OR = 0.86, 95% CI = 0.84 to 0.88) than NHW men (OR = 0.89, 95% CI = 0.89 to 0.90; Pheterogeneity = .005), driven by a larger decline among NHB men ages 40-54 years. The NHB to NHW IRR for total prostate cancer increased from 1.73 (95% CI = 1.69 to 1.76) in 2011 to 1.87 (95% CI = 1.83 to 1.92) in 2012 and has remained elevated, driven by differences in localized tumor incidence. Metastatic disease incidence is rising across all racial and ethnic groups.

Conclusions: The frequency of prostate cancer screening varies by race and ethnicity, and there was a modestly steeper decline in PSA testing among younger NHB men relative to NHW men since 2012. The NHB to NHW IRR for localized prostate cancer modestly increased following 2012.
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http://dx.doi.org/10.1093/jnci/djaa171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168268PMC
June 2021