bluuebunny/crossref_metadata_2025 huggingface dataset:
Disease characteristics, survival outcomes, and tumor molecular landscape in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) harboring CDK12 alterations (CDK12a) receiving intensified androgen deprivation therapy (ADTi).
Authors: Hage Chehade Chadi , Gebrael Georges , Srivastava Ayana , Tripathi Nishita , Sayegh Nicolas , Mathew Thomas Vinay , Galarza Fortuna Gliceida , Chigarira Beverly , Nordblad Blake , Campbell Patrick , Tandar Clara , Li Haoran , Maughan Benjamin L. , Agarwal Neeraj , Swami Umang
Published: January 2024

189

Background: CDK12 is one of the homologous recombination repair ( HRR) genes involved in genomic stability. The presence of CDK12a has been associated with worse survival outcomes in pts with metastatic prostate cancer [PMID: 32988971; 32462107]. However, the impact of CDK12a on outcomes in pts with mHSPC undergoing ADTi with doublets has never been reported. Herein, we sought to assess this impact while evaluating disease characteristics and tumor molecular landscape. Methods: This was a retrospective IRB-approved study. Eligibility: pts with mHSPC undergoing ADTi with either docetaxel or an androgen receptor pathway inhibitor (ARPI) (i.e., abiraterone, enzalutamide, apalutamide) harboring pathogenic CDK12a on comprehensive genomic profiling (CGP) of primary prostate tissue, metastatic lesion, or on cell-free DNA. Descriptive statistics were used for clinical features and survival outcomes. Optimal PSA response (PSA-R) was defined as PSA ≤ 0.2 ng/ml. Progression-free survival (PFS) was defined from the start of therapy for mHSPC to progression (per PCWG-3) or death from any cause. Overall survival (OS) was defined from treatment initiation for mHSPC to death from any reason or censored at the last follow-up. Concurrent genomic alterations with a frequency ≥ 10% were reported. Results: Of 323 pts with mHSPC receiving ADTi doublet with CGP testing, 19 pts harbored CDK12a and were included. The median age at diagnosis was 66.1 (56 – 77), with 63.2% of pts receiving ADTi with an ARPI. Baseline characteristics are summarized in the Table. Overall, 7 pts (36.8%) achieved an optimal PSA-R by 6 months (mo). The median PFS was 18.8 mo (95% CI 4.2 – 33.4 mo), and the median OS was 33.1 mo (95% CI 9.5 – 56.7 mo). CGP was performed on primary tissue (84.2%), followed by metastatic lesion (10.5%) and blood (5.3%). PIK3CA and TP53 were the most frequent associated genomic alterations (15.8%), followed by ARID1A, CTNNB1, RB1, and TMPRSS2 (10.5%). Conclusions: This is the first real-world study to report outcomes of pts with mHSPC and tumor CDK12a undergoing ADTi with doublets. We show these pts to have inferior outcomes than those enrolled in the registration trials of mHSPC with ADTi. Upon external validation in larger cohorts, these hypothesis-generating data may guide future clinical trial design for these pts, their preferential selection for trials, and counseling and prognostication in the clinic. [Table: see text]
Germline mutations in patients with metastatic prostate cancer: A prospective cohort study in South Korea (KCSG GU20-19).
Authors: Park Joo-Hwan , Park Inkeun , Kim Jinju , Lee Chang Seon , Park Kwonoh , Kim Jin Young , Kim Se Hyun , Kim Il Hwan , Lee Hyo Jin , Bae Woo Kyun , Huh Seok Jae , Kim Miso , Lee Min-Young , Shin Seong Hoon , Kim Ho Young , Sohn Byeong Seok , Kim In-Ho , Lee Jae-Lyun
Published: January 2024

193

Background: Several clinical guidelines recommend screening for hereditary prostate cancer in high-risk groups for metastatic prostate cancer. However, despite the recent increase in the diagnosis of prostate cancer in Korea, genetic testing for hereditary prostate cancer is not being performed, making it impossible to know the frequency of hereditary prostate cancer. This study aimed to determine the prevalence of germline mutations in unselected Korean patients with metastatic prostate cancer. Methods: Between July 2021 and December 2022, metastatic prostate cancer patients were enrolled prospectively, without any specific selection based on age or family history. Germline mutation analysis was performed on DNA from blood via next generation sequencing using SOLIDaccuTestTM DNA HRD (NgeneBio, Korea). Results: A total of 301 patients were enrolled and the prevalence of germline mutation was analyzed. At diagnosis, the median age was 67 (46-91 years old), and the median PSA was 150 ng/mL (3.07-5000). 250 patients had a Gleason score of 8 or higher. 36 patients (12.0 %) carried a pathogenic (14/301, 4.6 %)/likely pathogenic (22/301, 7.3 %) variant in a germline mutation. Of these patients, 11 patients (3.65 %) had BRCA2 mutations. ATM (6/301, 1.99 %) was the second most frequently mutated gene, followed by FH (4/301, 1.33 %), FANCA, FANCD2, MRE11, SLFN11, SMO (0.66 % of each, 2/301), BLM, CHEK2, ERBB3, MAP2K1, and VHL (0.33 % of each, 1/301). Further analysis will be conducted to evaluate the impact of germline mutations on somatic mutation results, treatment patterns, and clinical outcomes. Conclusions: The prevalence of pathogenic germline mutations among unselected Korean patients with metastatic prostate cancer was 12.0 %. Germline mutation prevalence in this cohort was comparable to previous reported results. This study provides the framework for the development of preventive and treatment strategies based on hereditary genetic factors for prostate cancer in the Korean population. [Table: see text]
Association of BTN2A1+ microvesicles with overall survival and the role of γδ T cells as a potential therapeutic target in patients with hormone-sensitive metastatic prostate cancer.
Authors: Billon Emilien , Imbert Caroline , Gorvel Laurent , Richaud Manon , Ghossoub Rania , Girault Virginie , Fest Thierry , Gravis Gwenaelle , Olive Daniel
Published: January 2024

194

Background: Despite the recent progress in cancer management, metastatic prostate cancer remains incurable. In the context of immunotherapy failure, we need to identify new immune biomarkers, to improve patient therapy, and explore their potential as therapeutic target. To this end, we screened the prognostic value of soluble immune checkpoints in the plasma of metastatic prostate cancer patients at diagnosis, and depicted their role in anti-tumor activities. Methods: Patients with hormone naive metastatic prostate cancer were prospectively included in the NK-Prostate study (NCT02963155). Blood collection was performed before treatment and patients were followed for 5 years. We determined by ELISA assay plasma levels the soluble form of PD-L1, Pan-BTN3A, BTN3A1, BTN2A1 and BTLA. Large extracellular vesicles (MVs) were pelleted at 10 000g by sequential ultracentrifugation. Results: 66 patients were included in the NK-Prostate with a median follow-up of 42.6 months. Only plasma levels of BTN2A1 were associated with overall survival > 50 months. Patients with enriched sBTN2A1 (soluble form of BTN2A1) presented poorer overall survival (HR for death 2.91 95%CI 1.33 – 6.33, p=0.0072) and progression-free survival than low-level patients (HR for progression 2.73 95%CI 1.48 – 5.05, p=0.0012). Prostate cancer cell line produced sBTN2A1, with 40% associated with extracellular vesicles. High level of BTN2A1+ microvesicles (MVs) were identified by spectral cytometry in patient’ plasma but not in healthy volunteer plasma, and deep phenotyping revealed that B cell-derived BTN2A1+ MVs were associated with shorter overall survival (HR 4.22 95%CI 1.68 – 10.57, p=0.0021). To evaluate the impact of BTN2A1+ MVs on γδ T cells, we generated BTN2A1 KO MVs, BTN2A1 overexpressed MVs, and BTN2A1 mutant overexpressed MVs (that do not interact with γδ TCR). We demonstrated that BTN2A1 overexpressed MVs could specifically interact with γδ T cell; and impaired their proliferation and cytotoxicity against prostate cancer cell lines (LNCaP, DU145 and PC3). Conclusions: Our study shows the negative impact of B cell derived BTN2A1+ MVs in hormone naïve metastatic prostate cancer. Plasma MVs phenotyping is an easy-to-perform test, accessible for all patients. Our results highlight the role of γδ T cell in the anti-tumor immunity in prostate cancer, making them an interesting target for immunotherapy in this pathology. Clinical trial information: NCT02963155 .
Molecular profiling and clinical relevance of low PTEN expression in patients with metastatic hormone-sensitive prostate cancer.
Authors: Garcia de Herreros Marta , Jiménez Natalia , Reig Torras Oscar , Ruiz de Porras Vicente , Pardo Juan Carlos , Font Pous Albert , Aversa Caterina , Ferrer-Mileo Laura , Mazariegos Manuel , Rodriguez-Carunchio Leonardo , Trias Isabel , Jordà Mireia , García-Esteve Samuel , Cros Costa Sara , Fernandez-Mañas Laia , Figols Mariona , Gonzalez-Billalabeitia Enrique , Chirivella Isabel , Rodriguez-Vida Alejo , Mellado-Gonzalez Begoña
Published: January 2024

198

Background: Genomic alterations in PTEN are associated with an aggressive disease and treatment resistance in patients (pts) with castration-resistant prostate cancer (PC). The aim of the present study is to characterize the molecular alterations associated to tumor PTEN-low mRNA expression in different cohorts of metastatic hormone-sensitive PC (mHSPC) pts and its prognostic value. Methods: This is an ongoing multicenter ambispective study enrolling mHSPC pts receiving different treatment strategies. PTEN status was assessed in FFPE tumor samples by mRNA expression by nCounter and RNA-seq. PTEN expression was correlated with castration resistance-free survival (CRPC-FS) and overall survival (OS) by Kaplan Meier and multivariate Cox analysis. Results: 297 pts were included: 125 treated with ADT + docetaxel (ADT+D), 79 with androgen deprivation therapy (ADT) + abiraterone or enzalutamide (A/E) and 93 with ADT alone. Median follow-up of 46.3 months (m) (6.7-223). Median age was 66.4 years, 75.7% of pts presented de novo stage IV and 67.9% had high-volume disease. RNA-seq analysis was performed to assess differences in gene expression between low vs. high/medium PTEN expression tumors in 66 pts. There was a significant correlation between PTEN expression detected by nCounter and by RNASeq (p=8.7e-11). Differential expression analysis found 13 genes differentially expressed (padj<0.05 &abs(LFC)>0.26) in PTEN-low (25.8%) vs the rest, including PTEN and 2 novel transcripts (Table). In the functional analysis PTEN-low tumors had overexpression of several pathways including cell cycle, DNA repair, metabolism and immune regulatory response, and infraexpression of the androgen-response hallmark. In the whole cohort (n=297 pts), PTEN-low (30.5%) was independently associated with low CRPC-FS (HR 1.8 (95% CI, 1.3 – 2.4), p=8.7e-5) and OS (HR 1.7 (95% CI, 1.2 – 2.2), p=0.0038). Conclusions: Lower expression of PTEN correlates with a distinct molecular profile and a more aggressive disease in pts with mHSPC, supporting the development of new therapeutic strategies in pts. [Table: see text]
Characterizing longitudinal molecular changes in ctDNA in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tran Eli , Jani Chinmay , Zhang Nicole , Tsai Jill , Pan Elizabeth , Panian Justine , McKay Rana R.
Published: January 2024

205

Background: Next-generation sequencing (NGS) of ctDNA is a novel technology that can complement tumor tissue NGS and has the potential to inform prognosis, treatment (tx) selection, and real time evolution of tumor molecular alterations. While tx options for pts with mCRPC have advanced, tx resistance is inevitable. Our real-world evidence study aims to evaluate longitudinal molecular changes in ctDNA following systemic tx to inform sequential tx strategies for pts with mCRPC. Methods: We interrogated data from GuardantINFORM, a clinical-genomics database with ctDNA molecular information and structured commercial payer-claims data. We conducted genetic mutations analysis in pts diagnosed with prostate cancer both before and after Androgen Receptor Signaling Inhibitors (ARSi), Poly(ADP‐ribose) Polymerase Inhibitors (PARPi), and taxanes. The post-tx analysis was performed on samples collected within 3 months of tx discontinuation prior to initiation of a subsequent tx as a proxy of disease progression. Mann-Whitney test was conducted to assess the differences in mutations observed pre and post tx. We also examined the association between ctDNA burden and overall survival (OS). Results: Overall, from a database of 21,682 patients with prostate cancer, following the above filters, we analyzed 145 pts with paired pre / post-ARSI, 54 with paired pre / post-PARPi, and 115 with paired pre / post-taxane samples. Table highlights the most commonly altered genes prevalent in post-tx samples. The most frequent (%pre/%post) AR alterations post-ARSI included AR amplifications (11%/23%), AR T878A (5%/9%), AR L702H (2%/6%), AR H875Y (0.7%/1.4%), and AR F877L (0%/1.4%). The most frequent HRR alterations post PARPi included ATM (25%/25%), BRCA2 (25%/18%), BRCA1 (3%/5%), CDK12 (6%/5%), and PALB2 (3%/2%). All three tx exhibited a significantly higher prevalence of mutations post-tx (mean increase in alterations 0.3-1.3, p<0.001 for all tx). Pts with higher ctDNA burden in pre-tx samples had worse OS compared to pts with low or undetectable burden. Conclusions: Our study revealed dynamic shifts in genetic mutations in pts with mCRPC following ARSi, PARPi and taxanes. Additionally, we highlight the prognostic significant of ctDNA burden in mCRPC. These data can help inform personalized sequential tx strategies for pts with mCRPC. [Table: see text]
Homologous recombination repair (HRR) alterations may be passenger events in patients with advanced prostate cancer (PC) with high tumor mutational burden (hTMB).
Authors: Bhatlapenumarthi Vineel , De Sarkar Navonil , Patwari Anannya , Antonarakis Emmanuel S. , Nelson Ariel Ann , Kilari Deepak
Published: January 2024

206

Background: HRR and microsatellite instability-high (MSI-H) alterations (alt) are typically mutually exclusive in pan-cancer cohorts. However, in PC 12.8% of BRCA1 and 3.4% of BRCA2 genomic alteration(alt) (Loss of function mutation or copy loss) co-occurred with MSI-H (PMID: 35772050) but were not associated with elevated genome-wide loss of heterozygosity (gLOH), suggesting that BRCA1/2 alt are likely ‘passenger’ events in the presence of MSI-H. further characterize this potential bystander phenomenon, we hypothesized that patients (pts) with HRR alt occurring in the context of hTMB will lack functional HRD signatures. Methods: We queried the Stand Up to Cancer (SU2C) East Coast Dream Team’s exome dataset (N=429) to identify pts with hTMB and at least monoallelic HRR alterations. Demographics, treatment, and outcome data were also collected. Adopting the approach per PMID: 34877933, we derived CSig3 (a COSMIC single-base-substitution mutational signature indicative of HR dysfunction [HRD]) and iHRD (a functional signature of HR deficiency developed by our group) in this subset to evaluate HRR functional activity. Results: 18 men with hTMB (>10mut/Mb) and concurrent HRR alt were identified in SU2C. Of those, 9 had biallelic, and 9 had monoallelic HRR alt. 22% had biallelic BRCA2, 22% had biallelic RAD and 39% had monoallelic BRCA2 alt. However, only 33% of these HRR-altered tumors were CSig3(+)/iHRD(+) (5 biallelic and 1 monoallelic HRR alt) and 67% were negative for both signatures (4 biallelic, 8 monoallelic HRR alt), indicating that the HRR alt in these instances are likely bystander events. In all of the CSig3(+)/iHRD(+) cases, TMB ranged between 10-20 mut/Mb, whereas when TMB was >20 mut/Mb, those tumors were invariably CSig3(-)/iHRD(-). None of these pts in the SU2C cohort were treated with Immune checkpoint inhibitors or PARPi. Conclusions: In PC pts with hTMB and concurrent HRR mutations, it is more likely that the HRR alteration is a ‘passenger’ event, and the likelihood increases as TMB rises above >20 mut/Mb. HRD signature (-) hTMB pts are unlikely to respond to PARPi monotherapy, even if they have a concurrent HRR alt. HR functional signatures such as CSig3 or iHRD could be utilized in treatment selection and to avoid diagnostic dilemmas.
Building a predictive model for outcomes with [177Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer using VISION data: Preliminary results.
Authors: Herrmann Ken , Gafita Andrei , De Bono Johann S. , Sartor A. Oliver , Chi Kim N. , Krause Bernd J. , Rahbar Kambiz , Tagawa Scott T. , Czernin Johannes , El-Haddad Ghassan , Wong Connie , Zhang Zhaojie , Wilke Celine , Mirante Osvaldo , Morris Michael J. , Fizazi Karim
Published: January 2024

208

Background: 177Lu-PSMA-617 is approved in adults with PSMA+ metastatic castration-resistant prostate cancer (mCRPC). This analysis of VISION data sought to build predictive models for clinical outcomes after 177Lu-PSMA-617. Methods: In VISION, adults with PSMA+ mCRPC received 177Lu-PSMA-617 (7.4 GBq every 6 weeks, ≤6 cycles) plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, 29 baseline parameters were assessed for prognostic and predictive value on overall survival (OS), radiographic progression-free survival (rPFS) and PSA response (≥50% reduction; PSA50). Parameters associated with outcome regardless of treatment were prognostic, and those associated with outcome after treatment with 177Lu-PSMA-617+SoC vs SoC were predictive. Cox proportional hazards (OS and rPFS) or logistic regression (PSA50) models were used in univariate analyses for parameter selection and to build statistical models. Here, univariate analyses are presented. Multiplicity was corrected by use of q values (α = 0.05). Results: Data from 831 adults were analyzed. In initial univariate analyses, 76%, 69% and 38% of parameters assessed were prognostic for OS, rPFS and PSA50, respectively; fewer were predictive of better outcomes after 177Lu-PSMA-617+SoC vs SoC (subset shown). Conclusions: Baseline prognostic and predictive parameters were identified for OS, as well as for rPFS and PSA50, in adults with mCRPC in VISION receiving 177Lu-PSMA-617+SoC or SoC alone. For clinical application, select parameters will be reassessed categorically, and multivariate predictive models will be developed using identified parameters and parameter shrinkage. [Table: see text]
Homologous recombination repair gene mutation (HRRm) testing patterns and treatment selection from a real-world cohort of patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Shore Neal D. , Craver Christopher , Blanc Simon , Sathyan Pratheesh , Aton Lindsay , Varughese Prateesh , Tierno Marni Brisson
Published: January 2024

210

Background: Routine germline and somatic testing is recommended by professional guidelines as standard of care for all mCRPC patients since the approvals of poly ADP ribose polymerase inhibitors (PARPi) for treatment in those with tumors harboring select HRRm. Yet, analyses suggest that many mCRPC patients are not offered testing and thus patients with HRRm+ tumors may not have the shared decision-making opportunity to consider PARPi therapy. We reviewed HRR testing and treatment patterns within a real-world cohort of mCRPC patients to identify potential clinical practice gaps. Methods: The IntegraConnect – Precision Q Database that includes electronic, practice management and payer data from 500 US sites of care was utilized to select a de-identified real-world cohort of newly diagnosed and actively treated mCRPC patients (excluding those with lymph node only metastasis) between 1/1/2020 – 12/31/2021. Patient charts were manually reviewed by medical curators to extract data including frequency and timing of germline and somatic testing for HRRm, testing modality (tissue or liquid biopsy), results of HRRm testing, and the use of PARPi in the HRRm+ patient cohort. Results: A total of 996 mCRPC patients met criteria with 93% managed by community oncologists, 6% community urologists, and 1% academic oncologists. 59.2% (n=590) received testing for HRRm (19.8% germline (n=117); 59.8% somatic (n=353); 4.1% (n=24) germline + somatic; 16.3% (n=96) unknown) with testing rates increasing after PARPi approval: 15% between 1/1/2020 – 5/31/2020; 23% between 6/1/2020 – 9/30/2020; 62% between 10/1/2020 – 12/31/2021. The vast majority (64%) were tested after receiving mCRPC treatment, with 48% tested after failure on first line therapy. Somatic tissue testing was the predominant testing modality over liquid biopsy and germline testing. 31.7% (n=187) of tested patients were HRRm+ (11.2% germline (n=21); 73.8% somatic (n=138); 2.1% (n=4) germline + somatic; 12.8% (n=24) unknown), though not all tests utilized included the 14 HRR genes in the olaparib approval. BRCA2, ATM, CHEK2, and CDK12 HRRm were most commonly detected with a higher frequency of ATM and CHEK2 mutations seen in liquid biopsies. Of the mCRPC patients who were HRRm+, 66.8% (n=125) received PARPi. Conclusions: In this real-world analysis, 40.8% of mCRPC patients did not receive germline or somatic testing while 33.2% of HRRm+ patients did not receive PARPi. Optimizing germline and somatic testing for mCRPC is a significant unmet need, which negatively impacts therapeutic offerings.
Effect of variants in the KLK3 gene on prostate cancer survival and time to metastases in a large biobank prostate cancer dataset.
Authors: Pagadala Meghana , Nelson Tyler J. , Lynch Julie Ann , Gao Anthony , Agiri Fatai , Pridgen Kathryn , Seibert Tyler , Lee Kyung Min , Rose Brent S. , Carter Hannah , Teerlink Craig , Hauger Richard
Published: January 2024

219

Background: Prostate Specific Antigen (PSA), a serine protease, is the most widely used clinical biomarker to detect prostate cancer. It is a product of the KLK3 gene. Several SNPs in KLK3 gene have previously been implicated in prostate cancer aggressiveness and PSA levels, however, the effect of KLK3 SNPs on survival and metastatic disease is not clear. We surveyed common and rare variants within 10-Kb of the KLK3 gene to estimate their effect on prostate cancer survival and time to metastasis in a large biobank data set. Methods: We analyzed a cohort of 5,287 men who developed prostate cancer after enrollment in the Million Veterans Program (MVP), 619 of whom developed metastatic disease. We analyzed 1,583 imputed SNPs (Info-R2 > 0.3) that occurred within 10-Kb of the KLK3 gene, regardless of minor allele frequency. We conducted two separate analyses, the first concerned survival times of prostate cancer specific mortality and the second analysis concerned time to metastatic disease using the Survival R package. For each analysis, variants were collectively assessed for an effect on survival using SKAT-O (metaSeq R package). We also performed a logistic regression to test each SNP for association with Gleason score 8-10 at diagnosis. Results: We identified seven rare SNPs that significantly affected prostate cancer survival (Bonferroni corrected p<3.16e-5) within 10-Kb of KLK3, 3 of which occurred within the gene boundaries (SKAT-O p=1e-4). We also identified 11 other SNPs that significantly affected time to metastasis (SKAT-O p=7e-3). The logistic regression of each SNP on Gleason score 8-10 at diagnosis identified 20 significant SNPs. The SNPs emerging from these analyses were all rare (minor allele frequency < 1e-4), and no SNPs were in linkage disequilibrium with each other, indicating that they comprise independent signals. Conclusions: Understanding the mechanism and role of rare SNPs in the KLK3 gene in prostate cancer detection has important clinical implications, especially in an era when patients’ genetics is being used to inform PSA screening. These finding may identify patients who should undergo prostate biopsy at lower PSA thresholds and/or for whom PSA biochemical recurrence is a less reliable predictor of disease progression. Ongoing prospective and retrospective analyses of Veterans with these variants both prior to and absent any prostate cancer diagnoses and progression.
Risk of suicide-related deaths (SRD) among patients diagnosed with metastatic genitourinary (mGU) cancers: A retrospective cohort study.
Authors: Ayaz Ahsan , Naqvi Syed Arsalan Ahmed , Imran Manal , Saxena Akshat , Raina Ammad , Khakwani Kaneez Zahra Rubab , Cobran Ewan Kemar , Mir Sajid Ahmad , Singh Parminder , Bryce Alan Haruo , Riaz Irbaz Bin
Published: January 2024

230

Background: Elevated suicide risk is established in cancer patients compared with the general population. We aim to investigate the risk of SRD among individuals diagnosed with mGU cancers. Methods: Surveillance, Epidemiology, and End Results (SEER) database (2004-2020) was queried to obtain data on suicide death in adults (>20 years of age) diagnosed with mGU cancers including bladder cancer (BC), kidney cancer (KC), and prostate cancer (PC). Standardized mortality ratios (SMRs) with 95% confidence interval (CI) were computed overall and by latency period of <1, 1-5, and >5 years (y) after the initial diagnosis of mGU cancers. SMR >1 indicated increased while <1 indicated decreased SRD. Stratification was done by age (<50y, 50-70y, >70y), race (White, Black, Asian, Native American), ethnicity (Hispanic, non-Hispanic), chemotherapy, radiotherapy, surgery, and marital. Results: This analysis included 87,357 mGU patients. In overall population, the risk of suicide-related deaths was highest <1y after diagnosis (SMR: 3.29, 95% CI: 2.47-4.29) followed by 1-5y (2.61, 2.0-3.35) and >5y (1.27, 0.61-2.34) after diagnosis. With respect to race, SRD was significantly higher in Whites (3.31, 2.46-4.36) but not in Blacks (2.58, 0.31-9.33), and Asians (2.03 (0.05-11.3). In ethnic subgroups, non-Hispanics were observed to have increased SRD (3.71, 2.77-4.86) but not Hispanics (0.83, 0.1-3.0). Patients who received chemotherapy (3.74, 2.10-6.18) or those who did not receive radiotherapy (3.66, 2.68-4.89) were more likely to die from suicide. In terms of marital status, single patients had a higher SRD (4.39, 2.94-6.30) compared to those who were married (2.54, 1.65-3.76). Detailed results are outlined in the Table. Conclusions: Patients with GU malignancies are at increased risk of SRD. Targeted and timely interventions in highest risk subgroups such as Non-Hispanic patients with a recent cancer diagnosis with no partner support, may reduce the risk of SRD in patients diagnosed with mGU cancers. [Table: see text]
Disparities in prostate cancer mortality and clinical trial availability across vulnerable populations.
Authors: Sekar Rishi , Morgan Todd Matthew , Wallner Lauren P. , Stensland Kristian , Herrel Lindsey A.
Published: January 2024

24

Background: Clinical trials provide high-level evidence and test novel therapies that have significantly improved cancer outcomes. However, disparities in clinical trial participation and cancer mortality persist across race/ethnicity and vulnerable populations, notably in patients with prostate cancer (PCa). Adverse social determinants of health (SDOH) and systemic barriers may underlie these disparities. Identifying and overcoming these barriers may improve access to and representation in clinical trials, thereby promoting equitable advancement and applicability of science. For these reasons, we evaluate the association between clinical trial availability, cancer mortality, and population-level SDOH in PCa. Methods: Using custom data linkage from ClinicalTrials.gov, Surveillance Epidemiology and End Results (SEER) Registry, and the Centers for Disease Control and Prevention Social Vulnerability Index (SVI), we performed a cross-sectional analysis of county-level PCa clinical trial data, cancer incidence and mortality rates, and population-level SDOH. We included Phase 2 and Phase 3 interventional PCa clinical trials with start dates from 2007 to 2022. The total number of clinical trials over the study period was calculated per county and population-adjusted for 100,000 residents. Counties were stratified into quintiles based on SVI (i.e., least vulnerable to most vulnerable). Population-adjusted clinical trial availability, cancer incidence, and cancer mortality were compared across SVI quintiles. Multivariable logistic and linear regression analyses were performed to evaluate the association between SVI and clinical trial availability and cancer mortality, respectively. Results: The mean number of PCa trials per 100,000 residents was 25.6, with the most vulnerable counties having fewer clinical trials compared to the least vulnerable counties (mean 18.1 vs. 50.0, p<0.05). Further, the most vulnerable counties had a lower PCa incidence rate per 100,000 residents (mean 393.8 vs. 411.7, p<0.05), but a higher PCa mortality rate per 100,000 residents (mean 85.7 vs. 72.0, p<0.05). On multivariable regression analysis, the most vulnerable counties were associated with significantly decreased odds of having any PCa clinical trial (OR 0.3, 95% CI 0.2 – 0.4) and significantly increased PCa mortality (10.8, 95% CI 7.4 – 14.3), while the presence of any PCa clinical trial was associated with significantly decreased PCa mortality (-6.9, 95% CI -9.1 – -4.7). Conclusions: The most vulnerable counties were far less likely to have any PCa clinical trials despite having a significantly higher PCa mortality rate. The presence of a PCa clinical trial was associated with a reduction in PCa mortality. These vulnerable counties represent scientifically underserved populations that may benefit from equity-driven clinical trial enrollment and cancer care infrastructure expansion.
Randomized trial of transperineal versus transrectal prostate biopsy to prevent infection complications.
Authors: Hu Jim C. , Vickers Andrew , Allaf Mohamad E. , Ehdaie Behfar , Cohen Andrew J , Ristau Benjamin T , Green David , Han Misop , Rezaee Michael , Pavlovich Christian P. , Montgomery Jeffrey S. , Kowalczyk Keith , Ross Ashley , Kundu Shilajit , Patel Hiten D , Wang Gerald J , Graham John N , Assel Melissa , Schaeffer Anthony J , Schaeffer Edward M. ,   PREVENT INVESTIGATORS
Published: January 2024

261

Background: Transrectal prostate biopsy is the predominant approach to prostate cancer detection in the U.S. and worldwide. The transperineal approach is traditionally preformed under general anesthesia. Recent advances enable prostate biopsy to be performed through the skin of the perineum (transperineal) under local anesthesia. There are potential advantages to this clean, percutaneous approach over the inherently contaminated transrectal approach. However, comparative evidence is limited. Methods: In a multicenter, randomized trial, we used two-stage consent and assigned participants with suspicion for prostate cancer to undergo transperineal biopsy without antibiotic prophylaxis vs. transrectal biopsy with targeted prophylaxis. The primary outcome was post-biopsy infection, with secondary outcomes of urinary retention, significant bleeding, cancer detection, and a numerical rating scale (0-10) for biopsy-related pain and discomfort during 7-days post-biopsy. Results: Six-hundred fifty-eight participants underwent randomization, and 567 (86%) of participants were included in the intent to treat analysis. Seventy-nine men declined to participate. There were zero transperineal versus 4 (1.4%) transrectal biopsy infections (adjusted difference -1.4%; 95% confidence interval -3.2, 0.3; P=0.059). Rates of other complications were very low and similar by approach. Importantly, detection of clinically significant cancer was similar (53% transperineal vs. 50% transrectal, adjusted difference 2.0%; 95% CI -6.0, 10; p=0.6). Participants undergoing transperineal biopsy experienced worse periprocedural pain (0.6 adjusted difference [0-10 scale] 95% CI 0.2, 0.9; P=0.002), but the effect was small and resolved by 7-days. Conclusions: Office-based transperineal biopsy is tolerable, does not compromise cancer detection and likely reduces the risk of infection without antibiotic prophylaxis, thereby improving antibiotic stewardship. Altogether, our findings support office based transperineal prostate biopsy without antibiotic prophylaxis as the new standard of care for prostate cancer detection with per patient and population-based antibiotic stewardship and healthcare cost benefits. Finally, two-stage consent facilitates accrual for surgical randomized trials, as evidenced by the relatively low rate of participants declining and withdrawing from the trial. Clinical trial information: NCT04815876 .
Stockholm3 validation in a multi-ethnic cohort for prostate cancer (SEPTA) detection: A multicentered, prospective trial.
Authors: Vigneswaran Hari Thambiah , Eklund Martin , Discacciati Andrea , Nordström Tobias , Hubbard Rebecca A. , Perlis Nathan , Abern Michael , Moreira Daniel , Eggener Scott E. , Yonover Paul M. , Chow Alexander , Watts Kara , Liss Michael A. , Thoreson Gregory R , Abreu Andre Luis , Sonn Geoffrey A , Palsdottir Thorgerdur , Wiklund Fredrik , Gronberg Henrik , Murphy Adam B ,   SEPTA STHLM3 Study Group
Published: January 2024

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Background: Stockholm3 is a multiparametric blood test incorporating germline risk, proteins and clinical data which improves prostate cancer (PC) risk stratification compared to PSA, however no validation exists in an ethnically diverse population. Methods: SEPTA is a prospective trial (NCT04583072) aimed to validate Stockholm3 in an ethnically diverse cohort of men referred for prostate biopsy at 17 North American sites from 2019 to 2023 (supplemented with bio-banked specimens 2008-2020). The trial had two prespecified primary aims when comparing Stockholm3 (≥15) compared to PSA (≥4 ng/ml): (1) Demonstrate non-inferior sensitivity in detecting clinically significant PC (csPC) (defined as ISUP Gleason Grade group ≥2) compared to PSA (non-inferiority margin of 20%). (2) Prove superior specificity thereby reducing the number of biopsies compared to PSA in men with benign or ISUP 1 biopsies. Both aims were assessed using a one-sided alpha of 0.025. A secondary aim was to evaluate Stockholm3 and PSA across ethnic subgroups. Statistical analysis plans were published before the analysis commenced. Results: The study involved 2,129 biopsied participants, categorized into self-identified groups: African American/Black (24%), White/Caucasian (46%), Hispanic/Latino (14%), and Asian (16%). Median participant age was 63 years. PSA and Stockholm3 median values were 6.1 ng/mL and 17, respectively. A total of 16% underwent MRI-targeted biopsies and 20% had a prior benign biopsy. On either systematic or targeted biopsy, csPC was found in 29%, 14% had ISUP 1 cancer, and 57% benign. The detection rate for csPC across groups were: African American/Black (37%), White/Caucasian (28%), Hispanic/Latino (29%), and Asian (21%). Overall, Stockholm3≥15 showed non-inferior sensitivity compared to PSA≥4 ng/ml (relative sensitivity: 0.95 [95% CI: 0.92-0.99]) and nearly 3 times superior specificity (relative specificity: 2.91 [95% CI: 2.63-3.22]). Results were consistent across ethnic subgroups: non-inferior sensitivity (0.91-0.98) and superior specificity (2.51-4.70). Stockholm3 ≥15 would have reduced benign and ISUP 1 biopsies by 45% overall and between 42-52% across ethnic subgroups compared to PSA ≥4 ng/ml. Stockholm3 exhibited higher AUC (0.82) compared to PSA (0.66), with similar trends in ethnic subgroups. Conclusions: In an ethnically diverse population, Stockholm3 would significantly reduce unnecessary prostate biopsies and diagnosis of ISUP 1 cancer at a similar sensitivity of PSA for detecting clinically significant cancer. Clinical trial information: NCT04583072 . [Table: see text]
The impact of perceived healthcare discrimination on health outcomes among patients with prostate cancer across racial and ethnic groups.
Authors: Sabater Minarim Daniel , Riviere Paul , Deshler Leah N. , Morgan Kylie M. , Duran Elizabeth A. , Banegas Matthew P. , Rose Brent S.
Published: January 2024

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Background: Black men face a disproportionately higher risk of mortality from PC (prostate cancer), and disparities in healthcare access have been associated with these outcomes. Discrimination in healthcare settings can profoundly affect health outcomes, especially for populations with significant health conditions. This study examined the association between race/ethnicity and perceived healthcare discrimination among individuals diagnosed with PC. We hypothesized that (1) racial/ethnic minorities with PC would be more likely to perceive healthcare discrimination and that (2) such perceived discrimination is associated with self-reported poor health. Methods: Using the 'All of Us' database, we focused on patients diagnosed with PC. We analyzed variables related to perceptions of respect, courtesy, and service quality from healthcare providers, categorized by race. These perception variables were then grouped to form a composite measure of "perceived healthcare discrimination." Multivariable logistic regression was used to study the effects of race/ethnicity on perceived discrimination and its subsequent impact on self-reported health, adjusting for demographics. Results: In our PC patient cohort of 3,129 participants, the race breakdown was: White: 2665, Black or African American: 150, Hispanic/Latino: 98, Other: 171, Asian: 27, Multirace: 18; Gender: Male: 3008, Gender Diverse: 121. A substantial number of patients with PC reported experiencing discrimination in healthcare settings. According to updated data, Black or African American patients were more likely to perceive discrimination with an Odds Ratio (OR) of 5.20, p < 0.00. Hispanic/Latino patients had an OR of 1.53, p = 0.19, whereas Asians had an OR of 2.11, p = 0.17, and individuals of multiple races had an OR of 2.43, p = 0.16. In terms of health outcomes, patients who felt respected by their healthcare provider had an OR of 0.426 for reporting worse health, p < 0.01. Conversely, those who perceived a lack of respect had an OR of 2.346 for poor health, p < 0.01. Conclusions: Our findings enhance the understanding of the nuances of perceived healthcare discrimination among PC patients across racial and ethnic boundaries. Persistent racial differences underscore the need for systemic interventions in healthcare settings for PC patients. The identified negative experiences correlate with worsened health outcomes. Recognizing the instances of perceived healthcare discrimination in PC patients is paramount for elevating care quality and equity. Health systems are encouraged to take proactive measures in addressing these disparities, aiming for enhanced patient trust, improved communication, and superior outcomes.
Difference in high-risk prostate cancer detection between transrectal and transperineal fusion approaches.
Authors: Semko Sofiya , Heidenreich Axel , Paffenholz Pia , Pfister David A. , Pikul Maksym
Published: January 2024

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Background: Present study aimed to gain insight into whether patients with high-risk prostate cancer (defined as Gleason 8-10) are being more precisely diagnosed by MRI fusion technique compared to TRUS-guided biopsy. Methods: A special retrospective cohort study database analysis was planned and conducted by urological department of University clinic of Cologne. After the database cut off the group of 779 patients with prostate cancer that underwent biopsy and further surgical treatment (radical prostatectomy) was selected. it was split into 2 cohorts according to biopsy type: TRUS guided biopsy and transperineal Fusion Biopsy. Standard systemic approach included 12 cores in TRUS and 18 in MRI-guided cohorts. Additional 5-6 cores were taken from the region of interest in the Fusion group. All the patients during analysis were divided into risk groups: Gleason 6 (3+3) - low risk group, Gleason 7a (3+4) - intermediate risk group, favourable prognosis, Gleason 7b (4+3) - intermediate risk group, unfavourable prognosis, Gleason 8-10 – high group. Concordance of primary and postoperative pathology was estimated by using re-grading levels and migration from low\intermediate to high-risk group. Additionally, the presence of one or more risk factors (perineural and lymphovascular invasion, presence of cribriform pattern, etc.) in primary specimens was evaluated. Results: The groups were statistically equal by age (p = 0,16), PSA risk-groups (χ2= 1,36; p = 0,53), density division ( χ2= 0,58; p = 0,74), prostate volume (p = 0,23) and ECOG status (Me [25 %; 75 %] p = 0,17). There were no significant differences between groups in terms of final pathology – number of cases in low, intermediate and high risk groups (χ2= 1,37; p= 0,5). Difference was observed in lower rate of upgrading to high-risk group and higher detection of risk factors in favour of transperineal-targeted biopsy (Table). Exposure of targeted biopsy increased the probability of detecting high risk PCa by 39% compared to systemic cores (OR 1.39, 95% CI: 0.9 - 1.9; p = 0,06). Conclusions: Transperineal fusion biopsy can be characterised by a higher possibility of detecting high-risk prostate cancer compared to conventional transrectal methods. A higher probability of discovering risk factors after transperineal fusion biopsy might be an important tool for proper staging and risk-adapted treatment strategy.[Table: see text]
Diagnosis of prostate cancer and benign prostatic hyperplasia based on urinary cell-free DNA methylation characteristics.
Authors: Luo Jindan , Dong Hang , Tang Haoran , Yi Jiahe , Du Pan , Jia Shidong , Xie Liping
Published: January 2024

275

Background: Distinguishing between early-stage prostate cancer (PCa) and benign prostatic hyperplasia (BPH) has posed a persistent clinical challenge. Exploring the epigenetic characteristics of urinary cell-free DNA (ucfDNA) offers potential for improving diagnosis. In this preliminary study, we aimed to investigate the feasibility of utilizing of urinary cfDNA methylation features as a non-invasive way to detect PCa. Methods: Paired tissue, plasma, and urine samples were collected from 12 PCa patients, along with paired plasma and urine samples from 12 BPH patients, and urine samples from 24 healthy donors. PredicineEPIC, a whole genome-based DNA methylation assay, was implemented to profile methylation features in all these samples. Results: We discovered that the methylation patterns of ucfDNA more closely resembled those of tumor tissue compared to plasma cfDNA, suggesting that urine can serve as an effectual alternative to blood for detecting cancer related signals. We identified 369 differentially methylated regions that contained PCa-specific methylation signals. Subsequently, we employed feature selection and applied a machine learning regression algorithm to construct a classification model. Validation on an independent GEO dataset yielded an impressive AUC of 0.83 for distinguishing between PCa and benign prostatic hyperplasia (BPH). Conclusions: This study demonstrated the potential of ucfDNA-based methylation markers in the early detection of prostate cancer.
Assessing the mid-term impact of enhanced prostate cancer screening in Caucasian men with germline DNA repair pathogenic variants.
Authors: Lazzeri Massimo , Fasulo Vittorio , Buffi Nicolò Maria , Casale Paolo , Hurle Rodolfo , Saita Alberto , Paciotti Marco , Finocchiaro Alessio , Aljoulani Muhannad , Asselta Rosanna , Soldà Giulia , De Simone Ilaria , Colombo Piergiuseppe , Cieri Miriam , Maura Federica , Cavalli Pietro , Lughezzani Giovanni
Published: January 2024

278

Background: Family history is a major prostate cancer (PCa) risk factor. Pathogenic gene variants (e.g., BRCA1/BRCA2) greatly increase PCa risk (2.5 to 8.6-fold for <65-year-olds) and affect outcomes. This study assesses an enhanced screening protocol's effectiveness and participant compliance. It combines PHI for familial cases and multiparametric MRI for those with pathogenic DNA repair gene (DRG) variants. Methods: This non-profit charity-funded study (AIRC - Fondazione AIRC project IG 2020 ID 25027) evaluates targeted screening for men at higher genetic risk of PCa due to PVs in a specific gene region (DRG). Conducted at a tertiary Hospital with collaboration from departments of Oncology, Breast Unit, Urology, Pathology, Radiology, Laboratory and Medical Genetics. It includes men aged 35-69 with documented deleterious DRG mutations who consent to planned screening. Exclusion criteria are prior prostate surgery, prostate cancer diagnosis, MRI contraindications, or variants of unknown significance (VUS). Results: Between 2020 and 2023, a total of 90 patients participated in this study. Their median age was 51.5 years (IQR 46.0-60.2). The median total PSA level was 0.9 (IQR 0.5-1.63), and the median PHI was 17 (IQR 12.3-23.8). Notably, 20.1% of patients had a family history of breast/ovarian cancer, while 79.9% had a family history of PCA. Most participants hailed from Northern Italy (69.4%). PVs were identified as follows: BRCA2 (55.7%), BRCA1 (17.8%), ATM (4.44%), PMS2 (3.33%), BRCA (3.33%), MSH2 (2.22%), TMPRSS2-ERG (2.22%), BRIP1 (1.11%), MLH1 (1.11%), MSH6 (1.11%), BRCA3 (1.11%), and 6.67% of patients reported mutations without specific details. In terms of screening compliance, 36 patients completed 1 visit, 31 completed 2 visits, 1 completed 3 visits, and 22 scheduled their first follow-up. Regarding PHI levels, 62.8% had PHI levels below 20, 33.5% fell in the 20-40 range, and 3.70% exceeded 40. For patients with PSA levels below 3 and PHI above 20 (n=17), only one exhibited a positive mpMRI result and is scheduled for a biopsy. Conversely, among patients with PSA levels above 3 and PHI below 20 (n=2), one underwent mpMRI, which yielded a negative result. Among the patients who underwent mpMRI, six underwent biopsy, and all resulted negatives. Conclusions: In summary, this study achieved high participant compliance with the screening method and underscores the importance of using PHI and multiparametric MRI, especially in those with genetic predispositions. These tools hold potential for enhancing prostate cancer detection accuracy and merit further exploration for early diagnosis in at-risk populations.