PCa-specific Death Research Articles

Clinical relevance of protein-truncating variants of germline DNA repair genes in prostate cancer

BackgroundInterpreting genetic variants remains a challenge in prostate cancer (PCa). Although many annotation tools are available for prioritizing causal variants, the clinical relevance of these variants is rarely studied.MethodsWe collected a cohort study that included 274 PCa patients from June 2017 to December 2020 and sequenced 19 DNA damage repair (DDR) genes in these patients and explored the clinical consequence of these different approaches. We also examined all-cause and PCa-specific survival in DDR gene mutation carriers compared to non-carriers after androgen receptor (AR)-directed therapy.ResultsWe identified 13 variants from 19 DDR genes in a total of 14 (5.1%) patients who had at least one presumed pathogenic mutation using different annotation methods. Four variants were annotated as pathogenic, 11 variants were predicted as protein-truncating variants (PTVs), four variants received proxy-deleterious (Combined Annotation-Dependent Depletion scores of > 30), and only one variant was identified as a pathogenic variant or as having a functional effect by all three methods. PCa patients with PTVs were significantly associated with early onset, high cancer stage, and a worse response to AR-directed treatment. However, patients carrying a proxy-deleterious variant were only associated with a higher T (tumor) stage and N (node) stage than those without such a variant, but not associated with other clinical characteristics. In patients treated with AR-directed therapy, patients with a PTV showed an increased risk of all-cause death (adjusted hazard ratio (aHR) = 3.51, 95% confidence interval (CI): 1.06 ~ 11.56) and PCa-specific death (aHR = 4.49, 95% CI: 1.87 ~ 10.77) compared to non-PTV carriers after adjustment. We were unable to examine gene-specific risks due to the small number of patients.ConclusionsPTVs may assist in guiding treatment and early screening in PCa, while population-specific data for pathogenic variants are still being amassed.

Excess weight, weight gain, and prostate cancer risk and prognosis: the PROCA-life study.

Studies of excess weight and weight changes throughout adult life for prostate cancer (PCa) risk and prognosis have shown inconsistent results. In a population-based cohort, the Prostate Cancer Study throughout life (PROCA-life), 16,960 healthy men from the prospective cohort Tromsø Study (1994-2016) were included. Body mass index (BMI) and weight were measured at all four attendings, and weight change was calculated as the difference between the first and last of either Tromsø4, Tromsø5 or Tromsø6. Overall, 904 men developed PCa during 16 years of follow-up, and Poisson regression with fractional polynomials was used to investigate trends in incidence. Cox proportional hazard and logistic regression models were used to study associations between measurements of BMI and weight change and PCa risk, severity, and mortality. At study entry, 46% of the participants (median age 44 years) were overweight, and 14% were obese (BMI > 30 kg/m2). We observed a 127% increase in overall age adjusted PCa incidence in the cohort during 1995 through 2019. No overall associations between BMI or weight change and PCa risk were observed. However, in sub-group analysis, weight gain among obese men was associated with a three-fold higher PCa risk (HR 3.03, 95% CI 1.39-6.58) compared with obese men with stable weight. Overweight was associated with lower risk of metastatic cancer (OR 0.48, 95% CI 0.30-0.75) at diagnosis. Men with obesity had higher risk of PCa-specific death (HR 1.72, 95% CI 1.03-2.88), while nonsmoking obese PCa cases had two times higher PCa-specific mortality compared with normal weighted PCa cases (HR 2.10, 95% CI 1.11-3.70). In our cohort, weight gain among obese men was associated with higher risk of PCa, and obesity was associated with higher PCa-specific mortality, especially among nonsmokers. The relationship between weight and risk for PCa remains complicated, and future studies are needed to determine clinical implications.

Quantification of collagen content and stromal cellularity within reactive stroma is predictive of prostate cancer biochemical recurrence and specific death

Semiquantitative reactive stromal grading has been shown to be a predictor of biochemical recurrence and prostate cancer (PCa) specific death. It has been extensively validated. In this study we tested novel technologies to introduce quantitative measures of host response, in particular collagen content and stromal cellularity. We use 3 large retrospective cohorts, the Baylor College of Medicine cohort, the Brady cohort and the Pound cohort. Slides were stained and digitized using image deconvolution and analyzed using image segmentation and image analyses. PicroSirius red stain histochemical stains were used for collagen quantification. Area of cancer and stroma were measured independently, without regard to quality of stroma. Cellularity, in each compartment, was measured using image deconvolution, image segmentation and image analysis. Two biomarkers were tested in 3 independent cohorts with two endpoints, biochemical recurrence and prostate cancer specific death. Stromal cellularity (qCollCell) and stromal collagen area (qCollArea) are independently predictive biochemical recurrence in the Hopkins Brady cohort, particularly in Gleason 6–7 patients. Multivariate analysis demonstrated that increased stroma cellularity (qCollCell) was a significant predictor of PCa specific death, when compared to an established model of PCa, in the Baylor cohort. Stromal collagen (qCollArea) independently predicts PCa-specific death in the Hopkins Pound cohort. The introduction of a computerized quantitative test of the host response increases the probability that this test will be reproducible in other cohorts. The ability to improve prediction of prostate cancer specific death might lie in the study of the host and its response.

Management of Localized Prostate Cancer in Men With Human Immunodeficiency Virus: Analysis of a Large Retrospective Cohort.

We aimed to characterize the clinicopathological characteristics and outcomes of HIV-positive patients with clinically localized, prostate cancer (PCa). A retrospective study was conducted of HIV-positive patients from a single institution with elevated PSA and diagnosis of PCa by biopsy. PCa features, HIV characteristics, treatment type, toxicities, and outcomes were analyzed by descriptive statistics. Kaplan-Meier analysis was used to determine progression-free survival (PFS). Seventy-nine HIV-positive patients were included with a median age at PCa diagnosis of 61 years-old and median duration from HIV infection to PCa diagnosis of 21 years. The median PSA level at diagnosis and Gleason Score was 6.85 ng/mL and 7, respectively. The 5-year PFS was 82.5% with the lowest survival observed in patients treated with radical prostatectomy (RP)+radiation therapy (RT), followed by cryosurgery (CS). There were no reports of PCa-specific deaths, and the 5-year overall survival was 97.5%. CD4 count declined post-treatment in pooled treatment groups that included RT (P=.02). We present the characteristics and outcomes of the largest cohort of HIV-positive men with prostate cancer in published literature. RP and RT ± ADT is well-tolerated in HIV-positive patients with PCa as seen by the adequate biochemical control and mild toxicity. CS resulted in worse PFS compared to alternative treatments for patients within the same PCa risk group. A decline in CD4 counts was observed in patients treated RT, and further studies are needed to investigate this relationship. Our findings support the use of standard-of-care treatment for localized PCa in HIV-positive patients.

Histomic and transcriptomic features of MRI-visible and invisible clinically significant prostate cancers are associated with prognosis.

Magnetic resonance imaging (MRI) is increasingly used to triage patients for prostate biopsy. However, 9% to 24% of clinically significant (cs) prostate cancers (PCas) are not visible in MRI. We aimed to identify histomic and transcriptomic determinants of MRI visibility and their association to metastasis, and PCa-specific death (PCSD). We studied 45 radical prostatectomy-treated patients with csPCa (grade group [GG]2-3), including 30 with MRI-visible and 15 with MRI-invisible lesions, and 18 men without PCa. First, histological composition was quantified. Next, transcriptomic profiling was performed using NanoString technology. MRI visibility-associated differentially expressed genes (DEGs) and Reactome pathways were identified. MRI visibility was classified using publicly available genes in MSK-IMPACT and Decipher, Oncotype DX, and Prolaris. Finally, DEGs and clinical parameters were used to classify metastasis and PCSD in an external cohort, which included 76 patients with metastatic GG2-4 PCa, and 84 baseline-matched controls without progression. Luminal area was lower in MRI-visible than invisible lesions and low luminal area was associated with short metastasis-free and PCa-specific survival. We identified 67 DEGs, eight of which were associated with survival. Cell division, inflammation and transcriptional regulation pathways were upregulated in MRI-visible csPCas. Genes in Decipher, Oncotype DX and MSK-IMPACT performed well in classifying MRI visibility (AUC = 0.86-0.94). DEGs improved classification of metastasis (AUC = 0.69) and PCSD (AUC = 0.68) over clinical parameters. Our data reveals that MRI-visible csPCas harbor more aggressive histomic and transcriptomic features than MRI-invisible csPCas. Thus, targeted biopsy of visible lesions may be sufficient for risk stratification in patients with a positive MRI.

Atopic allergic conditions and prostate cancer risk and survival in the Multiethnic Cohort study

BackgroundPrevious studies investigating relationship between atopic allergic conditions (AACs)—a highly reactive immune state—and prostate cancer (PCa) risk were inconclusive, and few have studied diverse racial/ethnic populations.MethodsWe analysed 74,714 men aged ≥45 years at enrollment in Multiethnic Cohort study. Using multivariable Cox regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for self-reported AAC status on PCa outcomes.ResultsThrough 2017, 8697 incident PCa and 1170 related deaths occurred. Twenty-one percent of men reported a history of AACs. AACs were not associated with incident PCa (HR = 0.98, 95% CI: 0.93–1.03) but were significantly inversely associated with PCa mortality (HR = 0.79, 95% CI: 0.67–0.92). This inverse association was consistently observed across all racial/ethnic groups (HR range: 0.60–0.90). Among men diagnosed with PCa, AACs were inversely associated with PCa-specific death (HR = 0.75, 95% CI: 0.63–0.89). Adjusting for potential confounding effect of PSA screening did not meaningfully change the results. No significant heterogeneity was observed in the effect of AACs on PCa incidence or mortality by Dietary Inflammatory Index.ConclusionsHyper-allergic conditions were not associated with PCa incidence but were inversely associated with PCa mortality, suggesting a potential role in reducing tumour progression. Further aetiological research is warranted to understand underlying mechanisms.

MP77-03 THE EFFECT OF NEIGHBORHOOD ARCHETYPE ON PROSTATE CANCER-SPECIFIC MORTALITY FOR WISCONSIN MEN

You have accessJournal of UrologyCME1 Apr 2023MP77-03 THE EFFECT OF NEIGHBORHOOD ARCHETYPE ON PROSTATE CANCER-SPECIFIC MORTALITY FOR WISCONSIN MEN Ashanda R. Esdaille, Arighno Das, Glenn Allen, Daniel Shapiro, Kyle Richards, E. Jason Abel, David Jarrard, and Tudor Borza Ashanda R. EsdailleAshanda R. Esdaille More articles by this author , Arighno DasArighno Das More articles by this author , Glenn AllenGlenn Allen More articles by this author , Daniel ShapiroDaniel Shapiro More articles by this author , Kyle RichardsKyle Richards More articles by this author , E. Jason AbelE. Jason Abel More articles by this author , David JarrardDavid Jarrard More articles by this author , and Tudor BorzaTudor Borza More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003351.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Socioeconomic factors are associated with prostate cancer (PCa) disparities. This study aimed to identify the association between rurality and neighborhood deprivation on prostate cancer-specific mortality (PCSM) for men diagnosed and treated in Wisconsin. METHODS: Wisconsin Cancer Reporting System (WCRS) data were used to identify all men diagnosed with PCa between 1995-2010. These data were merged with rural-urban commuting area (RUCA) codes to identify patients living in rural, small town, and urban areas. Deprivation was measured by the Area of Deprivation Index (ADI) at the census block group level using the Neighborhood Atlas®, a validated composite measure which allows for rankings of neighborhoods by socioeconomic disadvantage based on income, education, employment, and housing quality. ADIs were categorized into quartiles. Differences in baseline demographic and clinicopathologic characteristics were determined using chi-square tests. Cox proportional hazards models were used to estimate the effect of neighborhood archetype and deprivation on PCSM, adjusted for age, clinical grade, stage, diagnosis year +/- treatment. RESULTS: 62,474 men with PCa were identified with a median follow up of 5.7 years (primary) and 9.6 years (sensitivity analyses). 41,885 men (67%) resided in urban areas, 7,102 (11%) in small towns and 13,487 (22%) in rural areas. Men living in rural areas were diagnosed at older ages and more commonly had nodal and metastatic disease (p<0.001). Among all three neighborhood archetypes, definitive treatment increased in later time periods with overall higher rates of surgery versus radiation. In small towns, radiation was more prevalent. In comparison to men living in urban areas, there was no increased risk of PCSM for men in rural or small town areas (p=0.09-0.56). Further, there was no difference in PCSM risk for advantaged men living in urban, rural or small town areas (p=0.39-0.93). Disadvantaged rural men had increased risk of PCSM compared to disadvantaged urban men (Q3: aHR=1.2 (95% CI 1.0-1.35, p=0.042). This trend was not observed in men residing in the most deprived neighborhoods (Q4: p=0.21-0.53). CONCLUSIONS: Men living in rural areas had more aggressive disease on presentation in comparison to men residing in small towns and urban areas, possibly reflecting differences in screening patterns. Overall, there was no difference in PCa-specific deaths by neighborhood archetype; however, differences in deprivation status within the archetypes underscore the association between lack of neighborhood-level resources and oncologic outcome. Source of Funding: Esdaille: AUA/UCF Research Scholar Award Grant# 017-822959 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1102 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ashanda R. Esdaille More articles by this author Arighno Das More articles by this author Glenn Allen More articles by this author Daniel Shapiro More articles by this author Kyle Richards More articles by this author E. Jason Abel More articles by this author David Jarrard More articles by this author Tudor Borza More articles by this author Expand All Advertisement PDF downloadLoading ...

PD21-04 THE IMPACT OF NEIGHBORHOOD DEPRIVATION AND RACE ON PROSTATE CANCER-SPECIFIC MORTALITY FOR WISCONSIN MEN

You have accessJournal of UrologyCME1 Apr 2023PD21-04 THE IMPACT OF NEIGHBORHOOD DEPRIVATION AND RACE ON PROSTATE CANCER-SPECIFIC MORTALITY FOR WISCONSIN MEN Ashanda R. Esdaille, Arighno Das, Glenn O. Allen, Daniel Shapiro, Kyle Richards, E. Jason Abel, David Jarrard, and Tudor Borza Ashanda R. EsdailleAshanda R. Esdaille More articles by this author , Arighno DasArighno Das More articles by this author , Glenn O. AllenGlenn O. Allen More articles by this author , Daniel ShapiroDaniel Shapiro More articles by this author , Kyle RichardsKyle Richards More articles by this author , E. Jason AbelE. Jason Abel More articles by this author , David JarrardDavid Jarrard More articles by this author , and Tudor BorzaTudor Borza More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003287.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Neighborhood deprivation contributes to worsened prostate cancer (PCa) outcomes. In Wisconsin, 54% of the population resides in the most deprived neighborhoods and the state ranks #1 in PCa incidence for Black men. In this study, we aimed to identify the association between neighborhood deprivation, race, and PCa-specific mortality (PCSM) for Wisconsin men. METHODS: Wisconsin Cancer Reporting System (WCRS) data were used to identify all men diagnosed with PCa between 1995-2010. Deprivation was measured by the Area of Deprivation Index (ADI) at the census block group level using the Neighborhood Atlas®, a validated composite measure which allows for rankings of neighborhoods by socioeconomic disadvantage based on income, education, employment, and housing quality. ADIs were categorized into quartiles. Differences in baseline demographic and clinicopathologic characteristics were determined using chi-square tests. Cox proportional hazards models were used to estimate the effect of neighborhood deprivation and race on PCSM, adjusted for age, clinical grade, stage, diagnosis year +/- treatment. RESULTS: 62,474 men with PCa were identified including 58,777 White, 2,706 Black, and 991 Other with a median follow up of 5.7 years (primary) and 9.6 years (sensitivity analyses). 33,558 men resided in the most deprived neighborhoods (Q3-Q4): 30,678 White vs 2,282 Black vs 591 Other. PCa-specific deaths were more prevalent in Q4 (12.5%) vs Q1 (9.6%), p<0.001. Men living in the most deprived neighborhoods had a slightly higher risk for PCSM (Q4: [aHR]=1.1 [95% CI 1.0-1.15], p=0.037). Deprived Black men were at a higher risk of PCSM vs deprived (Q4: HR=1.2 [95%CI 1.06-1.38], p=0.005) and least deprived White men (HR=1.3 [95% CI 1.15-1.52], p<0.001), but these were not statistically significant on adjusted and sensitivity analyses (p=0.13-0.88). The least deprived Black men (Q1: aHR=1.1 [95% CI 0.57-2.05], p=0.79) were no more likely to die from PCa than the least deprived White men. CONCLUSIONS: Race is implicated in worsened PCa outcomes, however, these findings support the association between neighborhood deprivation and PCSM as a potential mediator for race effects. These data support that neighborhood-level resources or interventions, such as access to care, are essential to improve or equalize PCa outcomes. Source of Funding: AUA/UCF Research Scholar Award Grant# 017-822959 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e591 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ashanda R. Esdaille More articles by this author Arighno Das More articles by this author Glenn O. Allen More articles by this author Daniel Shapiro More articles by this author Kyle Richards More articles by this author E. Jason Abel More articles by this author David Jarrard More articles by this author Tudor Borza More articles by this author Expand All Advertisement PDF downloadLoading ...

Allopurinol and prostate cancer survival in a Finnish population-based cohort

BackgroundAllopurinol is gout medication that inhibits uric acid formation. Its possible anti-carcinogenic properties have been under research in past years. Studies based on Taiwanese registries showed that long term allopurinol use might reduce prostate cancer (PCa) incidence. However, our studies based on Finnish registries did not support those findings. In this study, we evaluate whether allopurinol use is associated with prostate cancer-specific survival (CSS) or overall survival (OS) in a Finnish population-based cohort.MethodsThe study cohort was originally enrolled for the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). We included all newly diagnosed PCa cases during 1996–2015, 9252 men in total. Information on allopurinol purchases was from the national prescription registry of the Social Insurance Institution of Finland. Information about deaths, treatments, and use of other medications was obtained from registries, and tumor stage and PSA at diagnosis from medical records. Follow-up started at diagnosis, and we analysed separately two endpoints: PCa-specific death and overall death. We used an extended Cox regression with adjustment for age at diagnosis, Charlson comorbidity index, FinRSPC trial arm, use of other drugs and EAU PCa risk group.ResultsDuring a median follow-up of 9.86 years, 2942 deaths occurred, including 883 from PCa. There was no difference in CSS between allopurinol user and non-users, but allopurinol users had lower OS (multivariable-adjusted hazard ratio 1.77; 95% CI: 1.57–2.00). However, this decrease in OS was mitigated along with increasing intensity of allopurinol use.ConclusionsWe found no marked difference in CSS by allopurinol use. Allopurinol users had lower OS but there were no significant differences by duration or intensity of allopurinol use. Allopurinol use may not have anticancer effects against prostate cancer; instead, it may be a surrogate for metabolic problems causing shorter OS among men with PCa.

Impact of COVID-19 pandemic on screening and diagnosis of patients with prostate cancer: a systematic review protocol

IntroductionWith the exponential progress of patients with COVID-19, unexpected restrictions were directed to limit SARS-CoV-2 dissemination and imposed health-system an entire reformation to diminish transmission risk. These changes likely have...

MP43-10 IMPACT OF FAMILY HISTORY AND GERMLINE GENETIC RISK VARIANTS ON LONG-TERM OUTCOMES OF ACTIVE SURVEILLANCE-ELIGIBLE PROSTATE CANCER

You have accessJournal of UrologyCME1 May 2022MP43-10 IMPACT OF FAMILY HISTORY AND GERMLINE GENETIC RISK VARIANTS ON LONG-TERM OUTCOMES OF ACTIVE SURVEILLANCE-ELIGIBLE PROSTATE CANCER Florian Rumpf, Anna Plym, Jane Vaselkiv, Mark Preston, Adam Kibel, Lorelei Mucci, and Keyan Salari Florian RumpfFlorian Rumpf More articles by this author , Anna PlymAnna Plym More articles by this author , Jane VaselkivJane Vaselkiv More articles by this author , Mark PrestonMark Preston More articles by this author , Adam KibelAdam Kibel More articles by this author , Lorelei MucciLorelei Mucci More articles by this author , and Keyan SalariKeyan Salari More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002609.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A family history of prostate cancer (PCa) and BRCA/DNA repair gene-associated cancers are risk factors for developing prostate cancer. In the last decade, >260 PCa-associated single nucleotide polymorphisms (SNPs) have been identified through large-scale genome-wide association studies that strongly stratify lifetime risk of prostate cancer. Few studies have examined the prognostic value of family history or PCa germline risk variants in patients with favorable-risk PCa eligible for active surveillance (AS). Here, we evaluate the impact of a positive family history and germline risk SNPs on outcomes on AS-eligible patients. METHODS: In a prospective cohort of 39,427 U.S. men in the Health Professionals Follow-up Study, 1,367 were diagnosed with clinically favorable-risk (NCCN very low-, low-, or favorable intermediate-risk) PCa from 1986 to 2016 and underwent genome-wide SNP genotyping. During the 30-year follow-up, 263 patients experienced disease recurrence and 52 patients died of PCa. A polygenic risk score was derived from 269 SNPs associated with development of PCa. Two loci associated with PCa survival were also assessed. Multivariable Cox proportional hazards models were used to estimate the association between family history of prostate, breast, or pancreatic cancer, germline risk SNPs, and PCa recurrence or death through 2019. RESULTS: The median follow up time from diagnosis was 14.1 years. A family history of prostate, breast, or pancreatic cancer was observed in 494 (36%) patients. Men with a positive family history had an 83% greater risk of PCa-specific death (95% CI 1.06-3.17, p=0.03), and greater than that of men with a family history of PCa alone. The polygenic risk score was not associated with either PCa recurrence or death. However, focusing on 2 loci on 8q24 and 19q13 with the strongest evidence in the literature for association with PCa aggressiveness, we observed a significant association between rs2735839 on 19q13 and PCa-specific death (HR 1.81, 95% CI 1.04-3.17, p=0.037). Using a risk score giving one point each to a positive family history and rs2735839 risk allele, each point of the heritable risk score was associated with a 72% increased risk of PCa-specific death (95% CI 1.16-2.54, p=0.006). CONCLUSIONS: Our study found that patients with AS-eligible PCa with a family history of prostate, breast, or pancreatic cancer or a 19q13 germline risk allele had elevated risks of PCa-specific death. These findings have implications for how germline genetic risk should be factored into AS selection criteria. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e744 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Florian Rumpf More articles by this author Anna Plym More articles by this author Jane Vaselkiv More articles by this author Mark Preston More articles by this author Adam Kibel More articles by this author Lorelei Mucci More articles by this author Keyan Salari More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP51-04 P-SCORE IN PREOPERATIVE BIOPSIES ACCURATELY PREDICTS P-SCORE IN FINAL PATHOLOGY AT RADICAL PROSTATECTOMY

You have accessJournal of UrologyCME1 May 2022MP51-04 P-SCORE IN PREOPERATIVE BIOPSIES ACCURATELY PREDICTS P-SCORE IN FINAL PATHOLOGY AT RADICAL PROSTATECTOMY Pontus Röbeck, Li-Di Xu, Dilruba Ahmed, Anca Dragomir, Pär Dahlman, Sam Ladjevardi, and Michael Häggman Pontus RöbeckPontus Röbeck More articles by this author , Li-Di XuLi-Di Xu More articles by this author , Dilruba AhmedDilruba Ahmed More articles by this author , Anca DragomirAnca Dragomir More articles by this author , Pär DahlmanPär Dahlman More articles by this author , Sam LadjevardiSam Ladjevardi More articles by this author , and Michael HäggmanMichael Häggman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002626.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostatype RT-qPCR kit analyses the expression of 3 genes (IGFBP3, F3, and VGLL3) in formalin-fixed paraffin-embedded prostate cancer (PCa) tissues. The gene parameter is combined with patient-specific clinical parameters in a pre-defined algorithm to calculate the P-score, which has previously been shown to improve prediction performance of PCa-specific death as compared to clinical parameters only. To establish the prognostic accuracy of P-score in MRI/TRUS fusion-guided diagnostic biopsies as compared to P-score in the paired radical prostatectomy specimens and to elucidate the concordance of P-score in the paired index- and concomitant non-index tumour foci. METHODS: 98 men with localized PCa, all diagnosed by MRI/TRUS fusion-guided biopsies, underwent robot-assisted radical prostatectomy. All prostatectomies were whole-mounted and tumour maps were drawn. From all biopsies and from index and non-index tumour foci of the corresponding prostatectomies, gene expression was assessed with Prostatype and P-score was computed. This P-score was calculated in a range of 0-15 with one as the smallest unit and categorised into three risk groups by using previously defined cut-offs. RESULTS: Preoperative biopsies yielded sufficient and technically analysable materials for comparison with the prostatectomy in 71 men. Biopsy P-score significantly correlated with P-score in corresponding prostatectomy with a Pearson correlation of 0.84 (95% CI: 0.75-0.89, p<0.0001). P-score in paired biopsy and prostatectomy were also in substantial agreement (weighted kappa score 0.68). P-score in index tumour significantly correlated with P-score in the paired concomitant foci (Pearson correlation: 0.83, 95% CI: 0.74-0.90, p<0.0001). P-score in the paired index tumour and the concomitant foci were also in agreement (weighted kappa score: 0.68). CONCLUSIONS: P-score in preoperative fusion-guided biopsies accurately predicts the P-score in the prostatectomy. P-score in index tumour and concomitant foci also show substantial concordance. Thus, biopsy P-score is adequate for assisting with predicting prostate cancer progression. Source of Funding: Uppsala University Hospital © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e876 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pontus Röbeck More articles by this author Li-Di Xu More articles by this author Dilruba Ahmed More articles by this author Anca Dragomir More articles by this author Pär Dahlman More articles by this author Sam Ladjevardi More articles by this author Michael Häggman More articles by this author Expand All Advertisement PDF DownloadLoading ...

Local failure, distant metastasis, and survival after definitive radiotherapy for intermediate- and high-risk prostate cancer: An individual patient-level meta-analysis of 18 randomized trials.

277 Background: The prognostic importance of local failure (LF) after definitive radiotherapy (RT) in patients with NCCN intermediate- (IRPCa) and high-risk prostate cancer (HRPCa) remains unclear, particularly given the likelihood that occult distant metastases (DMs) at presentation may be the true driver of natural history. Here, we leverage individual patient data (IPD) from 18 randomized control trials (RCTs) to evaluate the prognostic impact of LF and the kinetics of DM after RT. Methods: IPD for 18 RCTs were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium, comprising a total of 12533 patients (6288 HRPCa &amp; 6245 IRPCa). Multivariable Cox proportional hazards (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), DM-free survival (DMFS) &amp; LF as a time-dependent covariate, adjusted for clinicodemographic parameters. Markov PH models, defined via transitions between 4 states, were developed to evaluate the aforementioned relationship. Proportional hazards assumption was imposed and examined for both models. Time is from randomization. Results: Median follow-up was 9.1 years. There were 795 (13%) LF &amp; 1288 (21%) DM events for patients with HRPCa; these numbers were 449 (7%) &amp; 451 (7%) for IRPCa. For HRPCa &amp; IRPCa, 81% and 81% of DMs developed from a clinically relapse-free state (cRFS), with a median time of 46 and 60 months, respectively (p &lt; 0.0001). 39% &amp; 13% of DM events occurred within 2 years after RT for HRPCa &amp; IRPCa, respectively. At later time points, DM events were more likely to emerge after an LF event for both HRPCa (9% vs. 34% between 0-2 vs. 8-10 years post-RT, p = 0.001) and IRPCa (10% vs. 34% between 0-2 vs. 8-10 years post-RT, p = 0.008). LF was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75-2.33) &amp; DMFS (HR 1.94, 95% CI 1.75–2.15) (p &lt; 0.01 for all) in patients with HRPCa. LF was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not OS in patients with IRPCa. Patients who had not transitioned to the LF state had a significantly lower HR of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.32, 95% CI 0.21–0.50, p &lt; 0.001). Conclusions: LF is an independent prognosticator of OS, PCSS &amp; DMFS in HRPCa and of DMFS in IRPCa. The predominant mode of DM development is from the cRFS state, underscoring the importance of accurate upfront staging &amp; systemic therapy. However, particularly at late time points, an increasing proportion of DM events originated after diagnosis of a LF, constituting a “second wave” of DM events. This suggests that optimizing local control is also important, though the majority of DM events appear prior to a clinically-detected LF.

KLK3 germline mutation I179T complements DNA repair genes for predicting prostate cancer progression.

Germline mutations in DNA repair genes and KLK3 have been associated with adverse prostate cancer (PCa) outcomes in separate studies but never jointly. The objective of this study is to simultaneously assess these two types of germline mutations. Germline rare pathogenic mutations (RPMs) in 9 commonly tested DNA repair genes and KLK3 variants were tested for their associations with PCa progression in two PCa cohorts: (1) hospital-based PCa patients treated with radical surgery at the Johns Hopkins Hospital (JHH, N = 1943), and (2) population-based PCa patients in the UK Biobank (UKB, N = 10,224). Progression was defined as metastasis and/or PCa-specific death (JHH) and PCa-specific death (UKB). RPMs of DNA repair genes were annotated using the American College of Medical Genetics recommendations. Known KLK3 variants were genotyped. Associations were tested using alogistic regression model adjusting for genetic background (top ten principal components). In the JHH, 3.2% (59/1,843) of patients had RPMs in 9 DNA repair genes; odds ratio (OR, 95% confidence interval) for progression was 2.99 (1.6-5.34), P < 0.001. In comparison, KLK3 I179T mutation was more common; 9.7% (189/1,943) carried the mutation, OR = 1.6 (1.05-2.37), P = 0.02. Similar results were found in the UKB. Both types of mutations remained statistically significant in multivariable analyses. In the combined cohort, compared to patients without any mutations (RPMs-/KLK3-), RPMs-/KLK3+ patients had modestly increased risk for progression [OR = 1.54 (1.15-2.02), P = 0.003], and RPMs+/KLK3+ patients had greatly increased risk for progression [OR = 5.41 (2.04-12.99), P < 0.001]. Importantly, associations of mutations with PCa progression were found in patients with clinically defined low- or intermediate risk for disease progression. Two different cohorts consistently demonstrate that KLK3 I179T and RPMs of nine commonly tested DNA repair genes are complementary for predicting PCa progression. These results are highly relevant to PCa germline testing and provide critical information for KLK3 I179T to be considered in guidelines.

Intraductal Carcinoma of the Prostate as a Cause of Prostate Cancer Metastasis: A Molecular Portrait.

Simple SummaryMost men with prostate cancer will live as long as those who do not have prostate cancer. However, some men will die early of their disease due to a particular type of prostate cancer associated with recurrence and metastasis: intraductal carcinoma of the prostate. In this review, we discuss the associations between intraductal carcinoma of the prostate and metastasis, and the contemporary knowledge about the molecular alterations of intraductal carcinoma of the prostate.Intraductal carcinoma of the prostate (IDC-P) is one of the most aggressive types of prostate cancer (PCa). IDC-P is identified in approximately 20% of PCa patients and is associated with recurrence, metastasis, and PCa-specific death. The main feature of this histological variant is the colonization of benign glands by PCa cells. Although IDC-P is a well-recognized independent parameter for metastasis, mechanisms by which IDC-P cells can spread and colonize other tissues are not fully known. In this review, we discuss the molecular portraits of IDC-P determined by immunohistochemistry and genomic approaches and highlight the areas in which more research is needed.

Improved survival with post-diagnostic metformin and statin use in a racially diverse cohort of US Veterans with advanced prostate cancer.

To examine the association between post-diagnostic metformin or statin use with all-cause and prostate cancer (PCa)-specific mortality in men with advanced prostate cancer. Our study consisted of 4572 men (Black = 1352, White = 3192, Other Race = 28) diagnosed with advanced cancer (T4/M1/N1) between 1999 and 2013 in the Veteran Health Administration. The association between post-diagnostic (1) metformin and (2) statin use with all-cause and PCa-specific mortality was examined using multivariable, time-varying Cox Proportional Hazard Models. In a secondary analysis, models were stratified by race. Post-diagnostic metformin use was associated with a reduced risk of all-cause (Hazard Ratio (HR) 0.84, 95% Confidence Interval (CI): 0.73, 0.96) and PCa-specific death (HR: 0.76, 95% CI: 0.63, 0.91). In stratified analyses, the inverse association between post-diagnostic metformin use and both all-cause PCa-specific mortality was limited to White men. Post-diagnostic statin use was associated with a reduced risk of all-cause (HR: 0.75, 95% CI: 0.68, 0.83) and PCa-specific mortality (HR: 0.72; 95% CI: 0.64, 0.81). In stratified analyses, similar inverse associations were observed for post-diagnostic statin use and all-cause and PCa-specific mortality in both Black and White men. Post diagnostic metformin and statin use may prevent progression to lethal prostate cancer in men with advanced prostate cancer.

MP11-17 P-SCORE BASED ON THREE EMBRYONIC STEM CELL GENES IMPROVES PROGNOSTIC EVALUATION FOR METASTASIS AND DEATH IN PROSTATE CANCER - A RETROSPECTIVE VALIDATION STUDY

You have accessJournal of UrologyProstate Cancer: Staging (MP11)1 Sep 2021MP11-17 P-SCORE BASED ON THREE EMBRYONIC STEM CELL GENES IMPROVES PROGNOSTIC EVALUATION FOR METASTASIS AND DEATH IN PROSTATE CANCER - A RETROSPECTIVE VALIDATION STUDY Li-Di Xu, Arni Saemundsson, Florian Meisgen, Rong Cao, and Göran Ahlgren Li-Di XuLi-Di Xu More articles by this author , Arni SaemundssonArni Saemundsson More articles by this author , Florian MeisgenFlorian Meisgen More articles by this author , Rong CaoRong Cao More articles by this author , and Göran AhlgrenGöran Ahlgren More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001984.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A previously reported Prostatype algorithm (P-score) incorporating a three-gene signature (IGFBP3, F3, VGLL3) with clinical parameters (Gleason score, PSA and T-stage) was developed and validated in 596 historical patients selected from a population-based cohort. This study aims to retrospectively validate Prostatype algorithms´ capability to predict the risk of metastasis and prostate cancer (PCa) specific mortality in new diagnosed PCa patients. METHODS: All 716 patients included were diagnosed with PCa using core needle biopsy from January 2008 to December 2010 at Skåne University hospital Malmö and Lund Sweden with a follow-up time 8-10 years after diagnosis. Gene expression was assessed by RT-qPCR on all core needle biopsies from diagnosis. A predefined genes score was computed from the expression of the three-gene signature and then combined with clinical parameters (Gleason score, PSA and T-stage) to calculate the P-score (units: 0-15). Cox proportional hazard regression models were used to evaluate the association of gene signature with clinical outcomes. The risk stratification of the score system was evaluated by Kaplan-Meier curve. The receiver operating characteristic analysis and decision-curve analysis were used to assess the prediction accuracy and the net-benefit, respectively. Analysis results were compared to known risk scores such as D´Amico. RESULTS: Total 365 had valid data, 316 patients were without metastasis at diagnosis, 47 had secondary metastasis during follow up and 33 died due to PCa. All patients that died had a high P-score. The gene signature added significant prognostic information for metastasis (p<0.01) and PCa-specific death (p<0.01). One unit change in P-score has a hazard ratio (HR) of 1.6(95% CI: 1.41-1.82, p<0.0001) for predicting PCa death and HR of 1.48 (95% CI: 1.35-1.63, p<0.0001) for predicting PCa-specific death. P-score was significantly better than D´Amico for predicting end-point PCa death (0.89 v.s 0.77, p<0,0001) and metastasis (0.86 v.s 0.77, p<0,0001), unrelated to which treatment was given. Gene signature alone showed a similar prediction power as D’Amico for both end-points. P-score has a much higher net-benefit than D’Amico as revealed by decision curve analysis. CONCLUSIONS: P-score gave improved prognostic evaluation for metastasis and death in PCa compared to other known risk indicators. P-score can be a beneficial tool when treatment decision is made for patients with localised PCa. Source of Funding: Prostatype Genomics sponsored for the data collection © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e186-e186 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Li-Di Xu More articles by this author Arni Saemundsson More articles by this author Florian Meisgen More articles by this author Rong Cao More articles by this author Göran Ahlgren More articles by this author Expand All Advertisement Loading ...

Active Surveillance for Incidental (cT1a/b) Prostate Cancer: Long-Term Outcomes of the Prospective Noninterventional HAROW Study

Introduction: Optimal treatment for incidental prostate cancer (IPC) after surgical treatment for benign prostate obstruction is still debatable. We report on long-term outcomes of IPC patients managed with active surveillance (AS) in a German multicenter study. Methods: HAROW (2008–2013) was designed as a noninterventional, prospective, health-service research study for patients with localized prostate cancer (≤cT2), including patients with IPC (cT1a/b). A follow-up examination of all patients treated with AS was carried out. Overall, cancer-specific, and metastasis-free survival and discontinuation rates were determined. Results: Of 210 IPC patients, 68 opted for AS and were available for evaluation. Fifty-four patients had cT1a category and 14 cT1b category. Median follow-up was 7.7 years (IQR: 5.7–9.1). Eight patients died of which 6 were still under AS or watchful waiting (WW). No PCa-specific death could be observed. One patient developed metastasis. Twenty-three patients (33.8%) discontinued AS changing to invasive treatment: 12 chose radical prostatectomy, 7 radiotherapy, and 4 hormonal treatment. Another 19 patients switched to WW. The Kaplan-Meier estimated 10-year overall, cancer-specific, metastasis-free, and intervention-free survival was 83.8% (95% CI: 72.2–95.3), 100%, 98.4% (95% CI: 95.3–99.9), and 61.0% (95% CI: 47.7–74.3), respectively. In multivariable analysis, age (RR: 0.97; p < 0.001), PSA density ≥0.2 ng/mL² (RR: 13.23; p < 0.001), and PSA ≥1.0 ng/mL after surgery (RR: 5.19; p = 0.016) were significantly predictive for receiving an invasive treatment. Conclusion: In comparison with other AS series with a general low-risk prostate cancer population, our study confirmed the promising survival outcomes for IPC patients, whereas discontinuation rates seem to be lower for IPC. Thus, IPC patients at low risk of progression may be good candidates for AS.

Neuropeptide Y nerve paracrine regulation of prostate cancer oncogenesis and therapy resistance.

BackgroundNerves are key factors in prostate cancer (PCa) progression. Here, we propose that neuropeptide Y (NPY) nerves are key regulators of cancer–nerve interaction.MethodsWe used in vitro models for NPY inhibition studies and subsequent metabolomics, apoptotic and migration assays, and nuclear transcription factor‐κB (NF‐κB) translocation studies. Human naïve and radiated PCa tissues were used for NPY nerve density biomarker studies. Tissues derived from a Botox denervation clinical trial were used to corroborate metabolomic changes in humans.ResultsCancer cells increase NPY positive nerves in vitro and in preneoplastic human tissues. NPY‐specific inhibition resulted in increased cancer apoptosis, decreased motility, and energetic metabolic pathway changes. A comparison of metabolomic response in NPY‐inhibited cells with the transcriptome response in human PCa patients treated with Botox showed shared 13 pathways, including the tricarboxylic acid cycle. We identified that NF‐κB is a potential NPY downstream mediator. Using in vitro models and tissues derived from a previous human chemical denervation study, we show that Botox specifically, but not exclusively, inhibits NPY in cancer. Quantification of NPY nerves is independently predictive of PCa‐specific death. Finally, NPY nerves might be involved in radiation therapy (RT) resistance, as radiation‐induced apoptosis is reduced when PCa cells are cocultured with dorsal root ganglia/nerves and NPY positive nerves are increased in prostates of patients that failed RT.ConclusionThese data suggest that targeting the NPY neural microenvironment may represent a therapeutic approach for the treatment of PCa and resistance through the regulation of multiple oncogenic mechanisms.

Feasibility and performance of a novel probe panel to detect somatic DNA copy number alterations in clinical specimens for predicting prostate cancer progression.

To assess the feasibility of a novel DNA-based probe panel to detect copy number alterations (CNAs) in prostate tumor DNA and its performance for predicting clinical progression. A probe panel was developed and optimized to measure CNAs in trace amounts of tumor DNA (2 ng) isolated from formalin-fixed paraffin-embedded tissues. Ten genes previously associated with aggressive disease were targeted. The panel's feasibility and performance were assessed in 175 prostate cancer (PCa) patients who underwent radical prostatectomy with a median 10-year follow-up, including 42 men who developed disease progression (either metastasis and/or PCa-specific death). Association with disease progression was tested using univariable and multivariable analyses. The probe panel detected CNAs in all 10 genes in tumor DNA isolated from either diagnostic biopsies or surgical specimens. A four-gene model (PTEN/MYC/BRCA2/CDKN1B) had the strongest association with disease progression; 64.3% of progressors and 22.5% of non-progressors had at least one CNA in these four genes, odds ratio (OR) (95% confidence interval) = 6.21 (2.77-13.87), P = 8.48E-06. The association with disease progression remained significant after adjusting for known clinicopathological variables. Among the seven progressors of the 65 patients with clinically low-risk disease, three (42.9%) had at least one CNA in these four genes. The probe panel can detect CNAs in trace amounts of tumor DNA from biopsies or surgical tissues at the time of diagnosis or surgery. CNAs independently predict metastatic/lethal cancer, particularly among men with clinically low-risk disease at diagnosis. If validated, this may improve current abilities to assess tumor aggressiveness.