Addressing racial disparities in prostate cancer pathology prediction models: external validation and comparison of four models of pathological outcome prediction before radical prostatectomy in the multiethnic SEARCH cohort.

BACKGROUND: Certain widely used pathological outcome prediction models that were developed in tertiary centers tend to overpredict outcomes in the community setting; thus, the Michigan Urological-Surgery Improvement Collaborative (MUSIC) model was developed in general urology practice to address this issue. Additionally, the development of these models involved a relatively small proportion of Black men, potentially compromising the accuracy of predictions in this patient group. We tested the validity of the MUSIC and three widely used nomograms to compare their overall and race-stratified predictive performance. METHODS: We extracted data from 4139 (1138 Black) men from the Shared Equal Access Regional Cancer Hospital (SEARCH) database of the Veterans Affairs health system. The predictive performance of the MUSIC model was compared to the Memorial-Sloan Kettering (MSK), Briganti-2012, and Partin-2017 models for predicting lymph-node invasion (LNI), extra-prostatic extension (EPE), and seminal vesicle invasion (SVI). RESULTS: The median PSA of Black men was higher than White men (7.8 vs. 6.8 ng/ml), although they were younger by a median of three years and presented at a lower-stage disease. MUSIC model showed comparable discriminatory capacity (AUC:77.0%) compared to MSK (79.2%), Partin-2017 (74.6%), and Briganti-2012 (76.3%), with better calibration for LNI. AUCs for EPE and SVI were 72.7% and 76.9%, respectively, all comparable to the MSK and Partin models. LNI AUCs for Black and White men were 69.6% and 79.6%, respectively, while EPE and SVI AUCs were comparable between races. EPE and LNI had worse calibration in Black men. Decision curve analysis showed MUSIC superiority over the MSK model in predicting LNI, especially among Black men. CONCLUSION: Although the discriminatory performance of all models was comparable for each outcome, the MUSIC model exhibited superior net benefit to the MSK model in predicting LNI outcomes among Black men in the SEARCH population.

Do Hispanic Puerto Rican men have worse outcomes after radical prostatectomy? Results from SEARCH.

BACKGROUND: We previously reported that outcomes after radical prostatectomy (RP) were similar among non-Hispanic Black, non-Hispanic White, and Hispanic White Veterans Affairs (VA) patients. However, prostate cancer (PC) mortality in Puerto Rican Hispanics (PRH) may be higher than in other Hispanic groups. Data focused on PRH patients is sparse; thus, we tested the association between PR ethnicity and outcomes after RP. METHODS: Analysis included men in SEARCH cohort who underwent RP (1988-2020, n = 8311). PRH patients (n = 642) were treated at the PR VA, and outcomes were compared to patients treated in the Continental US regardless of race. Logistic regression was used to test the associations between PRH and PC aggressiveness, adjusting for demographic and clinicopathological features. Multivariable Cox models were used to investigate PRH versus Continental differences in biochemical recurrence (BCR), metastases, castration-resistant PC (CRPC), and PC-specific mortality (PCSM). RESULTS: Compared to Continental patients, PRH patients had lower adjusted odds of pathological grade group ≥2 (p < 0.001), lymph node metastasis (p < 0.001), and positive margins (p < 0.001). In contrast, PRH patients had higher odds of extracapsular extension (p < 0.001). In Cox models, PRH patients had a higher risk for BCR (HR = 1.27, p < 0.001), metastases (HR = 1.49, p = 0.014), CRPC (HR = 1.80, p = 0.001), and PCSM (HR = 1.74, p = 0.011). Further adjustment for extracapsular extension and other pathological variables strengthened these findings. CONCLUSIONS: In an equal access setting, PRH RP patients generally had better pathological features, but despite this, they had significantly worse post-treatment outcomes than men from the Continental US, regardless of race. The reasons for the poorer prognosis among PRH men require further research.

Initial Experience with 68Ga-FAP-2286 PET Imaging in Patients with Urothelial Cancer.

Improved imaging modalities are needed to accurately stage patients with muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma. Imaging with small-molecule ligands or inhibitors of fibroblast activation protein (FAP) is a promising modality that has demonstrated initial efficacy across a broad range of tumors. We present our experience with the novel FAP-peptide binder 68Ga-FAP-2286 in patients with MIBC. Methods: Patients with histopathologically confirmed bladder cancer who had either localized disease at diagnosis (localized cohort, n = 13) or known metastatic disease (metastatic cohort, n = 8) were imaged with 68Ga-FAP-2286 PET as part of a clinical trial (NCT04621435). The SUVmax of 68Ga-FAP-2286 PET-positive lesions and lesion size were documented. In patients who had available 18F-FDG PET performed within 45 d of 68Ga-FAP-2286 PET (n = 5), uptake on the 2 scans was compared. When there was a discrepancy between imaging modalities on retrospective review, biopsy of suggestive lesions was performed as the standard of care. Results: In the metastatic and localized cohorts, 36 and 18 68Ga-FAP-2286-avid lesions, respectively, were identified across multiple anatomic locations, including lymph nodes, visceral metastases, and bones. Fourteen of 36 lesions in the metastatic cohort and 14 of 18 lesions in the localized cohort were lymph nodes measuring less than 1 cm. Among lesions measuring less than 0.5 cm, 0.5-1 cm, and more than 1 cm, average SUVmax was 5.2 ± 2.6, 9.6 ± 3.7, and 13.0 ± 4.3, respectively, in the metastatic cohort and 10.5 ± 5.1, 10.8 ± 5.7, and 9.9 ± 5.4, respectively, in the localized cohort. Five patients had 18F-FDG PET available for comparison. The average SUVmax for lesions avid on 68Ga-FAP-2286 PET and 18F-FDG PET was 9.9 ± 3.4 versus 4.2 ± 1.9, respectively (n = 16 lesions). For 3 patients in the localized cohort, 68Ga-FAP-2286 PET informed clinical management, including identification of both false-positive findings on 18F-FDG PET and false-negative findings on conventional CT. Conclusion: 68Ga-FAP-2286 imaging is highly sensitive in patients with urothelial cancer and is effective in identifying metastatic lesions across a variety of anatomic sites, including subcentimeter lymph nodes that would not have raised suspicion on conventional scans. This novel imaging modality may inform clinical decision-making in patients with MIBC both by refining local nodal staging and by defining metastatic disease that would otherwise be undetectable on conventional imaging.

The impact of genomic biomarkers on a clinical risk prediction model for upgrading/upstaging among men with favorable-risk prostate cancer.

BACKGROUND: The challenge of distinguishing indolent from aggressive prostate cancer (PCa) complicates decision-making for men considering active surveillance (AS). Genomic classifiers (GCs) may improve risk stratification by predicting end points such as upgrading or upstaging (UG/US). The aim of this study was to assess the impact of GCs on UG/US risk prediction in a clinicopathologic model. METHODS: Participants had favorable-risk PCa (cT1-2, prostate-specific antigen [PSA] ≤15 ng/mL, and Gleason grade group 1 [GG1]/low-volume GG2). A prediction model was developed for 864 men at the University of California, San Francisco, with standard clinical variables (cohort 1), and the model was validated for 2267 participants from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (cohort 2). Logistic regression was used to compute the area under the receiver operating characteristic curve (AUC) to develop a prediction model for UG/US at prostatectomy. A GC (Oncotype Dx Genomic Prostate Score [GPS] or Prolaris) was then assessed to improve risk prediction. RESULTS: The prediction model included biopsy GG1 versus GG2 (odds ratio [OR], 5.83; 95% confidence interval [CI], 3.73-9.10); PSA (OR, 1.10; 95% CI, 1.01-1.20; per 1 ng/mL), percent positive cores (OR, 1.01; 95% CI, 1.01-1.02; per 1%), prostate volume (OR, 0.98; 95% CI, 0.97-0.99; per mL), and age (OR, 1.05; 95% CI, 1.02-1.07; per year), with AUC 0.70 (cohort 1) and AUC 0.69 (cohort 2). GPS was associated with UG/US (OR, 1.03; 95% CI, 1.01-1.06; p < .01) and AUC 0.72, which indicates a comparable performance to the prediction model. CONCLUSIONS: GCs did not substantially improve a clinical prediction model for UG/US, a short-term and imperfect surrogate for clinically relevant disease outcomes.

Amount of Gleason Pattern 3 Is Not Predictive of Risk in Grade Group 2-4 Prostate Cancer.

We investigated whether total Gleason pattern 3 or the proportion of Gleason pattern 4 on biopsy is a significant predictor of adverse pathology. Our findings suggest that quantifying the amount rather than the proportion of Gleason pattern 4 would improve grade group assignment for decision-making in localized prostate cancer.

Patient experiences with tissue-based genomic testing during active surveillance for prostate cancer.

Background: Tissue-based gene expression (genomic) tests provide estimates of prostate cancer aggressiveness and are increasingly used for patients considering or engaged in active surveillance. However, little is known about patient experiences with genomic testing and its role in their decision-making. Methods: We performed a qualitative study consisting of in-depth, semi-structured interviews of patients with low- or favourable-intermediate-risk prostate cancer managed with active surveillance. We purposively sampled to include patients who received biopsy-based genomic testing as part of clinical care. The interview guide focused on experiences with genomic testing during patients' decision-making for prostate cancer management and understanding of genomic test results. We continued interviews until thematic saturation was reached, iteratively created a code key and used conventional content analysis to analyse data. Results: Participants' (n = 20) mean age was 68 years (range 51-79). At initial biopsy, 17 (85%) had a Gleason grade group 1, and 3 (15%) had a grade group 2 prostate cancer. The decision to undergo genomic testing was driven by both participants and physicians' recommendations; however, some participants were unaware that testing had occurred. Overall, participants understood the role of genomic testing in estimating their prostate cancer risk, and the test results increased their confidence in the decision for active surveillance. Participants had some misconceptions about the difference between tissue-based gene expression tests and germline genetic tests and commonly believed that tissue-based tests measured hereditary cancer risk. While some participants expressed satisfaction with their physicians' explanations, others felt that communication was limited and lacked sufficient detail. Conclusion: Patients interact with and are influenced by the results of biopsy-based genomic testing during active surveillance for prostate cancer, despite gaps in understanding about test results. Our findings indicate areas for improvement in patient counselling in order to increase patient knowledge and comfort with genomic testing.

How older men live with stress urinary incontinence: Patient experience and navigation to treatment.

OBJECTIVES: To explore the context in which older men navigate treatment for stress urinary incontinence (SUI) following prostate surgery by characterizing lived experience of men with symptomatic SUI. SUBJECTS/PATIENTS AND METHODS: Mixed method study using surveys and semistructured interviews to examine a cohort of men who underwent evaluation for treatment of postprostatectomy SUI. RESULTS: Thirty-six men were interviewed after consultation for SUI and 31 had complete quantitative clinical data. Twenty-six underwent surgery and 10 chose no surgical intervention. In qualitative interviews, respondents experienced substantial decline in quality of life due to incontinence citing concerns associated with use of pads and worrying about incontinence. Most patients reported "workarounds"-efforts to mitigate or manage incontinence including Kegels, physical therapy, and garments. Participants also reported lifestyle changes including less strenuous physical activity, less sexual activity, and/or fewer social gatherings. Patients then described a "breaking point" where incontinence workarounds were no longer sufficient. After seeking evaluation, men described challenges in exploring treatment for SUI, including access to care and provider knowledge of treatment options. CONCLUSION: In a novel study of patients living with SUI a predictable lived experience was observed that culminated in a desire for change or "breaking point." In all men, this led to treatment-seeking behaviors and for many it led to SUI intervention. Despite effective treatments, patients continue to meet barriers gaining access to SUI evaluation and treatment.

Patient and physician perspectives on treatments for low-risk prostate cancer: a qualitative study.

BACKGROUND: Patients diagnosed with low-risk prostate cancer (PCa) are confronted with a difficult decision regarding whether to undergo definitive treatment or to pursue an active surveillance protocol. This is potentially further complicated by the possibility that patients and physicians may place different value on factors that influence this decision. We conducted a qualitative investigation to better understand patient and physician perceptions of factors influencing treatment decisions for low-risk PCa. METHODS: Semi-structured interviews were conducted among 43 racially and ethnically diverse patients diagnosed with low-risk PCa, who were identified through a population-based cancer registry, and 15 physicians who were selected to represent a variety of practice settings in the Greater San Francisco Bay Area. RESULTS: Patients and physicians both described several key individual (e.g., clinical) and interpersonal (e.g., healthcare communications) factors as important for treatment decision-making. Overall, physicians' perceptions largely mirrored patients' perceptions. First, we observed differences in treatment preferences by age and stage of life. At older ages, there was a preference for less invasive options. However, at younger ages, we found varying opinions among both patients and physicians. Second, patients and physicians both described concerns about side effects including physical functioning and non-physical considerations. Third, we observed differences in expectations and the level of difficulty for clinical conversations based on information needs and resources between patients and physicians. Finally, we discovered that patients and physicians perceived patients' prior knowledge and the support of family/friends as facilitators of clinical conversations. CONCLUSIONS: Our study suggests that the gap between patient and physician perceptions on the influence of clinical and communication factors on treatment decision-making is not large. The consensus we observed points to the importance of developing relevant clinical communication roadmaps as well as high quality and accessible patient education materials.

The Impact of Delayed Radical Prostatectomy on Recurrence Outcomes After Initial Active Surveillance: Results from a Large Institutional Cohort.

BACKGROUND AND OBJECTIVE: Active surveillance (AS) of prostate cancer (PCa) involves regular monitoring for disease progression. The aim is to avoid unnecessary treatment while ensuring appropriate and timely treatment for those whose disease progresses. AS has emerged as the standard of care for low-grade (Gleason grade 1, GG 1) PCa. Opponents are concerned that initial undersampling and delay of definitive management for patients with GG 2 disease may lead to adverse outcomes. We sought to determine whether the timing for definitive management of GG 2 PCa, either upfront or after initial AS, affects recurrence outcomes after radical prostatectomy (RP). METHODS: Participants were diagnosed with cT1-2N0/xM0/x, prostate-specific antigen (PSA) <20 ng/ml, and GG 1-2 PCa between 2000 and 2020 and underwent immediate RP for GG 2 or AS followed by delayed RP on upgrading to GG 2. The outcome was recurrence-free survival (RFS) after surgery, with recurrence defined as either biochemical failure (2 PSA measurements ≥0.2 ng/ml) or a second treatment. Multivariable Cox proportional-hazards regression models were used to calculate associations between the timing for definitive RP and the risk of recurrence, adjusted for age at diagnosis, percentage of positive biopsy cores (PPC), PSA density, PSA before RP, year of diagnosis, surgical margins, genomic risk score, and prostate MRI findings. KEY FINDINGS: Of the 1259 men who met the inclusion criteria, 979 underwent immediate RP after diagnosis of GG 2, 190 underwent RP within 12 mo of upgrading to GG 2 on AS, and 90 men underwent RP >12 mo after upgrading to GG 2. The 5-yr RFS rates were 81% for the immediate RP group, 80% for the delayed RP ≤12 mo, and 70% for the delayed RP >12 mo group (univariate log-rank p = 0.03). Cox multivariable regression demonstrated no difference in RFS outcomes between immediate RP for GG 2 disease and delayed RP after upgrading on AS. PPC (hazard ratio [HR] per 10% increment 1.08, 95% confidence interval [CI] 1.02-1.15; p = 0.01) and PSA before RP (HR 1.06, 95% CI 1.03-1.09; p < 0.01) were significantly associated with the risk of recurrence. CONCLUSIONS AND CLINICAL IMPLICATIONS: PPC and PSA before RP, but not the timing of definitive surgery after upgrade to GG 2, were associated with the risk of PCa recurrence after RP on multivariable analysis. These findings support the safety of AS and delayed definitive therapy for a subset of patients with GG 2 disease. PATIENT SUMMARY: In a large group of 1259 patients with low-grade prostate cancer, we found that delaying surgical treatment after an initial period of active surveillance resulted in no differences in prostate cancer recurrence. Our results support the safety of active surveillance for low-grade prostate cancer.

Prostate cancer risk stratification using magnetic resonance imaging-ultrasound fusion vs systematic prostate biopsy.

BACKGROUND: Image-guided approaches improve the diagnostic yield of prostate biopsy and frequently modify estimates of clinical risk. To better understand the impact of magnetic resonance imaging-ultrasound fusion targeted biopsy (MRF-TB) on risk assessment, we compared the distribution of National Comprehensive Cancer Network (NCCN) risk groupings, as calculated from MRF-TB vs systematic biopsy alone. METHODS: We performed a retrospective analysis of 713 patients who underwent MRF-TB from January 2017 to July 2021. The primary study objective was to compare the distribution of National Comprehensive Cancer Network risk groupings obtained using MRF-TB (systematic + targeted) vs systematic biopsy. RESULTS: Systematic biopsy alone classified 10% of samples as very low risk and 18.7% of samples as low risk, while MRF-TB classified 10.5% of samples as very low risk and 16.1% of samples as low risk. Among patients with benign findings, low-risk disease, and favorable/intermediate-risk disease on systematic biopsy alone, 4.6% of biopsies were reclassified as high risk or very high risk on MRF-TB. Of 207 patients choosing active surveillance, 64 (31%), 91 (44%), 42 (20.2%), and 10 (4.8%) patients were classified as having very low-risk, low-risk, and favorable/intermediate-risk and unfavorable/intermediate-risk criteria, respectively. When using systematic biopsy alone, 204 patients (28.7%) were classified as having either very low-risk and low-risk disease per NCCN guidelines, while 190 men (26.6%) received this classification when using MRF-TB. CONCLUSION: The addition of MRF-TB to systematic biopsy may change eligibility for active surveillance in only a small proportion of patients with prostate cancer. Our findings support the need for routine use of quantitative risk assessment over risk groupings to promote more nuanced decision making for localized cancer.

Long-term Prostate Cancer-specific Mortality After Prostatectomy, Brachytherapy, External Beam Radiation Therapy, Hormonal Therapy, or Monitoring for Localized Prostate Cancer.

BACKGROUND: The optimal treatment of localized prostate cancer (PCa) remains controversial. OBJECTIVE: To compare long-term survival among men who underwent radical prostatectomy (RP), brachytherapy (BT), external beam radiation therapy (EBRT), primary androgen deprivation therapy (PADT), or monitoring (active surveillance [AS]/watchful waiting [WW]) for PCa. DESIGN, SETTING, AND PARTICIPANTS: This is a cohort study with long-term follow-up from the multicenter, prospective, largely community-based Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. Men with biopsy-proven, clinical T1-3aN0M0, localized PCa were consecutively accrued within 6 mo of diagnosis and had clinical risk data and at least 12 mo of follow-up after diagnosis available. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PCa risk was assessed, and multivariable analyses were performed to compare PCa-specific mortality (PCSM) and all-cause mortality by primary treatment, with extensive adjustment for age and case mix using the Cancer of the Prostate Risk Assessment (CAPRA) score and a well-validated nomogram. RESULTS AND LIMITATIONS: Among 11 864 men, 6227 (53%) underwent RP, 1645 (14%) received BT, 1462 (12%) received EBRT, 1510 (13%) received PADT, and 1020 (9%) were managed with AS/WW. At a median of 9.4 yr (interquartile range 5.8-13.7) after treatment, 764 men had died from PCa. After adjusting for CAPRA score, the hazard ratios for PCSM with RP as the reference were 1.57 (95% confidence interval [CI] 1.24-1.98; p < 0.001) for BT, 1.55 (95% CI 1.26-1.91; p < 0.001) for EBRT, 2.36 (95% CI 1.94-2.87; p < 0.001) for PADT, and 1.76 (95% CI 1.30-2.40; p < 0.001) for AS/WW. In models for long-term outcomes, PCSM differences were negligible for low-risk disease and increased progressively with risk. Limitations include the evolution of diagnostic and therapeutic strategies for PCa over time. In this nonrandomized study, the possibility of residual confounding remains salient. CONCLUSIONS: In a large, prospective cohort of men with localized PCa, after adjustment for age and comorbidity, PCSM was lower after local therapy for those with higher-risk disease, and in particular after RP. Confirmation of these results via long-term follow-up of ongoing trials is awaited. PATIENT SUMMARY: We evaluated different treatment options for localized prostate cancer in a large group of patients who were treated mostly in nonacademic medical centers. Results from nonrandomized trials should be interpret with caution, but even after careful risk adjustment, survival rates for men with higher-risk cancer appeared to be highest for patients whose first treatment was surgery rather than radiotherapy, hormones, or monitoring.

Effect of a Home-based Walking Intervention on Cardiopulmonary Fitness and Quality of Life Among Men with Prostate Cancer on Active Surveillance: The Active Surveillance Exercise Randomized Controlled Trial.

BACKGROUND: Active surveillance (AS) is standard care for most men with low-risk prostate cancer (PC); yet, many men on AS eventually undergo curative therapy. Interventions to lower the risk of cancer progression and fear of recurrence among men on AS for PC are needed. OBJECTIVE: To determine the effect of aerobic exercise on cardiorespiratory fitness, body size, and quality of life (QOL) among men on AS for PC. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 1:1 randomized controlled trial among 51 men with low-risk PC who elected AS. Participants were enrolled at the University of California, San Francisco. INTERVENTION: The 16-wk intervention included a home-based walking program with a nonlinear exercise prescription tailored to baseline fitness level, heart rate monitor, and weekly phone call with an exercise physiologist. Controls received printed materials. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cardiorespiratory fitness was measured using VO2peak; secondary outcomes included change in body size, anxiety, and QOL. Analyses were based on intention to treat. RESULTS AND LIMITATIONS: Between 2016 and 2021, we randomized 51 men to intervention (n = 26) or control (n = 25). Follow-up was 88% (45/51), 85% (22/26) in the intervention and 92% (23/25) in the control group. At 16 wk, the intervention group had a higher mean VO2peak than the control group (31.9 ± 4.7 vs 27.2 ± 4.8 ml/kg/min; group × time effect p value: <0.001). Additionally, the intervention group reported less fear of PC recurrence and urinary obstruction/irritation, while controls reported more of these two QOL measures, from 0 to 16 wk (p = 0.04 and 0.03, respectively). Two participants discontinued the intervention, including one due to knee pain related to the study. CONCLUSIONS: A home-based walking program improved VO2peak and reduced urinary obstruction/irritation and fear of recurrence among men on AS for PC. PATIENT SUMMARY: Moderate to vigorous aerobic exercise improves fitness and quality of life among men on active surveillance for prostate cancer.

Ten-year work burden after prostate cancer treatment.

INTRODUCTION: We aim to characterize the magnitude of the work burden (weeks off from work) associated with prostate cancer (PCa) treatment over a 10-year period after PCa diagnosis and identify those at greatest risk. MATERIALS AND METHODS: We identified men diagnosed with PCa treated with radical prostatectomy, radiation therapy, or active surveillance/watchful waiting within CaPSURE. Patients self-reported work burden and SF36 general health scores via surveys before and 1,3,5, and 10 years after treatment. Using multivariate repeated measures generalized estimating equation modeling we examined the association between primary treatment with risk of any work weeks lost due to care. RESULTS: In total, 6693 men were included. The majority were White (81%, 5% Black, and 14% Other) with CAPRA low- (60%) or intermediate-risk (32%) disease and underwent surgery (62%) compared to 29% radiation and 9% active surveillance. Compared to other treatments, surgical patients were more likely to report greater than 7 days off work in the first year, with relatively less time off over time. Black men (RR 0.64, 95% CI 0.54-0.77) and those undergoing radiation (vs. surgery, RR 0.46, 95% CI 0.41-0.51) were less likely to report time off from work over time. Mean baseline GH score (73 [SD 18]) was similar between race and treatment groups, and stable over time. CONCLUSIONS: The work burden of cancer care continued up to 10 years after treatment and varied across racial groups and primary treatment groups, highlighting the multifactorial nature of this issue and the call to leverage greater resources for those at greatest risk.

Club-like cells in proliferative inflammatory atrophy of the prostate.

Club cells are a type of bronchiolar epithelial cell that serve a protective role in the lung and regenerate damaged lung epithelium. Single-cell RNA sequencing (scRNA-seq) of young adult human prostate and urethra identified cell populations in the prostatic urethra and collecting ducts similar in morphology and transcriptomic profile to lung club cells. We further identified club cell-like epithelial cells by scRNA-seq of prostate peripheral zone tissues. Here, we aimed to identify and spatially localize club cells in situ in the prostate, including in the peripheral zone. We performed chromogenic RNA in situ hybridization for five club cell markers (CP, LTF, MMP7, PIGR, SCGB1A1) in a series of (1) nondiseased organ donor prostate and (2) radical prostatectomy specimens from individuals with prostate cancer. We report that expression of club cell genes in the peripheral zone is associated with inflammation and limited to luminal epithelial cells classified as intermediate cells in proliferative inflammatory atrophy (PIA). Club-like cells were enriched in radical prostatectomy specimens compared to nondiseased prostates and associated with high-grade prostate cancer. We previously reported that luminal epithelial cells in PIA can rarely harbor oncogenic TMPRSS2:ERG (ERG+) gene fusions, and we now demonstrate that club cells are present in association with ERG+ PIA that is transitioning to early adenocarcinoma. Finally, prostate epithelial organoids derived from prostatectomy specimens demonstrate that club-like epithelial cells can be established in organoids and are sensitive to anti-androgen-directed treatment in vitro in terms of decreased androgen signaling gene expression signatures compared to basal or hillock cells. Overall, our study identifies a population of club-like cells in PIA and proposes that these cells play an analogous role to that of club cells in bronchiolar epithelium. Our results further suggest that inflammation drives lineage plasticity in the human prostate and that club cells in PIA may be prone to oncogenic transformation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Long-term complications and health-related quality of life outcomes after radical prostatectomy with or without subsequent radiation treatment for prostate cancer.

BACKGROUND: To report objective long-term complications and health related quality of life (HRQOL) outcomes after radical prostatectomy (RP) with and without radiation therapy (RT) for prostate cancer (CaP). METHODS: We analyzed patients diagnosed with CaP who underwent RP from the UCSF Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry between 1995 and 2020. Cox proportional hazards were used to assess risk of postoperative complications which included cystitis, gastrointestinal (GI) toxicity, incontinence requiring a surgical procedure, ureteral injury and urinary stricture. Repeated measures mixed models were used to assess the effects of radiation and complications on patient-reported urinary, bowel, and sexual function after surgery. RESULTS: Of 6,258 men who underwent RP, cumulative incidence of EBRT was 9.1% at 5 years after surgery. Patients who received postoperative radiation were at increased risk for onset of cystitis (HR 5.60, 95% CI 3.40-9.22, P < 0.01). Receipt of RT was not associated with other complications. In repeated measures analysis, postoperative RT was associated with worsening general health scores, adjusting for complications of incontinence, urinary stricture, GI toxicity or ureteral injury, independent of whether patients had those complications. CONCLUSIONS: RT after RP was associated with an increase in the risk of cystitis and worse general health in the long term. Other complications and HRQOL outcomes did not demonstrate differences by whether patients had RT or not. While post-operative RT is the only curative option for CaP after RP, patients and providers should be aware of the increased risks when making treatment decisions.

Transcriptomic Heterogeneity of Expansile Cribriform and Other Gleason Pattern 4 Prostate Cancer Subtypes.

BACKGROUND: Prostate cancers featuring an expansile cribriform (EC) pattern are associated with worse clinical outcomes following radical prostatectomy (RP). However, studies of the genomic characteristics of Gleason pattern 4 subtypes are limited. OBJECTIVE: To explore transcriptomic characteristics and heterogeneity within Gleason pattern 4 subtypes (fused/poorly formed, glomeruloid, small cribriform, EC/intraductal carcinoma [IDC]) and the association with biochemical recurrence (BCR)-free survival. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study including 165 men with grade group 2-4 prostate cancer who underwent RP at a single academic institution (2016-2020) and Decipher testing of the RP specimen. Patients with Gleason pattern 5 were excluded. IDC and EC patterns were grouped. Median follow-up was 2.5 yr after RP for patients without BCR. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Prompted by heterogeneity within pattern 4 subtypes identified via exploratory analyses, we investigated transcriptomic consensus clusters using partitioning around medoids and hallmark gene set scores. The primary clinical outcome was BCR, defined as two consecutive prostate-specific antigen measurements >0.2 ng/ml at least 8 wk after RP, or any additional treatment. Multivariable Cox proportional-hazards models were used to determine factors associated with BCR-free survival. RESULTS AND LIMITATIONS: In this cohort, 99/165 patients (60%) had EC and 67 experienced BCR. Exploratory analyses and clustering demonstrated transcriptomic heterogeneity within each Gleason pattern 4 subtype. In the multivariable model controlled for pattern 4 subtype, margin status, Cancer of the Prostate Risk Assessment Post-Surgical score, and Decipher score, a newly identified steroid hormone-driven cluster (hazard ratio 2.35 95% confidence interval 1.01-5.47) was associated with worse BCR-free survival. The study is limited by intermediate follow-up, no validation cohort, and lack of accounting for intratumoral and intraprostatic heterogeneity. CONCLUSIONS: Transcriptomic heterogeneity was present within and across each Gleason pattern 4 subtype, demonstrating there is additional biologic diversity not captured by histologic subtypes. This heterogeneity can be used to develop novel signatures and to classify transcriptomic subtypes, which may help in refining risk stratification following RP to further guide decision-making on adjuvant and salvage treatments. PATIENT SUMMARY: We studied prostatectomy specimens and found that tumors with similar microscopic appearance can have genetic differences that may help to predict outcomes after prostatectomy for prostate cancer. Our results demonstrate that further gene expression analysis of prostate cancer subtypes may improve risk stratification after prostatectomy. Future studies are needed to develop novel gene expression signatures and validate these findings in independent sets of patients.

Explainable ML models for a deeper insight on treatment decision for localized prostate cancer.

Although there are several decision aids for the treatment of localized prostate cancer (PCa), there are limitations in the consistency and certainty of the information provided. We aimed to better understand the treatment decision process and develop a decision-predicting model considering oncologic, demographic, socioeconomic, and geographic factors. Men newly diagnosed with localized PCa between 2010 and 2015 from the Surveillance, Epidemiology, and End Results Prostate with Watchful Waiting database were included (n = 255,837). We designed two prediction models: (1) Active surveillance/watchful waiting (AS/WW), radical prostatectomy (RP), and radiation therapy (RT) decision prediction in the entire cohort. (2) Prediction of AS/WW decisions in the low-risk cohort. The discrimination of the model was evaluated using the multiclass area under the curve (AUC). A plausible Shapley additive explanations value was used to explain the model's prediction results. Oncological variables affected the RP decisions most, whereas RT was highly affected by geographic factors. The dependence plot depicted the feature interactions in reaching a treatment decision. The decision predicting model achieved an overall multiclass AUC of 0.77, whereas 0.74 was confirmed for the low-risk model. Using a large population-based real-world database, we unraveled the complex decision-making process and visualized nonlinear feature interactions in localized PCa.

Are associations between obesity and prostate cancer outcomes following radical prostatectomy the same in smokers and non-smokers? Results from the SEARCH Cohort.

PURPOSE: Obesity and smoking have been associated with poor prostate cancer (PC) outcomes. We investigated associations between obesity and biochemical recurrence (BCR), metastasis, castrate resistant-PC (CRPC), PC-specific mortality (PCSM), and all-cause mortality (ACM) and examined if smoking modified these associations. METHODS: We analyzed SEARCH Cohort data from men undergoing RP between 1990 and 2020. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between body mass index (BMI) as a continuous variable and weight status classifications (normal: 18.5 ≤ 25 kg/m2; overweight: 25-29.9 kg/m2; obese: ≥ 30 kg/m2) and PC outcomes. RESULTS: Among 6,241 men, 1,326 (21%) were normal weight, 2,756 (44%) overweight and 2159 (35%) obese; 1,841 (30%) were never-smokers, 2,768 (44%) former and 1,632 (26%) current-smokers. Among all men, obesity was associated with non-significant increased risk of PCSM, adj-HR = 1.71; 0.98-2.98, P = 0.057, while overweight and obesity were inversely associated with ACM, adj-HR = 0.75; 0.66-0.84, P < 0.001 and adj-HR = 0.86; 0.75-0.99, P = 0.033, respectively. Other associations were null. BCR and ACM were stratified for smoking status given evidence for interactions (P = 0.048 and P = 0.054, respectively). Among current-smokers, overweight was associated with an increase in BCR (adj-HR = 1.30; 1.07-1.60, P = 0.011) and a decrease in ACM (adj-HR = 0.70; 0.58-0.84, P < 0.001). Among never-smokers, BMI (continuous) was associated with an increase in ACM (adj-HR = 1.03; 1.00-1.06, P = 0.033). CONCLUSIONS: While our results are consistent with obesity as a risk factor for PCSM, we present evidence of effect modification by smoking for BCR and ACM highlighting the importance of stratifying by smoking status to better understand associations with body weight.