Morphologic patterns observed in prostate biopsy cases with discrepant grade group and molecular risk classification.

BACKGROUND: Molecular-based risk classifier tests are increasingly being utilized by urologists and radiation oncologists to guide clinical decision making. The Decipher prostate biopsy test is a 22-gene RNA biomarker assay designed to predict likelihood of high-grade disease at radical prostatectomy and risk of metastasis and mortality. The test provides a risk category of low, intermediate, or high. We investigated histologic features of biopsies in which the Grade Group (GG) and Decipher risk category (molecular risk) were discrepant. METHODS: Our institutional urologic outcomes database was searched for men who underwent prostate biopsies with subsequent Decipher testing from 2016 to 2020. We defined discrepant GG and molecular risk as either GG1-2 with high Decipher risk category or GG ≥ 3 with low Decipher risk category. The biopsy slide on which Decipher testing was performed was re-reviewed for GG and various histologic features, including % Gleason pattern 4, types of Gleason pattern 4 and 5, other "high risk" features (e.g., complex papillary, ductal carcinoma, intraductal carcinoma [IDC]), and other unusual and often "difficult to grade" patterns (e.g., atrophic carcinoma, mucin rupture, pseudohyperplastic carcinoma, collagenous fibroplasia, foamy gland carcinoma, carcinoma with basal cell marker expression, carcinoma with prominent vacuoles, and stromal reaction). Follow-up data was also obtained from the electronic medical record. RESULTS: Of 178 men who underwent prostate biopsies and had Decipher testing performed, 41 (23%) had discrepant GG and molecular risk. Slides were available for review for 33/41 (80%). Of these 33 patients, 23 (70%) had GG1-2 (GG1 n = 5, GG2 n = 18) with high Decipher risk, and 10 (30%) had GG ≥ 3 with low Decipher risk. Of the 5 GG1 cases, one case was considered GG2 on re-review; no other high risk features were identified but each case showed at least one of the following "difficult to grade" patterns: 3 atrophic carcinoma, 1 collagenous fibroplasia, 1 carcinoma with mucin rupture, and 1 carcinoma with basal cell marker expression. Of the 18 GG2 high Decipher risk cases, 2 showed GG3 on re-review, 5 showed large cribriform and/or other high risk features, and 10 showed a "difficult to grade" pattern. Of the 10 GG ≥ 3 low Decipher risk cases, 5 had known high risk features including 2 with large cribriform, 1 with IDC, and 1 with Gleason pattern 5. CONCLUSIONS: In GG1-2 high Decipher risk cases, difficult to grade patterns were frequently seen in the absence of other known high risk morphologic features; whether these constitute true high risk cases requires further study. In the GG ≥ 3 low Decipher risk cases, aggressive histologic patterns such as large cribriform and IDC were observed in half (50%) of cases; therefore, the molecular classifier may not capture all high risk histologic patterns.

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.

Large cribriform glands (> 0.25 mm diameter) as a predictor of adverse pathology in men with Grade Group 2 prostate cancer.

AIMS: A recent outcome-based, radical prostatectomy study defined > 0.25 mm diameter to distinguish large versus small cribriform glands, with > 0.25 mm associated with worse recurrence-free survival. This study evaluates whether identification of > 0.25 mm cribriform glands in Grade Group 2 patients at biopsy is associated with adverse pathology at radical prostatectomy. METHODS AND RESULTS: Tumours containing biopsy slides for 133 patients with Grade Group 2 prostate cancer with subsequent radical prostatectomy were re-reviewed for large cribriform glands (diameter > 0.25 mm). The primary outcome was adverse pathology (Grade Groups 3-5; stage pT3a or greater, or pN1). The secondary outcome was recurrence-free survival. Cribriform pattern was present in 52 of 133 (39%) patients; of these, 16 of 52 (31%) had large cribriform glands and 36 of 52 (69%) had only small cribriform glands. Patients with large cribriform glands had significantly more adverse pathology at radical prostatectomy compared to patients with small cribriform glands and no cribriform glands (large = 11 of 16, 69%; small = 12 of 36, 33%; no cribriform = 25 of 81, 31%; χ2 P-value 0.01). On multivariate analysis, large cribriform glands were also associated with adverse pathology, independent of age, prostate-specific antigen (PSA)/PSA density at diagnosis, year of diagnosis and biopsy cores percentage positive (global P-value 0.02). Large cribriform glands were also associated with increased CAPRA-S surgical risk score (Kruskal-Wallis P-value 0.02). CONCLUSIONS: Large cribriform glands using a diameter > 0.25 mm definition in Grade Group 2 patients on biopsy are associated with increased risk of adverse pathology at radical prostatectomy. The presence of large cribriform histology should be considered when offering active surveillance for those with Grade Group 2 disease.

Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage.

AIMS: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. METHODS AND RESULTS: Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. CONCLUSIONS: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.

Long-Term Outcomes in Patients Using Protocol-Directed Active Surveillance for Prostate Cancer.

Importance: Outcomes from protocol-directed active surveillance for favorable-risk prostate cancers are needed to support decision-making. Objective: To characterize the long-term oncological outcomes of patients receiving active surveillance in a multicenter, protocol-directed cohort. Design, Setting, and Participants: The Canary Prostate Active Surveillance Study (PASS) is a prospective cohort study initiated in 2008. A cohort of 2155 men with favorable-risk prostate cancer and no prior treatment were enrolled at 10 North American centers through August 2022. Exposure: Active surveillance for prostate cancer. Main Outcomes and Measures: Cumulative incidence of biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment in patients treated after the first or subsequent surveillance biopsies. Results: Among 2155 patients with localized prostate cancer, the median follow-up was 7.2 years, median age was 63 years, 83% were White, 7% were Black, 90% were diagnosed with grade group 1 cancer, and median prostate-specific antigen (PSA) was 5.2 ng/mL. Ten years after diagnosis, the incidence of biopsy grade reclassification and treatment were 43% (95% CI, 40%-45%) and 49% (95% CI, 47%-52%), respectively. There were 425 and 396 patients treated after confirmatory or subsequent surveillance biopsies (median of 1.5 and 4.6 years after diagnosis, respectively) and the 5-year rates of recurrence were 11% (95% CI, 7%-15%) and 8% (95% CI, 5%-11%), respectively. Progression to metastatic cancer occurred in 21 participants and there were 3 prostate cancer-related deaths. The estimated rates of metastasis or prostate cancer-specific mortality at 10 years after diagnosis were 1.4% (95% CI, 0.7%-2%) and 0.1% (95% CI, 0%-0.4%), respectively; overall mortality in the same time period was 5.1% (95% CI, 3.8%-6.4%). Conclusions and Relevance: In this study, 10 years after diagnosis, 49% of men remained free of progression or treatment, less than 2% developed metastatic disease, and less than 1% died of their disease. Later progression and treatment during surveillance were not associated with worse outcomes. These results demonstrate active surveillance as an effective management strategy for patients diagnosed with favorable-risk prostate cancer.

PSA density does not improve predictive accuracy of the UCSF-CAPRA score.

INTRODUCTION: The University of California, San Francisco Cancer of the Prostate Risk Assessment (CAPRA) score is a validated tool using factors at diagnosis to predict prostate cancer outcomes after radical prostatectomy (RP). This study evaluates whether substitution of prostate-specific antigen (PSA) density for serum PSA improves predictive performance of the clinical CAPRA model. METHODS: Participants were diagnosed in 2000-2019 with stage T1/T2 cancer, underwent RP, with at least a 6-month follow-up. We computed standard CAPRA score using diagnostic age, Gleason grade, percent positive cores, clinical T stage, and serum PSA, and an alternate score using similar variables but substituting PSA density for PSA. We reported CAPRA categories as low (0-2), intermediate (3-5), and high (6-10) risk. Recurrence was defined as two consecutive PSA ≥ 0.2 ng/mL or receipt of salvage treatment. Life table and Kaplan-Meier analysis evaluated recurrence-free survival after prostatectomy. Cox proportional hazards regression models tested associations of standard or alternate CAPRA variables with recurrence risk. Additional models tested associations between standard or alternate CAPRA score with recurrence risk. Cox log-likelihood ratio test (-2 LOG L) assessed model accuracy. RESULTS: A total of 2880 patients had median age 62 years, GG1 30% and GG2 31%, median PSA 6.5, and median PSA density 0.19. Median postoperative follow-up was 45 months. Alternate CAPRA model was associated with shifts in risk scores, with 16% of patients increasing and 7% decreasing (p < 0.01). Recurrence-free survival after RP was 75% at 5 years and 62% at 10 years. Both CAPRA component models were associated with recurrence risk after RP on Cox regression. Covariate fit statistics showed better fit for standard CAPRA model versus alternate (p < 0.01). Standard (hazard ratio [HR]: 1.55; 95% confidence interval [CI]: 1.50-1.61) and alternate (HR: 1.50; 95% CI: 1.44-1.55) CAPRA scores were associated with recurrence risk, with better fit for standard model (p < 0.01). CONCLUSIONS: In a 2880 patient cohort followed for median 45 months after RP, alternate CAPRA model using PSA density was associated with higher biochemical recurrence (BCR) risk, but performed inferior to standard CAPRA at predicting BCR. While PSA density is an established prognostic variable in prediagnostic settings and sub-stratifying low-risk disease, it does not improve BCR model predictive accuracy when applied across a range of cancer risk.

Post-diagnostic health behaviour scores and risk of prostate cancer progression and mortality.

BACKGROUND: Individual behaviours are associated with prostate cancer (PC) progression. Behavioural scores, comprised of multiple risk factors, allow assessment of the combined impact of multiple behaviours. METHODS: We examined the association between six a priori scores and risk of PC progression and mortality among 2156 men with PC in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) cohort: two scores developed based on the PC survivorship literature ('2021 Score [+ Diet]'); a score developed based on pre-diagnostic PC literature ('2015 Score'); and three scores based on US recommendations for cancer prevention ('WCRF/AICR Score') and survival ('ACS Score [+ Alcohol]'). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for progression and PC mortality via parametric survival models (interval censoring) and Cox models, respectively. RESULTS: Over a median (IQR) of 6.4 (1.3, 13.7) years, we observed 192 progression and 73 PC mortality events. Higher (i.e., healthier) 2021 Score + Diet and WCRF/AICR Scores were inversely associated with risk of PC progression (2021 + Diet: HRcontinuous = 0.76, 95% CI: 0.63-0.90. WCRF/AICR: HRcontinuous = 0.83, 95% CI: 0.67-1.02) and mortality (2021 + Diet: HRcontinuous = 0.65, 95% CI: 0.45-0.93. WCRF/AICR: HRcontinuous = 0.71; 95% CI: 0.57-0.89). The ACS Score + Alcohol was only associated with progression (HRcontinuous = 0.89, 95% CI: 0.81-0.98) while the 2021 Score was only associated with PC mortality (HRcontinuous = 0.62, 95% CI: 0.45-0.85). The 2015 was not associated with PC progression or mortality. CONCLUSION: Findings strengthen the evidence that behavioural modifications following a prostate cancer diagnosis may improve clinical outcomes.

Artificial Intelligence-Based PTEN Loss Assessment as an Early Predictor of Prostate Cancer Metastasis After Surgery: A Multicenter Retrospective Study.

Phosphatase and tensin homolog (PTEN) loss is associated with adverse outcomes in prostate cancer and can be measured via immunohistochemistry. The purpose of the study was to establish the clinical application of an in-house developed artificial intelligence (AI) image analysis workflow for automated detection of PTEN loss on digital images for identifying patients at risk of early recurrence and metastasis. Postsurgical tissue microarray sections from the Canary Foundation (n = 1264) stained with anti-PTEN antibody were evaluated independently by pathologist conventional visual scoring (cPTEN) and an automated AI-based image analysis pipeline (AI-PTEN). The relationship of PTEN evaluation methods with cancer recurrence and metastasis was analyzed using multivariable Cox proportional hazard and decision curve models. Both cPTEN scoring by the pathologist and quantification of PTEN loss by AI (high-risk AI-qPTEN) were significantly associated with shorter metastasis-free survival (MFS) in univariable analysis (cPTEN hazard ratio [HR], 1.54; CI, 1.07-2.21; P = .019; AI-qPTEN HR, 2.55; CI, 1.83-3.56; P < .001). In multivariable analyses, AI-qPTEN showed a statistically significant association with shorter MFS (HR, 2.17; CI, 1.49-3.17; P < .001) and recurrence-free survival (HR, 1.36; CI, 1.06-1.75; P = .016) when adjusting for relevant postsurgical clinical nomogram (Cancer of the Prostate Risk Assessment [CAPRA] postsurgical score [CAPRA-S]), whereas cPTEN does not show a statistically significant association (HR, 1.33; CI, 0.89-2; P = .2 and HR, 1.26; CI, 0.99-1.62; P = .063, respectively) when adjusting for CAPRA-S risk stratification. More importantly, AI-qPTEN was associated with shorter MFS in patients with favorable pathological stage and negative surgical margins (HR, 2.72; CI, 1.46-5.06; P = .002). Workflow also demonstrated enhanced clinical utility in decision curve analysis, more accurately identifying men who might benefit from adjuvant therapy postsurgery. This study demonstrates the clinical value of an affordable and fully automated AI-powered PTEN assessment for evaluating the risk of developing metastasis or disease recurrence after radical prostatectomy. Adding the AI-qPTEN assessment workflow to clinical variables may affect postoperative surveillance or management options, particularly in low-risk patients.

Gleason Grade 1 Prostate Cancer Volume at Biopsy Is Associated With Upgrading but Not Adverse Pathology or Recurrence After Radical Prostatectomy: Results From a Large Institutional Cohort.

PURPOSE: Clinical guidelines suggest that for low-grade, clinically localized prostate cancer, patients with higher volume of disease at diagnosis may benefit from definitive therapy, although the data remain unclear. Our objective was to determine associations between low-grade prostate cancer volume and outcomes in men managed with primary radical prostatectomy. MATERIALS AND METHODS: Men with cT1-2N0/xM0/x prostate cancer, prostate specific antigen at diagnosis <10 ng/mL, and Gleason grade group 1 pathology on diagnostic biopsy managed with primary radical prostatectomy were included. Outcomes were pathological upgrade at radical prostatectomy (≥Gleason grade group 2), University of California, San Francisco adverse pathology at radical prostatectomy (≥Gleason grade group 3, pT3/4, or pN1), alternate adverse pathology at radical prostatectomy (≥Gleason grade group 3, ≥pT3b, or pN1), and recurrence (biochemical failure with 2 prostate specific antigen ≥0.2 ng/mL or salvage treatment). Multivariable logistic regression models were used to estimate associations between percentage of positive cores and risk of upgrade and adverse pathology at radical prostatectomy. Multivariable Cox proportional hazards regression models were used to estimate associations between percentage of positive cores and hazard of recurrence after radical prostatectomy. RESULTS: A total of 1,029 men met inclusion criteria. Multivariable logistic regression models demonstrated significant associations between percentage of positive cores and pathological upgrade (OR 1.31, 95% CI 1.1-1.57, P < .01), but not University of California, San Francisco adverse pathology at radical prostatectomy (P = .84); percentage of positive cores was negatively associated with alternate adverse pathology (OR 0.67, 95% CI 0.48-0.93, P = .02). Multivariable Cox regression models demonstrated no association between percentage of positive cores and hazard of recurrence after radical prostatectomy (P = .11). CONCLUSIONS: In men with Gleason grade group 1 prostate cancer, tumor volume may be associated with upgrading at radical prostatectomy, but not more clinically significant outcomes of adverse pathology or recurrence.

Stability of Prognostic Estimation Using the CAPRA Score Incorporating Imaging-based vs Physical Exam-based Staging.

PURPOSE: Although official T-staging criteria for prostate cancer are based on digital rectal examination findings, providers increasingly rely on transrectal US and MRI to define pragmatic clinical stage to guide management. We assessed the impact of incorporating imaging findings into T-staging on performance of a well-validated prognostic instrument. MATERIALS AND METHODS: Patients who underwent radical prostatectomy for prostate cancer diagnosed between 2000 and 2019 with stage ≤cT3a on both digital rectal examination and imaging (transrectal US/MRI) were included. The University of California, San Francisco CAPRA (Cancer of the Prostate Risk Assessment) score was computed 2 ways: (1) incorporating digital rectal examination-based T stage and (2) incorporating imaging-based T stage. We assessed for risk changes across the 2 methods and associations of CAPRA (by both methods) with biochemical recurrence, using unadjusted and adjusted Cox proportional hazards models. Model discrimination and net benefit were assessed with time-dependent area under the curve and decision curve analysis, respectively. RESULTS: Of 2,222 men included, 377 (17%) increased in CAPRA score with imaging-based staging (P < .01). Digital rectal examination-based (HR 1.54; 95% CI 1.48-1.61) and imaging-based (HR 1.52; 95% CI 1.46-1.58) CAPRA scores were comparably accurate for predicting recurrence with similar discrimination and decision curve analyses. On multivariable Cox regression, positive digital rectal examination at diagnosis (HR 1.29; 95% CI 1.09-1.53) and imaging-based clinical T3/4 disease (HR 1.72; 95% CI 1.43-2.07) were independently associated with biochemical recurrence. CONCLUSIONS: The CAPRA score remains accurate whether determined using imaging-based staging or digital rectal examination-based staging, with relatively minor discrepancies and similar associations with biochemical recurrence. Staging information from either modality can be used in the CAPRA score calculation and still reliably predict risk of biochemical recurrence.

Delphi consensus project on prostate-specific membrane antigen (PSMA)-targeted surgery-outcomes from an international multidisciplinary panel.

PURPOSE: Prostate-specific membrane antigen (PSMA) is increasingly considered as a molecular target to achieve precision surgery for prostate cancer. A Delphi consensus was conducted to explore expert views in this emerging field and to identify knowledge and evidence gaps as well as unmet research needs that may help change practice and improve oncological outcomes for patients. METHODS: One hundred and five statements (scored by a 9-point Likert scale) were distributed through SurveyMonkey®. Following evaluation, a consecutive second round was performed to evaluate consensus (16 statements; 89% response rate). Consensus was defined using the disagreement index, assessed by the research and development project/University of California, Los Angeles appropriateness method. RESULTS: Eighty-six panel participants (72.1% clinician, 8.1% industry, 15.1% scientists, and 4.7% other) participated, most with a urological background (57.0%), followed by nuclear medicine (22.1%). Consensus was obtained on the following: (1) The diagnostic PSMA-ligand PET/CT should ideally be taken < 1 month before surgery, 1-3 months is acceptable; (2) a 16-20-h interval between injection of the tracer and surgery seems to be preferred; (3) PSMA targeting is most valuable for identification of nodal metastases; (4) gamma, fluorescence, and hybrid imaging are the preferred guidance technologies; and (5) randomized controlled clinical trials are required to define oncological value. Regarding surgical margin assessment, the view on the value of PSMA-targeted surgery was neutral or inconclusive. A high rate of "cannot answer" responses indicates further study is necessary to address knowledge gaps (e.g., Cerenkov or beta-emissions). CONCLUSIONS: This Delphi consensus provides guidance for clinicians and researchers that implement or develop PSMA-targeted surgery technologies. Ultimately, however, the consensus should be backed by randomized clinical trial data before it may be implemented within the guidelines.

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.

Dietary Patterns and Risk of Gleason Grade Progression among Men on Active Surveillance for Prostate Cancer: Results from the Canary Prostate Active Surveillance Study.

Modifiable lifestyle factors, such as following a healthy dietary pattern may delay or prevent prostate cancer (PCa) progression. However, few studies have evaluated whether following specific dietary patterns after PCa diagnosis impacts risk of disease progression among men with localized PCa managed by active surveillance (AS). 564 men enrolled in the Canary Prostate Active Surveillance Study, a protocol-driven AS study utilizing a pre-specified prostate-specific antigen monitoring and surveillance biopsy regimen, completed a food frequency questionnaire (FFQ) at enrollment and had ≥ 1 surveillance biopsy during follow-up. FFQs were used to evaluate adherence to the Dietary Guidelines for Americans (Healthy Eating index (HEI))-2015, alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH) dietary patterns. Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals were estimated using Cox proportional hazards models. During a median follow-up of 7.8 years, 237 men experienced an increase in Gleason score on subsequent biopsy (grade reclassification). Higher HEI-2015, aMED or DASH diet scores after diagnosis were not associated with significant reductions in the risk of grade reclassification during AS. However, these dietary patterns have well-established protective effects on chronic diseases and mortality and remain a prudent choice for men with prostate cancer managed by AS.

Seeing the unseen: how can we best identify transgender women within the Veterans Affairs healthcare system's electronic medical record?

BACKGROUND: One challenge in transgender research is reliably identifying patients through electronic medical records data, as there is no universal transgender International Classification of Diseases (ICD) code, but rather multiple ICD codes that can be used. AIM: To explore the sensitivity and specificity of 5 commonly used ICD codes to identify transgender patients overall and transgender women specifically (assigned male sex at birth) by using data from the Veterans Affairs (VA), the largest integrated health system in the United States. METHODS: Patients aged ≥18 years were identified via ICD-9 codes 302.5 and 302.6 (Ninth Revision) and ICD-10 codes F64.0, F64.8, and F64.9 (Tenth Revision) using VA health records from 2000 to 2021 and stratified by bilateral orchiectomy status. OUTCOMES: Detailed chart review was performed on 32 randomly selected patients for each code (half with and half without orchiectomy) to confirm transgender status and to perform descriptive analyses. RESULTS: For each ICD code, rates of confirmed transgender status ranged from 88% to 100% for those with and without an orchiectomy, with the majority being transgender women (consistent with most veterans being assigned male sex at birth). Most transgender women (66%-100%) were undergoing estrogen gender-affirming therapy. The majority of provider-driven entries of transgender status took place from 2011 to 2020, with 75% of entries made from 2011 to 2020, consistent with increased recognition and societal acceptance of this population. False negatives were detected at a rate of 15%. Based upon these 5 ICD codes alone, we estimate that the VA has records for 9,449 to 10,738 transgender individuals. CLINICAL IMPLICATIONS: All 5 codes are very sensitive in identifying transgender patients, and the combination of these codes with orchiectomy is extremely sensitive in identifying transgender women, specifically. STRENGTHS AND LIMITATIONS: Major strengths of the study are the use of universal ICD codes and a large patient sample size that spans health records nationally and across multiple decades, potentially making our data more generalizable. The main limitation of this study is that subanalyses were performed on a limited number of patients, which prevented us from capturing all false positives and thus from calculating specificity for each code. Similarly, our true negatives were derived from a small, random subset of the population; as such, our calculation for specificity is an estimate. CONCLUSION: This study highlights a novel method to identify transgender women and paves the way for further research.

Barriers and confidence among colorectal and prostate cancer survivors participating in two behavioral intervention studies.

PURPOSE: Exercise and healthy diet are key components of cancer survivorship. We sought to explore perceived barriers to engaging in healthy diet and exercise, and whether these barriers change throughout remote-based behavioral interventions. METHODS: Smart Pace (SP) and Prostate 8 (P8) were two 12-week pilot randomized controlled trials (RCTs) among 42 colorectal cancer (CRC) survivors and 76 prostate cancer (PC) survivors, respectively, that encouraged participants to implement exercise (both) and healthy diet (P8 only) through text messaging and wearable fitness monitors; P8 also included web materials. Participants completed surveys on perceived barriers and confidence in their ability to implement healthy behaviors at enrollment and 12 weeks; P8 also included a 52-week assessment. RESULTS: At enrollment, CRC survivors commonly reported a lack of discipline/willpower (36%), time (33%), and energy (31%); PC survivors often reported a lack of knowledge about healthy dietary behaviors (26%). Not having anyone with whom to exercise with was a common barrier among both groups (21% in CRC, 20% in PC). Among the intervention groups in both studies, various enrollment barriers (overall, functional/psychological disability, aversiveness, excuses, and inconveniences) were associated with change in behavior over time. CONCLUSIONS: Among CRC and PC survivors, there are multiple potential barriers related to motivation, time, social support, and lack of knowledge, that can be addressed and overcome to improve healthy behaviors. Tailoring lifestyle interventions to participants' individual barriers and confidence is needed to promote and sustain behavior change long-term.

Comparison of outcomes of different biopsy schedules among men on active surveillance for prostate cancer: An analysis of the G.A.P.3 global consortium database.

BACKGROUND: The optimal interval for repeat biopsy during active surveillance (AS) for prostate cancer is yet to be defined. This study examined whether risk of upgrading (to grade group ≥ 2) or risk of converting to treatment varied according to intensity of repeat biopsy using data from the GAP3 consortium's global AS database. MATERIALS AND METHODS: Intensity of surveillance biopsy schedules was categorized according to centers' protocols: (a) Prostate Cancer Research International Active Surveillance project (PRIAS) protocols with biopsies at years 1, 4, and 7 (10 centers; 7532 men); (b) biennial biopsies, that is, every other year (8 centers; 4365 men); and (c) annual biopsy schedules (4 centers; 1602 men). Multivariable Cox regression was used to compare outcomes according to biopsy intensity. RESULTS: Out of the 13,508 eligible participants, 56% were managed according to PRIAS protocols (biopsies at years 1, 4, and 7), 32% via biennial biopsy, and 12% via annual biopsy. After adjusting for baseline characteristics, risk of converting to treatment was greater for those on annual compared with PRIAS biopsy schedules (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.51-1.83; p < 0.001), while risk of upgrading did not differ (HR = 0.96; 95% CI = 0.84-1.10). CONCLUSION: Results suggest more frequent biopsy schedules may deter some men from continuing AS despite no evidence of grade progression.

Treatment in the absence of disease reclassification among men on active surveillance for prostate cancer.

BACKGROUND: Maintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort. METHODS: This study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66). CONCLUSIONS: A substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions. LAY SUMMARY: This analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.

Analysis of separate training and validation radical prostatectomy cohorts identifies 0.25 mm diameter as an optimal definition for "large" cribriform prostatic adenocarcinoma.

Cribriform growth pattern is well-established as an adverse pathologic feature in prostate cancer. The literature suggests "large" cribriform glands associate with aggressive behavior; however, published studies use varying definitions for "large". We aimed to identify an outcome-based quantitative cut-off for "large" vs "small" cribriform glands. We conducted an initial training phase using the tissue microarray based Canary retrospective radical prostatectomy cohort. Of 1287 patients analyzed, cribriform growth was observed in 307 (24%). Using Kaplan-Meier estimates of recurrence-free survival curves (RFS) that were stratified by cribriform gland size, we identified 0.25 mm as the optimal cutoff to identify more aggressive disease. In univariable and multivariable Cox proportional hazard analyses, size >0.25 mm was a significant predictor of worse RFS compared to patients with cribriform glands ≤0.25 mm, independent of pre-operative PSA, grade, stage and margin status (p < 0.001). In addition, two different subset analyses of low-intermediate risk cases (cases with Gleason score ≤ 3 + 4 = 7; and cases with Gleason score = 3 + 4 = 7/4 + 3 = 7) likewise demonstrated patients with largest cribriform diameter >0.25 mm had a significantly lower RFS relative to patients with cribriform glands ≤0.25 mm (each subset p = 0.004). Furthermore, there was no significant difference in outcomes between patients with cribriform glands ≤ 0.25 mm and patients without cribriform glands. The >0.25 mm cut-off was validated as statistically significant in a separate 419 patient, completely embedded whole-section radical prostatectomy cohort by biochemical recurrence, metastasis-free survival, and disease specific death, even when cases with admixed Gleason pattern 5 carcinoma were excluded. In summary, our findings support reporting cribriform gland size and identify 0.25 mm as an optimal outcome-based quantitative measure for defining "large" cribriform glands. Moreover, cribriform glands >0.25 mm are associated with potential for metastatic disease independent of Gleason pattern 5 adenocarcinoma.

Androgen Deprivation Therapy and the Risk of Dementia after Treatment for Prostate Cancer.

PURPOSE: The association between androgen deprivation therapy (ADT) and dementia in men with prostate cancer remains inconclusive. We assessed the association between cumulative ADT exposure and the onset of dementia in a nationwide longitudinal registry of men with prostate cancer. MATERIALS AND METHODS: A retrospective analysis of men aged ≥50 years from the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) registry was performed. The primary outcome was onset of dementia after primary treatment. ADT exposure was expressed as a time-varying independent variable of total ADT exposure. The probability of receiving ADT was estimated using a propensity score. Cox proportional hazards regression was performed to determine the association between ADT exposure and dementia with competing risk of death, adjusted for propensity score and clinical covariates among men receiving various treatments. RESULTS: Of 13,570 men 317 (2.3%) were diagnosed with dementia after a median of 7.0 years (IQR 3.0-12.0) of followup. Cumulative ADT use was significantly associated with dementia (HR 2.02; 95% CI 1.40-2.91; p <0.01) after adjustment. In a subset of 8,506 men, where propensity score matched by whether or not they received ADT, there was also an association between ADT use and dementia (HR 1.59; 95% CI 1.03-2.44; p=0.04). There was no association between primary treatment type and onset of dementia in the 8,489 men in the cohort who did not receive ADT. CONCLUSIONS: Cumulative ADT exposure was associated with dementia. This increased risk should be accompanied by a careful discussion of the needs and benefits of ADT in those being considered for treatment.

The Natural History of Untreated Biopsy Grade Group Progression and Delayed Definitive Treatment for Men on Active Surveillance for Early-Stage Prostate Cancer.

PURPOSE: For men with clinically localized prostate cancer outcomes of continuing active surveillance (AS) after biopsy progression are not well understood. We aim to determine the impact of continuing AS and delayed definitive treatment after biopsy progression on oncologic outcomes. MATERIALS AND METHODS: Participants in our prospective AS cohort (1990-2018) diagnosed with grade group (GG) 1, localized prostate cancer, with prostate specific antigen <20 who were subsequently upgraded to ≥GG2, and underwent further surveillance (biopsy/imaging/prostate specific antigen) were identified. Patients were stratified by post-progression followup into 3 groups: continue AS untreated, pursue early radical prostatectomy (RP) ≤6 months, or undergo late RP within 6 months to 5 years of progression. Patients receiving other treatments were excluded. We compared characteristics between groups and examined the associations of early vs late RP with risk of adverse pathology (AP) at RP and recurrence-free survival (RFS) after RP. RESULTS: Of 531 patients with biopsy progression and further surveillance 214 (40%) remained untreated, 192 (36%) pursued early RP and 125 (24%) underwent late RP. Among patients who underwent early vs late RP, there was no difference in GG (p=0.15) or AP (55% vs 53%, p=0.74) rate at RP, or 3-year RFS (80% vs 87%, log-rank p=0.64) after RP. In multivariable models, only Cancer of Prostate Risk Assessment post-surgical score was associated with risk of RFS (HR=1.42 per point, 95% CI 1.24-1.64). CONCLUSIONS: Among patients continuing AS after biopsy progression, 60% underwent surgery within 5 years. Delayed surgery after progression was not associated with higher risk of AP or RFS. This suggests select patients may be able to safely delay treatment after progression.