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.

Sarcomatoid Urothelial Carcinoma Is Associated With Limited Response to Neoadjuvant Chemotherapy and Poor Oncologic Outcomes After Radical Cystectomy.

INTRODUCTION: To examine oncologic outcomes and response to neoadjuvant chemotherapy (NAC) in patients with sarcomatoid urothelial carcinoma (SUC) treated with radical cystectomy (RC). MATERIALS AND METHODS: We retrospectively queried our institutional database (2003-18) and Surveillance, Epidemiology, and End Results (SEER)-Medicare (2004-2015) for patients with cT2-4, N0-2, M0 SUC and conventional UC (CUC) treated with RC. Clinicopathologic characteristics were described using descriptive statistics (t test, χ2-test and log-rank-test for group comparison). Overall (OS) and recurrence-free-survival (RFS) after RC were estimated with the Kaplan Meier method and associations with OS were evaluated with Cox proportional hazards models. RESULTS: We identified 38 patients with SUC and 287 patients with CUC in our database, and 190 patients with SUC in SEER-Medicare. In the institutional cohort, patients with SUC versus CUC had higher rates of pT3/4 stage (66% vs. 35%, P < 0.001), lower rates of ypT0N0 (6% vs. 35%, P = .02), and worse median OS (17.5 vs. 120 months, P < .001). Further, patients with SUC in the institutional versus SEER-Medicare cohort had similar median OS (17.5 vs. 21 months). In both cohorts, OS was comparable between patients with SUC undergoing NAC+RC vs. RC alone (17.5 vs. 18.4 months, P = .98, institutional cohort; 24 vs. 20 months, P = .56, SEER cohort). In Cox proportional hazards models for the institutional RC cohort, SUC was independently associated with worse OS (HR 2.3, CI 1.4-3.8, P = .001). CONCLUSION: SUC demonstrates poor pathologic response to NAC and worse OS compared with CUC, with no OS benefit associated with NAC. A unique pattern of rapid abdominopelvic cystic recurrence was identified.

Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, Part I: Introduction, Risk Assessment, Staging, and Risk-Based Management.

PURPOSE: The summary presented herein represents Part I of the three-part series dedicated to Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, discussing risk assessment, staging, and risk-based management in patients diagnosed with clinically localized prostate cancer. Please refer to Parts II and III for discussion of principles of active surveillance, surgery and follow-up (Part II), and principles of radiation and future directions (Part III). MATERIALS AND METHODS: The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles. RESULTS: The Clinically Localized Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with clinically localized prostate cancer. Statements regarding risk assessment, staging, and risk-based management are detailed herein. CONCLUSIONS: This guideline aims to inform clinicians treating patients with clinically localized prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to further improve care for these men.

Social and Clinical Correlates of Neoadjuvant Chemotherapy in Medicare Beneficiaries With Muscle Invasive Bladder Cancer From 2004-2015.

OBJECTIVE: To assess social and clinical correlates of neoadjuvant chemotherapy (NAC) utilization among Medicare beneficiaries. MATERIALS AND METHODS: A cohort of SEER-Medicare (2004-2015) patients with muscle-invasive bladder cancer treated by radical cystectomy were stratified into 3-groups: standard of care NAC (cisplatin-based combination), non-standard of care NAC, and upfront cystectomy. Multivariable logistic regression analysis was used to assess social, demographic and clinical correlates of each treatment category. Survival analyses were performed to compare propensity matched treatment groups. RESULTS: In total, 6214 patients were identified with a median follow-up of 21 [IQR 7-54] months. NAC utilization increased from 10.7% to 39.1%, between 2004 and 2015, largely due to increased use of standard of care regimens. The most commonly used nonstandard regimen was gemcitabine/carboplatin (50.2%). Older age, Hispanic and Black race, lower socioeconomic status, and contraindications to cisplatin were associated with increased odds of receiving nonstandard of care NAC compared to standard of care. Standard of care NAC was associated with improved overall survival HR 0.85 (95% CI 0.76, 0.94) and HR 0.75 (95% CI 0.63, 0.89) compared to both upfront cystectomy and nonstandard of care NAC, respectively. CONCLUSION: NAC utilization has increased to nearly 40%; however, the use of non-standard of care NAC regimen have persisted (~8%). Cisplatin-ineligibility, older age, race/ethnicity, and lower socioeconomic status were correlated with nonstandard of care NAC, which provided no clinical benefit at the risk of potential harm. In accordance with current clinical guidelines, cisplatin-ineligible patients should be considered for timely upfront cystectomy or novel clinical trials.

Response to Neoadjuvant Chemotherapy and Survival in Micropapillary Urothelial Carcinoma: Data From a Tertiary Referral Center and the Surveillance, Epidemiology, and End Results (SEER) Program.

BACKGROUND: Micropapillary urothelial carcinoma (MPC) is a rare urothelial carcinoma variant with conflicting data guiding clinical practice. In this study, we explored oncologic outcomes in relation to neoadjuvant chemotherapy (NAC) in a retrospective cohort of patients with MPC, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare. PATIENTS AND METHODS: We retrospectively identified patients with MPC or conventional urothelial carcinoma (CUC) without any variant histology undergoing radical cystectomy (RC) in our institution (2003-2018). SEER-Medicare was also queried to identify patients diagnosed with MPC (2004-2015). Clinicopathologic data and treatment modalities were extracted. Overall survival (OS) was estimated with the Kaplan-Meier method. Mann-Whitney-Wilcoxon and chi-square tests were used for comparative analysis and Cox regression for identifying clinical covariates associated with OS. RESULTS: Our institutional database yielded 46 patients with MPC and 457 with CUC. In SEER-Medicare, 183 patients with MPC were identified, and 63 (34%) underwent RC. In the institutional cohort, patients with MPC had significantly higher incidence of cN+ (17% vs. 8%), pN+ stage (30% vs. 17%), carcinoma-in-situ (43% vs. 25%), and lymphovascular invasion (30% vs. 16%) at RC versus those with CUC (all P < .05). Pathologic complete response (ypT0N0) to NAC was 33% for MPC and 35% for CUC (P = .899). Median OS was lower for institutional MPC versus CUC in univariate analysis (43.6 vs. 105.3 months, P = .006); however, MPC was not independently associated with OS in the multivariate model. Median OS was 25 months in the SEER MPC cohort for patients undergoing RC, while NAC was not associated with improved OS in that group. CONCLUSION: Pathologic response to NAC was not significantly different between MPC and CUC, while MPC histology was not an independent predictor of OS. Further studies are needed to better understand biological mechanisms behind its aggressive features as well as the role of NAC in this histology variant.

PSA screening, prostate biopsy, and treatment of prostate cancer in the years surrounding the USPSTF recommendation against prostate cancer screening.

BACKGROUND: The 2012 United States Preventive Services Task Force recommendation against screening for prostate cancer has impacted rates of prostate-specific antigen (PSA) screening and appears to be associated with declining prostate cancer incidence. Our objective was to characterize health care utilization that may explain these observed trends. METHODS: MarketScan claims, which capture >30 million privately insured patients in the United States, were queried for all men aged 40-64 years for the years 2008-2014. PSA testing, prostate biopsy, prostate cancer diagnosis, and definitive local treatment were determined using associated International Classification of Diseases, Ninth Revision and Current Procedural Terminology, Fourth Edition codes. RESULTS: There were approximately 6 million qualifying men with a full year of data. PSA testing, prostate biopsy, and prostate cancer detection declined significantly between 2009 and 2014, most notably after 2011. The prostate biopsy rate per 100 patients with a PSA test decreased over the study period from 1.95 (95% confidence interval [CI], 1.92-1.97) to 1.52 (95% CI, 1.50-1.54). Prostate cancer incidence per prostate biopsy increased over the study period from 0.36 (95% CI, 0.35-0.36) to 0.39 (95% CI, 0.39-0.40). Of new prostate cancer diagnoses, the proportion managed with definitive local treatment decreased from 69% (95% CI, 69%-70%) to 54% (95% CI, 53%-55%). Both PSA testing and prostate cancer incidence decreased significantly after 2011 (P < .001). CONCLUSION: In a large cohort of privately insured men, PSA testing, prostate biopsy, prostate cancer incidence, and local definitive treatment for prostate cancer decreased between 2008 and 2014, most notably after 2011. This decrease may be driven by differential referral patterns from primary care providers to urologists. Cancer 2018;124:2733-2739. © 2018 American Cancer Society.

Disparities in Access and Regionalization of Care in Testicular Cancer.

INTRODUCTION: Timely mobilization of specialized resources are needed to achieve optimal outcomes in testicular cancer. We used the National Cancer Database to investigate the hospital and demographic features driving disparity. PATIENTS AND METHODS: We identified adult men with testicular tumors diagnosed from 2004 to 2013. We a priori examined the association among race/ethnicity, socioeconomic status (SES), travel burden, hospital characteristics, and indicators of delays in testicular cancer care. The outcomes included large primary tumor, stage III at diagnosis, orchiectomy delay, and mortality. The analyses included multivariable Cox proportional hazards regression for time-dependent outcomes and logistic regression for categorical outcomes. RESULTS: Of 31,964 men, 29% had a large primary tumor, 17% presented with stage III disease, 10% experienced an orchiectomy delay, and 6% died. Black race or Hispanic ethnicity, low SES, and underinsurance were associated with poorer outcomes (P < .001 for all). Higher hospital volume, cancer center status, and lower travel burden were associated with improved outcomes (P < .001 for all). CONCLUSION: Nonwhite race/ethnicity, low SES, and underinsurance were associated with diminished access to testicular cancer care. Insurance status, a marker of SES, had the most consistent association with poor outcomes. This finding highlights the oncologic imperative to improve access to adequate health insurance. Regionalization of subspecialty care might, paradoxically, improve outcomes but also create additional barriers in the form of an added travel burden.

Validating the total illness burden index for prostate cancer (TIBI-CaP) in men with castration-resistant prostate cancer: data from TRUMPET.

AIM: To validate the total illness burden index for prostate cancer (TIBI-CaP) in castration-resistant prostate cancer (CRPC) patients. PATIENTS & METHODS: Baseline comorbidity scores collected using the TIBI-CaP were compared with the baseline patient-reported health-related quality of life using the SF-12v2 and FACT-P questionnaires in 302 patients enrolled in the Treatment Registry for Outcomes in CRPC Patients (TRUMPET). RESULTS: Baseline TIBI-CaP scores were negatively correlated with all baseline SF-12v2 domain/composite (p < 0.001) and FACT-P subscale/total (p < 0.020) scores. There was a significant decreasing linear trend in SF12v2 and FACT-P scores over the categories based on TIBI-CaP quartiles of comorbidity burden (from 'least' to 'severe'). CONCLUSION: The TIBI-CaP is a valid measure of comorbidity burden in patients with CRPC in the real world.

Association Between Combined TMPRSS2:ERG and PCA3 RNA Urinary Testing and Detection of Aggressive Prostate Cancer.

IMPORTANCE: Potential survival benefits from treating aggressive (Gleason score, ≥7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease. OBJECTIVE: To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort. INTERVENTIONS/EXPOSURES: Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy. MAIN OUTCOMES AND MEASURES: Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes. RESULTS: Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men. CONCLUSIONS AND RELEVANCE: Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings.

15 Years of penile cancer management in the United States: An analysis of the use of partial penectomy for localized disease and chemotherapy in the metastatic setting.

BACKGROUND: Penile cancer remains a rare disease in the United States, and its understanding may be limited by the uncommon nature of the malignancy. We sought to describe recent penile cancer treatment patterns using the National Cancer Data Base. METHODS: A retrospective review of data obtained from the National Cancer Data Base from 1998 to 2012 was performed. We obtained demographic information and therapeutic approaches within the following2 clinical scenarios: performance of partial penectomy for early stage disease (clinical Ta-T2) and the use of chemotherapy for metastatic disease. Multivariate logistic analysis was performed. RESULTS: A total of 2,677 patients presented with early stage penile carcinoma. The proportion receiving partial penectomy increased from 74% in 1998 to 2000 to 80% in 2010 to 2012 (P<0.001). Partial penectomy was more common in the elderly (age>80, odd ratios [OR] = 1.53, 95% CI: 1.05-2.23), young (age<50, OR = 1.46, 95% CI: 1.02-2.07), and in African Americans (OR = 1.45, 95% CI: 1.00-2.12). Increasing tumor size was significantly associated with decreased likelihood of receiving partial penectomy. Of those presenting with metastatic disease (n = 819), use of chemotherapy increased over the time period from 39% receiving chemotherapy in 1998 to 2000 to 49% in 2010 to 2012 (P<0.03). Patients least likely to receive chemotherapy were older and with higher Comorbidity score (both P<0.05), African American (OR = 0.46, 95% CI: 0.30-0.73), and living≥50 miles from the nearest treatment hospital (OR = 0.37, 95% CI: 0.25-0.55). CONCLUSIONS: Penile-sparing surgery for early stage disease and the use of chemotherapy for metastatic disease are becoming more commonly utilized over the past several years. Further work is needed to define clinical and nonclinical factors associated with the treatment.

Treatment registry for outcomes in patients with castration-resistant prostate cancer (TRUMPET): a methodology for real-world evidence and research.

AIM: This study seeks to improve the understanding of treatment patterns and associated health-related quality of life (HRQoL), clinical outcomes and healthcare utilization in US patients with castration-resistant prostate cancer (CRPC). PATIENTS & METHODS: Treatment Registry for Outcomes in CRPC Patients (TRUMPET) is a US-based, prospective, observational multicenter registry (NCT02380274) involving patients with CRPC and their caregivers. Patients initiating their first active treatment course will be enrolled from urology and medical oncology practices, with data captured up to 4 years. RESULTS: Information on prescribing patterns, HRQoL, clinical outcomes and healthcare utilization will be collected. CONCLUSION: TRUMPET will enable scientific understanding of disease management in terms of HRQoL, clinical outcomes and healthcare utilization in clinical practice for patients with CRPC.