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PURPOSE Programmed cell death protein-1 (PD-1) receptor and ligand interactions are the target of immunotherapies for more than 20 cancer types. Biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden, and programmed death ligand-1 (PD-L1) immunohistochemistry. Structural variations (SVs) in PD-L1 ( CD274) and PD-L2 ( PDCD1LG2) have been observed in cancer, but the comprehensive landscape is unknown. Here, we describe the genomic landscape of PD-L1 and PD-L2 SVs, their potential impact on the tumor microenvironment, and evidence that patients with these alterations can benefit from immunotherapy. METHODS We analyzed sequencing data from cancer cases with PD-L1 and PD-L2 SVs across 22 publications and four data sets, including Foundation Medicine Inc, The Cancer Genome Atlas, International Cancer Genome Consortium, and the Oncology Research Information Exchange Network. We leveraged RNA sequencing to evaluate immune signatures. We curated literature reporting clinical outcomes of patients harboring PD-L1 or PD-L2 SVs. RESULTS Using data sets encompassing 300,000 tumors, we curated 486 cases with SVs in PD-L1 and PD-L2 and observed consistent breakpoint patterns, or hotspots. Leveraging The Cancer Genome Atlas, we observed significant upregulation in PD-L1 expression and signatures for interferon signaling, macrophages, T cells, and immune cell proliferation in samples harboring PD-L1 or PD-L2 SVs. Retrospective review of 12 studies that identified patients with SVs in PD-L1 or PD-L2 revealed > 50% (52/71) response rate to PD-1 immunotherapy with durable responses. CONCLUSION Our findings show that the 3′-UTR is frequently affected, and that SVs are associated with increased expression of ligands and immune signatures. Retrospective evidence from curated studies suggests this genomic alteration could help identify candidates for PD-1/PD-L1 immunotherapy. We expect these findings will better define PD-L1 and PD-L2 SVs in cancer and lend support for prospective clinical trials to target these alterations.

Urothelial carcinoma (UC) presents most frequently as bladder cancer and is the most common cancer of the urinary system in the United States. UC relapse and progression are common and impose a significant negative impact on the lives of patients and healthcare resources. To elucidate the biological mechanisms of UC and find novel biomarkers, we analyzed the clinical and genomic data in the Oncology Research Information Exchange Network (ORIEN). We conducted gene-based and gene-set based association tests on rare germline variants comparing the exome sequencing of 336 UC patients and genome sequencing of 366 healthy controls (42 unrelated individuals from the Centre d'Etudes du Polymorphisme Humain [CEPH] families and 324 from the University of Utah Heritage 1000 [H1K] Projects). The analysis of loss-of-function (LoF) variants revealed that the forkhead box (FOX) J2 gene set was significantly associated with UC at the genome-wide level (Bonferroni-corrected p-value=0.01). Genes in this gene set contain a motif that matches the FOXJ2 transcription factor binding site. Firth-penalized Cox proportional hazard regression on overall survival identified LoF variants in genes down-regulated in naive CD8 T cells to be associated with worse prognosis (Bonferroni-corrected p-value=0.032, hazard ratio=28.2, and 95% confidence interval 6.66 to 119.0). In exome sequencing of tumor tissues, we searched for driver genes and pathways by testing for higher variant allelic fractions than the genome average. The tests yielded eleven genes with genome-wide significance (Table 1). By gene set analysis using the MSigDB Hallmark database, significant pathways included the P53 pathway (p Table 1. Genes with high allelic fractions Gene P-value Number of Variants TP53 Citation Format: Bing-Jian Feng, Wendy Kohlmann, David A. Nix, Aaron Atkinson, Kenneth M. Boucher, Courtney Carroll, Jill Kolesar, Eric A. Singer, Stephen B. Edge, Kamal Sahu, Alejandro Sanchez, Mikaela Larson, Michelle L. Churchman, Laura Graham, John D. Carpten, Yousef Zakharia, Lindsey Byrne, Rohit K. Jain, Kenneth G. Nepple, Ahmad Shabsigh, Jad Chahoud, Sumati Gupta. Germline and somatic genomic profiling of urothelial carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6074.

Rescue intravesical therapies for patients with bacillus Calmette-Guérin failure nonmuscle invasive bladder cancer remain a critical focus of ongoing research. Sequential intravesical gemcitabine and docetaxel therapy has shown safety and efficacy in 2 retrospective, single institution cohorts. This doublet has since been adopted as an intravesical salvage option at multiple institutions. We report the results of a multi-institutional evaluation of gemcitabine and docetaxel.Each institution retrospectively reviewed all records of patients treated with intravesical gemcitabine and docetaxel for nonmuscle invasive bladder cancer between June 2009 and May 2018. Only patients with recurrent nonmuscle invasive bladder cancer and a history of bacillus Calmette-Guérin treatment were included in the analysis. If patients were disease-free after induction, maintenance was instituted at the treating physician's discretion. Posttreatment surveillance followed American Urological Association guidelines. Survival analysis was performed using the Kaplan-Meier method and risk factors for treatment failure were assessed with Cox regression models.Overall 276 patients (median age 73 years, median followup 22.9 months) received treatment. Nine patients were unable to tolerate a full induction course. One and 2-year recurrence-free survival rates were 60% and 46%, and high grade recurrence-free survival rates were 65% and 52%, respectively. Ten patients (3.6%) had disease progression on transurethral resection. Forty-three patients (15.6%) went on to cystectomy (median 11.3 months from induction), of whom 11 (4.0%) had progression to muscle invasion. Analysis identified no patient, disease or prior treatment related factors associated with gemcitabine and docetaxel failure.Intravesical gemcitabine and docetaxel therapy is well tolerated and effective, providing a durable response in patients with recurrent nonmuscle invasive bladder cancer after bacillus Calmette-Guérin therapy. Further prospective study is warranted.

BACKGROUND: Expectant management (EM) has been widely recommended for men with low-risk prostate cancers (PCa). We evaluated trends in EM and the sociodemographic and clinical factors associated with EM, initiating a National Comprehensive Cancer Network guideline-concordant active surveillance (AS) monitoring protocol, and switching from EM to active treatment (AT). METHODS: We used the SEER-Medicare database to identify men ages 66+ diagnosed with a low-risk PCa (PSA < 10 ng/mL, Gleason ≤ 6, stage ≤ T2a) in 2010–2013 with ≥1 year of follow-up. We used claims data to capture (1) PCa treatments, including surgical procedures, radiotherapy, and hormone therapy, and (2) AS monitoring procedures, including PSA tests and prostate biopsy. We defined EM as receiving no AT within 1 year of diagnosis. We used multivariable regression techniques to identify factors associated with EM, initiating AS monitoring, and switching to AT. RESULTS: During the study period, EM increased from 29.4% to 49.0%, p < 0.01. Age < 77, being married/partnered, non-Hispanic ethnicity, higher median ZIP code income, lower PSA levels, stage T1c, and more recent year of diagnosis were associated with EM. Nearly 39% of the EM cohort initiated AS monitoring; age 10 years, implying that a substantial proportion was being managed by watchful waiting. AS monitoring was associated with switching to AT, suggesting that treatment decisions likely were based on cancer progression.

BackgroundObesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes.MethodsWe investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, ‘BMI’ ≥30 kg/m2) or non-obese (BMI 2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString.ResultsWith obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1β in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors.ConclusionsWe find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1β levels, highlighting the need for continued study of this critical issue.

INTRODUCTION AND OBJECTIVE:After the recurrence of NMIBC following BCG therapy, risk stratified management directs patients toward radical cystectomy, clinical trial enrollment, and off-label use o...

Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1β, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.

497 Background: Bacillus Calmette-Guerin (BCG) is currently recommended as adjuvant therapy following complete transurethral resection of bladder tumor (TURBT) for high-risk non-muscle invasive bladder cancer (NMIBC). However, continued BCG production shortages have precluded the use of BCG in many urologic practices. Efficacy of sequential intravesical gemcitabine and docetaxel (Gem/Doce) in the BCG failure setting has been reproduced across multiple institutions. In response to the continuing BCG shortage, Gem/Doce has been utilized at our institution in the BCG-naïve setting. We report the outcomes of a large cohort of patients with high-risk BCG-naïve NMIBC treated with Gem/Doce. Methods: We retrospectively identified all patients with BCG-naïve high-risk NMIBC who were treated with Gem/Doce from May 2013 through April 2021. We included patients with intent to receive 6 weekly intravesical instillations of sequential 1 gram gemcitabine and 37.5mg docetaxel after complete TURBT. Monthly maintenance of 2 years was initiated if disease free at first follow-up. The primary outcome was recurrence-free survival (RFS) and efficacy was evaluated in an intention-to-treat manner. Recurrence was defined as pathologically confirmed tumor relapse in the bladder or prostatic urethra. Progression was defined as T-stage increase from Ta or CIS to T1 or development of muscle invasive or metastatic disease. Survival was assessed using the Kaplan-Meier method and log rank test, indexed from the first Gem/Doce instillation. Results: One hundred seven patients with median follow-up of 15 months were included in the analysis. There were 47 with any CIS, 55 with T1 disease, and 7 with micropapillary variant histology. Four patients did not complete a full induction cycle due to hematuria (3) and severe frequency/nocturia (1). 19 patients sustained a recurrence at any point during follow-up. RFS was 89%, 85%, and 82% at 6, 12, and 24 months, respectively. No difference in RFS was seen in patients with or without CIS (p = 0.42). No patients met criteria for either form of disease progression. One patient underwent cystectomy due to end-stage lower urinary tract symptoms, with final pathology pTisN0. No patients died of bladder cancer. Overall survival was 84% at 24 months. 46 patients reported any symptoms during treatment. Common side effects included urinary frequency/urgency (36%), hematuria (11%), and dysuria (8%). Conclusions: In a large cohort of high-risk, BCG-naïve NMIBC patients, Gem/Doce showed excellent efficacy (84% 2-year HG-RFS). These rates are similar to modern treatment naïve cohorts receiving BCG. Prospective comparative analysis of Gem/Doce in BCG-naïve populations is warranted.[Table: see text]

496 Background: Intravesical gemcitabine-docetaxel (Gem/Doce) has emerged as an efficacious and well-tolerated therapy for NMIBC. At first cytoscopic evaluation, success rate for BCG failures is 75-80% with 60% of responders remaining disease free at 24 months. Success rates are even higher for BCG naïve patients with close to 90% disease free at 3 months, and 93% of responders HG disease free at 24 months. There is an unmet need for effective bladder-sparing regimens for Gem/Doce failures. FDA-approved agents in this setting have poor long-term efficacy; Valrubicin has an 8% 24-month disease free rate, and recently approved Pembrolizumab has less than 20% complete response at 1 year. Based on poor efficacy of alternatives, we evaluated sequential intravesical valrubicin-docetaxel (Val/Doce) as a rescue therapy for NMIBC. Methods: We retrospectively identified all patients with NMIBC who were treated with Val/Doce between April 2013 and June 2021. Patients were included with intent to receive 6 weekly intravesical instillations of sequential 800 mg valrubicin and 37.5 mg docetaxel after complete TURBT. Monthly maintenance of 2 years was initiated if disease free at 3-month cytoscopic evaluation. The primary outcome was recurrence-free survival (RFS). Progression events included the development of muscle invasive or metastatic disease as well as any cystectomy. Survival was assessed using the Kaplan-Meier method and log rank test, indexed from start of Val/Doce induction. Surveillance was performed according to AUA guidelines. Results: The final cohort included 75 patients with median follow-up of 21 months. Of these patients, 12 were treated with Val/Doce for low-grade Ta disease, with 60% disease free at 2 years and no subsequent HG occurrences. The remaining 63 patients had high-grade disease of which 86% were BCG failures and 89% were Gem/Doce unresponsive. The 2 year RFS for high-grade patients was 39%. CIS was present in 56% of the cohort. RFS was similar for those with and without CIS. Progression occurred in 12 of the patients with high-grade disease. Of note, 10 underwent cystectomy and 2 died of metastatic bladder cancer, yielding a bladder cancer specific death rate of 3%. Overall and cystectomy-free survival was 88 and 85% at 24 months, respectively. The most commonly reported side effects were bladder spasms (24%), urinary frequency (13%), and dysuria (11%). There were 3 patients who could not tolerant a full induction course. Conclusions: Sequential intravesical valrubicin-docetaxel will rescue a substantial portion of patients with HG NMIBC failing Gem/Doce or BCG. Thus, the regimen allows a high proportion of patients ( > 80%) to retain their bladders with an acceptable ( < 20%) progression rate without succumbing to bladder cancer-related death ( < 5%).[Table: see text]

451 Background: Outside of Lynch syndrome, few genetic factors have been associated with urothelial cancer (UC). This project seeks to describe the frequency of germline variants in a multi-center UC cohort. Methods: Patients diagnosed with UC from 1980 to 2019 and consented to the Total Cancer Care protocol by members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. The ORIEN program includes a convenience sample of cases with both germline and tumor samples available, though this analysis was germline only. Whole exome sequencing data were analyzed using a GATK best practices for germline variant analysis. A series of quality control (allele frequency > = 0.3, read depth > = 20, genotype quality > = 20), annotation, functional impact (loss of function/splicing), and region (cancer predisposition genes/pathways) filters were applied to identify variants of significant consequence. Results: 348 exomes were evaluated. This identified 60 variants classified as pathogenic/likely pathogenic (P/LP) and 17 novel, high impact variants in genes associated with high, moderate, or recessively inherited cancer risk in 77 individuals (22.1%). 15 (4.5%) had P/LP variants in genes associated with a high or moderate cancer risk, and 10 (3%) of these variants were considered to be clinically actionable with associated with cancer screening, risk reduction or treatment recommendations. The high/moderate risk genes with P/LP variants included CHEK2 (n = 5), FANCM (n = 4), MSH6 (n = 2) and single cases of MSH2, BRCA2, ERCC3, and BRIP1. The average age of diagnosis in those with and without a high/moderate risk P/LP variant was 67.6 (57-80 yrs) and 68.9 (45-91 yrs). Family history of cancer was reported for 73% of those with a germline LP/PV and 60% of those without, but this trend was not significant (p =.44). Conclusions: Individuals with UC have a high frequency of germline variants that warrant further study for association with cancer risk. A smaller, but significant portion also carry germline variants that may be clinically relevant to them and/or family members. Currently UC is not included in genetic testing criteria. This study adds to the growing body of research indicating that diverse types of cancer patients harbor germline variants. Strategies for expanding testing should be considered.

573 Background: Intravesical bacillus Calmette-Guérin (BCG) is the first-line treatment for high-risk non-muscle invasive bladder cancer (NMIBC). Unfortunately, disease recurrence/progression is common and associated with increased risk of death from bladder cancer. While radical cystectomy remains the preferred treatment for BCG unresponsive NMIBC, many patients are either unwilling or unfit to undergo surgery. Previous retrospective studies have demonstrated the efficacy of intravesical gemcitabine and docetaxel (Gem/Doce) for treating NMIBC after BCG failure. However, the long-term outcomes of this cohort are unknown. We report 5-year survival outcomes of patients treated with intravesical Gem/Doce after BCG failure. Methods: We retrospectively identified patients at our institution who were treated with Gem/Doce for high-risk NMIBC after BCG failure between 2009 and 2017. Patients received six weekly intravesical Gem/Doce instillations. Initial responders received monthly maintenance instillations for 2 years. Surveillance was performed according to American Urological Association guidelines. Survival time was measured from start of Gem/Doce induction. Outcomes included high-grade recurrence-free survival (HG-RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS) and overall survival (OS). Recurrence was defined as pathologically confirmed tumor relapse in the bladder or prostatic urethra. Progression was defined as recurrence of disease with stage T2 or greater, cystectomy or death due to bladder cancer. Survival probabilities were calculated with the Kaplan-Meier method. Results: A total of 97 patients with a median age of 73 years were treated with Gem/Doce after BCG failure. Median follow-up was 49 months. BCG failure was further stratified as BCG unresponsive (35%), BCG relapsing (38%), BCG intolerant (11%) or unspecified (16%). 71% and 21% of patients had carcinoma in-situ and high-grade T1 disease, respectively. Complete response at initial surveillance was 74% and median duration of response was 26 months. Overall HG-RFS at 1, 2 and 5 years was 60%, 51% and 31%, respectively. HG-RFS was similar among BCG unresponsive patients and the overall cohort (see table). During follow-up, 18 patients (19%) underwent radical cystectomy and 28 patients (29%) experienced disease progression. PFS, CFS, CSS and OS at 5 years was 68%, 75%, 91% and 64%, respectively. Conclusions: Intravesical Gem/Doce for high-risk NMIBC after BCG failure offers long-term efficacy and substantial durability of response with a high likelihood of bladder preservation at five years after induction. Future prospective trials assessing Gem/Doce are warranted.[Table: see text]

Repeat BCG induction remains an option for select non-muscle invasive bladder cancer (NMIBC) patients who fail initial therapy. Alternative salvage intravesical regimens such as Gemcitabine and Docetaxel (Gem/Doce) have been investigated. We aimed to compare the efficacy BCG plus interferon a-2b (BCG/IFN) and Gem/Doce in patients with recurrent NMIBC after a single prior BCG course.The National Phase II BCG/IFN trial database and multi-institutional Gem/Doce database were queried for patients with recurrent NMIBC after one prior BCG induction course, excluding those with BCG unresponsive disease. Stabilized inverse probability treatment weighted survival curves were estimated using the Kaplan-Meier method and compared. Propensity scores were derived from a logistic regression model. The primary outcome was recurrence free survival (RFS); secondary outcomes were high-grade (HG) RFS and risk factors for treatment failure.We identified 197 BCG/IFN and 93 Gem/Doce patients who met study criteria. Patients receiving Gem/Doce were older and more likely to have HG disease, CIS, and persistent disease following induction BCG (all P0.01). After propensity score-based weighting, the adjusted 1- and 2-year RFS was 61% and 53% after BCG/IFN versus 68% and 46% after Gem/Doce (P = 0.95). Adjusted 1- and 2-year HG-RFS was 60% and 51% after BCG/IFN versus 63% and 42% after Gem/Doce (P = 0.68). Multivariable Cox regression revealed that Gem/Doce treatment was not associated with an increased risk of failure (HR = 0.97, P = 0.89) as compared to BCG/IFN.Patients with recurrent NMIBC after a single induction BCG failure and not deemed BCG unresponsive had similar oncologic outcomes with Gem/Doce and BCG/IFN in a post-hoc analysis. Additional prospective studies are needed.

To provide a comprehensive update of the joint consultation of the International Consultation on Urological Diseases (ICUD) for the diagnosis and management of non-urothelial cancer of the urinary bladder. A detailed analysis of the literature was conducted reporting on the epidemiology, etiology, diagnosis, treatment and outcomes of non-urothelial cancer of the urinary bladder. An international, multidisciplinary expert committee evaluated and graded the evidence according to the Oxford System of Evidence-based Medicine modified by the ICUD. The major non-urothelial cancers of the urinary bladder are squamous cell carcinoma, adenocarcinoma, and neuroendocrine tumors. Several other non-urothelial tumors are rare but important to identify because of their aggressive behavior when compared to urothelial bladder tumors. Radical cystectomy and urinary diversion, preceded by neoadjuvant radiation or chemotherapy in some of these tumors, is the main method or treatment for resectable disease. Adjuvant therapy is not usually successful and no novel targeted or immunotherapeutic agents have been identified to provide benefit. Patients with small cell neuroendocrine tumors of the bladder should be offered chemotherapy before surgery. Because non-urothelial cancers are usually locally advanced and/or metastatic at the time of diagnosis, 5-year survival is generally poor. Non-urothelial cancers of the urinary bladder are rare and mostly lack established protocols for treatment. The prognosis of most of these tumors is poor because they are usually advanced at the time of diagnosis. A multimodal treatment approach should be considered to improve outcomes.

PURPOSE: The purpose of this study was to determine the association of marital status, a marker of social support, with all-cause and prostate cancer-specific mortality in a cohort of men with early-stage prostate cancer treated with radical prostatectomy. METHODS: We conducted a retrospective cohort study of 3579 men treated for localized (stage 1–2) prostate cancer with radical prostatectomy at a single institution between 1994 and 2004. Marital status (not married vs. married) and marital history (never married, divorced, widowed vs. married) at the time of prostatectomy were examined in relation to (1) all-cause mortality and (2) prostate cancer-specific mortality using Cox proportional hazards regression. RESULTS: Not being married (vs. married) at the time of radical prostatectomy was associated with an increased risk of all-cause mortality (Hazard Ratio (HR): 1.42; 95% Confidence Interval (CI): 1.10, 1.85). Similarly, in analyses of marital history, never married men were at highest risk of all-cause mortality (HR: 1.77, 95% CI: 1.19, 2.63). Unmarried status (vs. married) was also associated with an increased risk of prostate cancer-specific mortality (HR: 1.97; 95% CI: 1.01, 3.83). CONCLUSIONS: Unmarried men with prostate cancer were at greater risk for death after radical prostatectomy. Among married men with prostate cancer, marriage likely serves as a multi-faceted proxy for many protective factors including social support. Future studies should explore the mechanisms underlying these findings to inform the development of novel prostate cancer survival interventions for unmarried men and those with low social support.

322 Background: Hypoxia induced factor 1α/2α (HIFs) and vascular endothelial growth factor (VEGF) are overexpressed in ccRCC and associated with increased tumor angiogenesis, vascular instability and drug resistance. In xenografts, high dose SLM resulted in sustained down regulation of HIFs, normalization of tumor vasculature that resulted in increased drug delivery, and therapeutic synergy with anti-VEGF therapeutic. These effects were highly SLM dose, sequence, and schedule dependent. Methods: After completion of the escalating phase I (3+3) trial, the non-toxic SLM dose of 4000μg was administered orally twice daily (BID) for 14 days, followed by once daily in combination with axitinib 5 mg BID. The primary endpoint is safety and the secondary end point include overall response rate (ORR), progression free survival (PFS), and overall survival (OS). To assess the potential effects of SLM on tumor vascular function, dual energy computed tomography (DECT) was conducted at baseline, day 14 of SLM, and at 3 months of SLM + axitinib. Results: Thirty subjects are screened. Of whom 25 have efficacy data (3 subjects screen failure, 1 withdrew, 1 taken off study prior to first scan due to progression with brain lesions likely present prior to study entry). 13/25 (52%) have confirmed response (CR/PR). Two subjects had CR lasting for at least 35 and 44 months, 6 subjects achieved stable disease (SD) lasting at least 6 months accounting for disease control rate (DCR) of 76%, mPFS is 9.5 months. 5/30 patients have sarcomatoid features, all of which are evaluable for efficacy with 1 PR achieved (20%). In the 20 patients without sarcomatoid features, 12/20 achieved PR (60%). The most prevalent adverse events (AE) included fatigue, diarrhea, anorexia, nausea, hoarseness, weight loss, and hypertension. No deaths nor grade 4 toxicities observed. The blood selenium concentrations achieved in the 4000μg SLM dose cohorts are similar to those determined molecularly and therapeutically synergistic with axitinib in xenografts and are being achieved clinically without significant toxicity. DECT data demonstrated increased iodine uptake by tumor lesions, but not in normal tissues, on day 14 SLM treatment and decreased in these same lesions at 3 months of SLM/axitinib. Conclusions: Blood selenium concentrations and duration of treatment seem to be critical determinants of response. Pre and concurrent treatment with SLM enhance the ORR and PFS of axitinib, with no additional toxicity. Currently documented responses are similar across IMDC risk groups. Clinical trial information: NCT02535533 .

Intravesical Bacillus Calmette-Guérin (BCG) remains the standard of care in the treatment of bladder carcinoma in situ and as adjuvant therapy after thorough transurethral resection of high-grade non-muscle-invasive bladder cancer. Despite BCG therapy, in up to 40% of patients it would recur and 60% to 70% of those would fail repeat BCG induction be deemed BCG unresponsive. For such patients, cystectomy remains the preferred treatment option per the American Urological Association and European Association of Urology, though some patients would be medically unfit or refuse radical surgery. Further intravesical therapy for bladder-preservation therapies may preserve quality of life in these patients and in some cases can be curative. There are numerous non-BCG intravesical salvage options available, including immunotherapy, single-agent chemotherapy, combination chemotherapy, and device-assisted chemotherapy. In addition, investigation of radiation-based treatment and other novel therapies including checkpoint inhibitors (programmed death-1/programmed death ligand-1), are currently underway. In this review, we examine the current status of alternatives to BCG in salvage therapy for bladder preservation.

634 Background: Response to checkpoint inhibitors (CPIs) for renal cell cancer (RCC) remains variable, with markers like PDL1 proving unreliable. Preclinical models suggest that obesity could affect CPI outcomes. We conducted a retrospective study on the effect of obesity on outcomes in RCC patients treated with CPIs. Methods: RCC patients treated with nivolumab +/- Ipilimumab at university of Alabama at Birmingham (UAB) and University of Iowa (UIOWA) from 2015 - 2018 were classified according to WHO standard definition of BMI as non-obese (NOB-30Kg/m2). Overall survival (OS) was defined as the interval from the first CPI dose to date of death or to last follow up date if patients were still alive. Progression free survival (PFS) was defined as the interval from the first dose of CPI to date of progression or date of death and censored at last follow-up date if patients were still alive without progression. Multivariable Cox proportional hazard regression model was used to evaluate the association between OS/PFS and obesity status, controlling for age, sex, race and number of prior therapies. All analyses were performed using SAS 9.4. Results: 84 patients with at least 6 months follow-up received a median of 9 doses of CPI with median follow of 72 weeks. 48 patients were NOB while 36 patients were OB, with 40 patients deceased at time of analysis. The most common response was stable disease in 45%, with CR in 5% and PR in 10% for a disease control rate of 63%. The median OS was 30 months in NOB patients and 20 months in the OB group. The 2 yr survival was 59% in the NOB group vs 28 % in the OB group with a HR of 0.60 (0.32-1.14; p=0.12). Median PFS was 13 months in the NOB group vs 7.3 months in the OB group with 2 yr PFS of 28% in the NOB group vs 5.5% in the OB group (HR 0.58 {0.35-0.98}; p=0.04). Conclusions: In this analysis of RCC patients treated with CPI, BMI < 30 predicts better OS and PFS. Further studies are required to better understand the effect of BMI on CPI outcomes in RCC.[Table: see text]

487 Background: Advanced bladder cancer is the most common malignancy of the urinary system with 5-year OS rates of 5-7%. Platinum based chemotherapy and checkpoint inhibitors are currently available treatment options but with limited benefit. We hypothesize that combining Avelumab (anti-PD-L1 immunotherapy) with Docetaxel is safe and will lead to cancer cell death releasing neoantigens with enhanced anti-tumor immune mediated cytotoxicity. Methods: This is a phase 1b, single arm, non-randomized, open label prospective clinical trial to evaluate the combination of Avelumab and Docetaxel in adult subjects with locally advanced or metastatic urothelial carcinoma with disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. It has two phases: Phase 1b dose de-escalation of docetaxel (Level 0: 75, Level -1: 60 or Level -2: 45 mg/m2) with standard dose avelumab (10 mg/kg) to establish phase 2 dose in the standard 3+3 design. In the dose expansion phase, the phase 2 dose of docetaxel with avelumab will be evaluated for efficacy. The combination therapy is administered every 3 weeks for 6 cycles and then avelumab alone is continued every 2 weeks. Primary endpoint is safety. Efficacy endpoints include objective response rate, progression free survival and overall survival. Results: At the cutoff date of 10/21/2019, 10 eligible patients were enrolled in the study. Only one of the six patients treated with level 0 dose of docetaxel had a dose limiting toxicity (neutropenic fever). Docetaxel at 75 mg/m2 along the avelumab was deemed safe for dose expansion cohort. Additional 4 patients were enrolled in the dose expansion cohort. Efficacy data is preliminary with 1 patient achieving CR, 2 pts had PR, 2 pts had SD, 1 pt PD and 4 pts are not yet evaluable. The most common Grade 3 or 4 AEs were febrile neutropenia, urinary tract infection and confusion. No treatment related deaths were noted. Conclusions: The combination of docetaxel in combination with avelumab is safe and the preliminary data showed promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT03575013.

Several tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptors and molecules inhibiting the mammalian target of rapamycin are being used for management of metastatic renal cell carcinoma (mRCC); however, there is still a potential for improvement. Immune checkpoint inhibitors like nivolumab and other PD-1/PD-L1 inhibitors provide an alternative approach for patients with mRCC. In this article, the authors review the safety profile and outcomes of phase 1, 2, and 3 clinical trials of nivolumab in mRCC.

Background Bacillus Calmette-Guerin (BCG) is the most effective initial intravesical therapy for high-grade non–muscle invasive bladder cancer, but many patients still fail. Combination intravesical BCG and interferon (IFN) will salvage some patients but results remain suboptimal. Objective We hypothesized that further immunostimulation with intravesical interleukin-2 and subcutaneous granulocyte-macrophage colony-stimulating factor may improve response to intravesical BCG and IFN in patient with prior BCG failure(s). Methods A retrospective review was performed. Patients received 6 treatments of quadruple immunotherapy (intravesical solution with one-third dose BCG, 50 million units IFN, and 22 million units interleukin-2, along with a 250-mcg subcutaneous sargramostim injection). Surveillance began 4 to 6 weeks after treatment completion. Patients received maintenance if recurrence-free. Success was defined as no recurrence (bladder or extravesical) and bladder preservation. Analysis was performed by Kaplan-Meier method (P Results Fifty-two patients received treatment with a median recurrence follow-up of 16.3 months and overall follow-up of 41.8 months. All patients had at least 1 prior BCG failure and 13% had 2 or more prior failures. Only 3 patients (6%) were unable to tolerate full induction. Treatment success was 55% at 1 year, and 53% at 2 years. Thirteen patients (25%) underwent cystectomy at a median time of 17.3 months with disease progression to T2 in 1 patient and T3 in 2 patients. No patients had positive surgical margins or positive lymph nodes. Conclusions In patients with non–muscle-invasive bladder cancer with prior BCG failure, quadruple immunotherapy demonstrated good treatment success in some patients and warrants further evaluation.

ObjectiveActive surveillance (AS) is an increasingly utilized strategy for monitoring men with low-risk prostate cancer (PCa) that allows them to defer active treatment (AT) in the absence of cancer progression. Studies have explored reasons for selecting AS and for then switching to AT, but less is known about men's experiences being on AS. We interviewed men to determine the clinical and psychological factors associated with selecting and adhering to AS protocols.MethodsWe conducted semi-structured interviews with men with a low-risk PCa at two academic medical centers. Subjects had either been on AS for ≥ 1 year or had opted for AT after a period of AS. We used an iterative, content-driven approach to analyze the interviews and to identify themes.ResultsWe enrolled 21 subjects, mean age 70.4 years, 3 racial/ethnic minorities, and 16 still on AS. Men recognized the favorable prognosis of their cancer (some had sought second opinions when initially offered AT), valued avoiding treatment complications, were reassured that close monitoring would identify progression early enough to be successfully treated, and trusted their urologists. Although men reported feeling anxious around the time of surveillance testing, those who switched to AT did so based only on evidence of cancer progression.ConclusionsOur selected sample was comfortable being on AS because they understood and valued the rationale for this approach. However, this highlights the importance of ensuring that men newly diagnosed with a low-risk PCa are provided sufficient information about prognosis and treatment options to make informed decisions.

Background The overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses and schedules of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods This is a phase I (3 + 3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with standard dose axitinib to patients with metastatic ccRCC. Primary endpoint is safety; secondary endpoint is efficacy including overall response rate, progression free survival and overall survival. Results Twelve evaluable patients (pts) with metastatic ccRCC who progressed on one or more prior lines of treatment were enrolled. The first 3 pts were treated at 4000 µg, the second and third 3 pts were treated at 2500 and 3000 µg respectively. Additional 3 pts were added to 4000 µg. No dose limiting toxicity was seen. Most common AEs included fatigue, diarrhea, hypertension, nausea, anorexia, cough, proteinuria and weight loss. Of the 4000 µg cohort, 2 pts achieved complete response with ongoing responses at 31 and 29 months, 1 pt had partial response (PR) for 24 months. Of the 2500 µg cohort, 1 pt with ongoing PR for 21 months. The 3000 µg cohort, one pt has ongoing PR for 12 months. Conclusions SLM of 4000 µg is safe and the recommended phase 2 dose in combination with standard dose axitinib. The combination has promising efficacy with phase 2 trial is ongoing. Further data to be presented at the meeting. Clinical trial identification NCT02535533. Legal entity responsible for the study Yousef Zakharia. Funding Holden Comprehensive Cancer Centre. Disclosure Y. Zakharia: Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche Diagnostics; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jansen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Castle Bioscience; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bayer; Advisory / Consultancy: Array. M. Milhem: Advisory / Consultancy: Amgen; Advisory / Consultancy: Trieza; Advisory / Consultancy: Biontech; Advisory / Consultancy: Blueprint Medicines Corporation; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Array. All other authors have declared no conflicts of interest.

469 Background: Bacillus Calmette-Guerin (BCG) is the standard of care for patients with new non-muscle invasive bladder cancer (NMIBC) after transurethral tumor resection. While BCG has been compared to single agent intravesical chemotherapy as first-line therapy, few studies exist comparing BCG to sequential intravesical chemotherapy regimens. The objective of this work was to determine the efficacy of sequential intravesical gemcitabine and docetaxel (Gem/Doce) in BCG naïve patients with NMIBC. Methods: Patients without prior BCG exposure who underwent Gem/Doce intravesical treatments were retrospectively identified. These patients had been treated with 6 weekly instillations of gemcitabine (1 gram of gemcitabine in 50 ml of sterile water) followed immediately by docetaxel (37.5 mg of docetaxel in 50 mL of saline). Patients without recurrence then underwent maintenance therapy with monthly instillations for two years. Treatment success was defined as no bladder cancer recurrence and no cystectomy. Survival analysis was performed using the Kaplan Meier method. Results: 30 patients were treated with a median follow-up of 18 months. Eighty percent (n=24) of patients had high risk disease. Median age was 78 years old. The most common indications for Gem/Doce therapy were “advanced age/frailty” (n=15), “immunosuppression” (n=4), and “BCG Shortage” (n=4). Treatment success was 96% at 3 months, 89% at 1 year, and 89% at 2 years. No patients progressed or required cystectomy. Treatments were generally well tolerated, with only one patient unable to finish induction and two patients declining maintenance. Side-effects included urinary urgency/frequency (30%), dysuria (26%), and hematuria (23%). A need for dose reduction or delay was uncommon (16%). The all-cause mortality rate was 3.5% at 1 year, and 16.5% at 2 years. Neither bladder cancer nor the treatments were the cause of any of the deaths. Conclusions: Sequential intravesical gemcitabine and docetaxel is an effective treatment for BCG naïve NIMBC. Treatments are generally well tolerated even in a frail and comorbid patient population. Further evaluation of this combination therapy for BCG naïve disease is warranted.

660 Background: The overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with standard dose axitinib to patients with metastatic RCC. Primary endpoint is safety. Secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 12 evaluable patients (pts) with metastatic RCC who progressed on one or more prior lines of treatment were enrolled. The first 3 pts were treated at 4000 µg, the second and third 3 pts were treated at 2500 and 3000 µg respectively. Additional 3 pts were added to 4000 µg. No dose limiting toxicity (DLT) was seen. Most common AEs included fatigue, diarrhea, hypertension, nausea, anorexia, cough, proteinuria and weight loss. Of the 4000 µg cohort, 2 pts achieved CR with ongoing responses at 31 and 29 months, 1 pt had PR for 24 months and 1 had PD at 3 months, 2 pts are not assessed yet. Of the 2500 µg cohort, 1 pt with ongoing PR for 21 months, 1 pt had stable disease for 6 months, and 1 pt had PD at 2 months. The 3000 µg cohort, one pt has ongoing PR for 12 months; another pt had PR lasting 10 months, the 3rd pt had SD for 4 months. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy. Further data including biomarkers will be presented at the meeting. Clinical trial information: NCT02535533.

Objective Endorectal MRI (ER-MRI) may identify areas suspicious for prostate cancer. We evaluated the accuracy of ER-MRI compared with subsequent pathology specimen from prostatectomy. Materials and methods We reviewed 309 open radical retropubic prostatectomy cases (RRP) from 2003 to 2008 to identify 94 men with a preoperative ER-MRI, which was obtained in patients with high-risk factors suspicious for local extension (Gleason grade ≥ 4+3, PSA ≥ 10 ng/ml, abnormal rectal exam, or extensive biopsy core involvement). Findings of extracapsular extension (ECE), seminal vesicle invasion (SVI), and lymphadenopathy (LAD) on ER-MRI were compared with subsequent findings on pathology specimens. Results Ninety-four men underwent preoperative ER-MRI. No tumor was seen on ER-MRI in 9 men (10%). Of 94 ER-MRIs, 4% showed SVI, and 12% had ECE. At prostatectomy, lymph nodes were pathologically positive in 10 men, none of which were enlarged on ER-MRI. RRP was aborted in 3 of these 10 patients due to positive nodes confirmed on frozen section. Comparing ER-MRI results to subsequent prostatectomy specimen the results for accuracy, positive predictive value, negative predictive value, sensitivity, specificity were 70%, 27%, 76%, 14%, 88% for ECE and 93%, 75%, 94%, 38%, 99% for SVI. The accuracy of ECE prediction was 86% in abnormal rectal exam vs. 66% in normal exam (P Conclusions Endorectal MRI in the evaluation of high-risk prostate cancer was moderately accurate for SV involvement but inaccurate for ECE and insensitive for metastatic lymph node involvement. The predictive accuracy of ER-MRI improved in patients with an abnormal rectal exam.

Prostate cancer is a leading cause of morbidity and mortality in men and has significant treatment-associated complications. Prostate cancer chemoprevention has the potential to decrease the morbidity and mortality associated with this disease. Chemoprevention research to date has primarily focused on nutrients and 5 alpha-reductase inhibitors (5ARIs). A large randomized trial (SELECT) found no favorable effect of selenium or vitamin E on prostate cancer prevention. Two large randomized placebo controlled trials (the PCPT and REDUCE trials) have been published and have supported the role of 5ARIs in prostate cancer chemoprevention; however, these trials also have prompted concerns regarding the increase in high-grade disease seen with treatment and have not been approved by the US Food and Drug Administration (FDA) for chemoprevention. Conclusive evidence for the chemopreventive benefit of nutrients or vitamins is lacking, whereas the future role of 5ARIs remains to be clarified.

The purpose of this article is to provide an update on the current literature evaluating outcomes with laparoscopic prostatectomy. The reported perioperative, oncologic, and functional outcomes with this approach are reviewed and comparisons are made to the open and robotic-assisted approaches.

Patients with high-grade muscle invasive bladder cancer (NMIBC) receive intravesical therapy with bacillus Calmette-Guerin (BCG) as the well-established standard-of-care. However, even with prompt induction of intravesical therapy, approximately 40 % of patients will recur within 2 years. For patients who fail BCG, options include radical cystectomy, repeat BCG therapy, or alternative intravesical salvage therapy. In this review, we will discuss the most recent published evidence on salvage intravesical therapy with an emphasis on a more in-depth report of our therapeutic strategy with sequential gemcitabine and docetaxel intravesical therapy for this treatment-refractory population. In addition, we will provide practical advice on our approach to this challenging patient population including the use of operative staging to aid early identification of treatment failures.

630 Background: The overexpression of hypoxia induced factor (HIF) 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses and schedules of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with the standard dose of axitinib to patients with metastatic RCC. Primary endpoint is safety, secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 9 patients with metastatic RCC; who failed one or more prior lines of treatment; are enrolled. The first 3 patients were treated at 4000 µg, the second and third 3 patients were treated at 2500 and 3000 µg respectively. No dose limiting toxicity (DLT) is encountered. Six patients are evaluable to date. Of the 4000 µg cohort, 2 patients achieved complete remission (CR) at 18 and 20 months, 1 patient with partial response (PR) at 19 month. Of the 2500 µg cohort, one patient achieved PR at 9 months, 1 patient had stable disease for 9 months before progression, and 1 patient had disease progression at 4 months. The 3000 µg cohort is too early to evaluate for efficacy. Of interest the 4000μg SLM dose yielded a plasma selenium concentration of 40-50μM which is comparable with SLM dose determined synergistic with anti-cancer drugs in preclinical models. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT02535533.

PurposeGleason 6 (3+3) is the most commonly diagnosed prostate cancer among men with prostate specific antigen screening, the most histologically well differentiated and is associated with the most favorable prognosis. Despite its prevalence, considerable debate exists regarding the genetic features, clinical significance, natural history, metastatic potential and optimal management.Materials and methodsMembers of the Young Urologic Oncologists in the Society of Urologic Oncology cooperated in a comprehensive search of the peer reviewed English medical literature on Gleason 6 prostate cancer, specifically focusing on the history of the Gleason scoring system, histological features, clinical characteristics, practice patterns and outcomes.ResultsThe Gleason scoring system was devised in the early 1960s, widely adopted by 1987 and revised in 2005 with a more restrictive definition of Gleason 6 disease. There is near consensus that Gleason 6 meets pathological definitions of cancer, but controversy about whether it meets commonly accepted molecular and genetic criteria of cancer. Multiple clinical series suggest that the metastatic potential of contemporary Gleason 6 disease is negligible but not zero. Population based studies in the U.S. suggest that more than 90% of men newly diagnosed with prostate cancer undergo treatment and are exposed to the risk of morbidity for a cancer unlikely to cause symptoms or decrease life expectancy. Efforts have been proposed to minimize the number of men diagnosed with or treated for Gleason 6 prostate cancer. These include modifications to prostate specific antigen based screening strategies such as targeting high risk populations, decreasing the frequency of screening, recommending screening cessation, incorporating remaining life expectancy estimates, using shared decision making and novel biomarkers, and eliminating prostate specific antigen screening entirely. Large nonrandomized and randomized studies have shown that active surveillance is an effective management strategy for men with Gleason 6 disease. Active surveillance dramatically reduces the number of men undergoing treatment without apparent compromise of cancer related outcomes.ConclusionsThe definition and clinical relevance of Gleason 6 prostate cancer have changed substantially since its introduction nearly 50 years ago. A high proportion of screen detected cancers are Gleason 6 and the metastatic potential is negligible. Dramatically reducing the diagnosis and treatment of Gleason 6 disease is likely to have a favorable impact on the net benefit of prostate cancer screening.

Background: We analyzed differences in patient selection and perioperative outcomes between robotic-fellowship trained and non-fellowship trained surgeons in their initial experience with robotic-assisted laparoscopic partial nephrectomy. Methods: Data through surgeon case 10 was analyzed. Forty patients were identified from two fellowship trained surgeons (n = 20) and two non-fellowship trained surgeons (n = 20). Results: Fellowship trained surgeons performed surgery on masses of higher nephrometry score (8.0 vs. 6.0, p = 0.007) and more posterior location (60 vs. 25%, p = 0.03). Retroperitoneal approach was more common (50 vs. 0%, p = 0.0003). Fellowship trained surgeons trended toward shorter warm ischemia time (25.5 vs. 31.0 min, p = 0.08). There was no significant difference in perioperative complications (35 vs. 35%, p = 0.45) or final positive margin rates (0 vs. 15%, p = 0.23). Conclusion: Fellowship experience may allow for treating more challenging and posterior tumors in initial practice and significantly more comfort performing retroperitoneal robotic-assisted laparoscopic partial nephrectomy.

Objectives Obesity, typically defined as a body mass index (BMI)≥30 kg/m 2 , is an established risk factor for renal cell carcinoma (RCC) but is paradoxically linked to less advanced disease at diagnosis and improved outcomes. However, BMI has inherent flaws, and alternate obesity-defining metrics that emphasize abdominal fat are available. We investigated 3 obesity-defining metrics, to better examine the associations of abdominal fat vs. generalized obesity with renal tumor stage, grade, or R.E.N.A.L. nephrometry score. Methods and materials In a prospective cohort of 99 subjects with renal masses undergoing resection and no evidence of metastatic disease, obesity was assessed using 3 metrics: body mass index (BMI), radiographic waist circumference (WC), and retrorenal fat (RRF) pad distance. R.E.N.A.L. nephrometry scores were calculated based on preoperative CT or MRI. Univariate and multivariate analyses were performed to identify associations between obesity metrics and nephrometry score, tumor grade, and tumor stage. Results In the 99 subjects, surgery was partial nephrectomy in 51 and radical nephrectomy in 48. Pathology showed benign masses in 11 and RCC in 88 (of which 20 had stage T3 disease). WC was positively correlated with nephrometry score, even after controlling for age, sex, race, and diabetes status ( P = 0.02), whereas BMI and RRF were not ( P = 0.13, and P = 0.57, respectively). WC in stage T2/T3 subjects was higher than in subjects with benign masses ( P = 0.03). In contrast, subjects with Fuhrman grade 1 and 2 tumors had higher BMI ( P P = 0.04) than subjects with grade 3 and 4 tumors. Conclusions Our data suggest that obesity measured by WC, but not BMI or RRF, is associated with increased renal mass complexity. Tumor Fuhrman grade exhibited a different trend, with both high WC and BMI associated with lower-grade tumors. Our findings indicate that WC and BMI are not interchangeable obesity metrics. Further evaluation of RCC-specific outcomes using WC vs. BMI is warranted to better understand the complex relationship between general vs. abdominal obesity and RCC characteristics.

Despite known survival benefits, overall use of neoadjuvant chemotherapy before cystectomy is low, raising concerns about quality of care. However, not all patients undergoing cystectomy are eligible for this therapy. We establish the maximum proportion of patients expected to receive neoadjuvant chemotherapy if all those eligible had a consultation with medical oncology.From institutional data (January 2010 through December 2012) we identified 215 patients treated with radical cystectomy for bladder cancer. After excluding patients not eligible for neoadjuvant chemotherapy, we fit models assessing patient disease and health factors affecting referral to medical oncology and receipt of neoadjuvant chemotherapy. Expected use of chemotherapy was then determined for increasingly broad groups of patients treated with cystectomy after controlling for factors precluding the use of neoadjuvant chemotherapy.Of the 215 patients identified 127 (59%) were eligible for neoadjuvant chemotherapy. After additional consideration of patient factors (patient refusal, health status and poor renal function), maximum receipt of neoadjuvant chemotherapy increased from 42% to 71% as more restrictive definitions for the eligible patient cohort were used.Substantial variability exists in the proportion of patients eligible for neoadjuvant chemotherapy based on the population identified. While there is substantial underuse of neoadjuvant chemotherapy, the development of quality metrics for this essential therapy depends on correct identification of the cystectomy population being assessed. Even with referral of all appropriate patients for medical oncology evaluation, use of chemotherapy would likely not exceed 50% of patients in nationally representative cystectomy data.

Prostate cancer detection and management continues to be an area of immense study, debate, and controversy. Despite the best efforts of urologists, radiation oncologists, and medical oncologists, some men will die of prostate cancer despite the currently available options for prostate cancer treatment. On the opposite end of the spectrum from that aggressive form of prostate cancer is the indolent prostate cancer that never affects the man who bears the diagnosis. Thus, this creates a primary problem in the use of prostate cancer screening: some men with aggressive prostate cancer may not be readily identified and treated despite efforts at prostate cancer screening and biopsy; however, other men who have an indolent small volume prostate cancer are unlikely to be harmed from the prostate cancer itself but are subjected to the side effects associated with treatment.

INTRODUCTION AND OBJECTIVES: Prostate cancer (CaP) has a protracted natural history relative to other solid malignancies, and the risk of competing causes of mortality is important to weigh at the time of treatment decision-making. We endeavored to develop nomograms predicting all-cause mortality (ACM) and prostate cancer specific mortality (PCSM) following definitive therapy for localized CaP. METHODS: A total of 10,429 patients who had undergone radical prostatectomy (RP, n 6,485), external beam radiotherapy (EBRT, n 2,264), or interstitial brachytherapy (PI, n 1,680) for localized CaP at Cleveland Clinic or Barnes-Jewish Hospital between 1995 and 2005 were included in the analysis. Prognostic variables included age, PSA, biopsy Gleason grade ( 6, 7, or 8), clinical T stage, treatment modality, and comorbidity status (none, mild, moderate, or severe). ACM was modeled using Cox regression analysis; PCSM was modeled using Fine and Gray competing risk analysis. We performed internal validation using bootstrapping and cross-validation. The calibration was assessed graphically. RESULTS: The median follow-up was 5.5 years, and 1,532 (14.7%) of survivors had follow-up greater than 10 years. Overall, 1,256 deaths (12.0%) were observed, 182 (1.7%) of which were attributed to prostate cancer. Age, treatment modality, PSA, biopsy Gleason grade, and comorbidity status were significantly predictive of ACM. In regards to PCSM, age, PSA, biopsy Gleason grade, and clinical T stage were significantly predictive of outcome. Nomograms were constructed for these outcomes with good concordance (c 0.74 and 0.81, respectively). CONCLUSIONS: The pre-treatment risk of ACM and PCSM can be predicted with reasonable accuracy. This information is essential when counseling patients particularly the elderly and those with significant comorbid illnesses prior to proceeding with definitive therapy for localized CaP. Source of Funding: None

Prostate cancer is a leading cause of morbidity and mortality with significant treatment associated complications. Chemoprevention could potentially decrease the morbidity and mortality from the disease. Prostate cancer has been an attractive target for chemoprevention. Research has primarily focused on 5 alpha reductase inhibitors and nutrients including three large randomized placebo controlled trials published between 2003 and 2010 with a total of 61,144 patients. The Prostate Cancer Prevention Trial examined the utility of finasteride in low risk men with no prior prostate biopsy. They reported a 24.4 % reduction in overall prostate cancer risk (18.4 % vs. 24.4 %), but an increased risk for high grade tumors. Subsequent analysis has demonstrated this increased risk for high grade disease is likely an artifact. The Reduction by Dutasteride of Prostate Cancer Events trial of dutasteride in a higher risk group of men with a negative baseline biopsy found a 22.8 % relative risk reduction in prostate cancer (19.9 % vs. 25.1 %) with no increase in high grade prostate cancer. With respect to nutrient use, the Selenium and Vitamin E Cancer Prevention Trial found no favorable effect of selenium or vitamin E on prostate cancer prevention. In summary, the data are strongest for the use of 5 alpha reductase inhibitor dutasteride in prostate cancer chemoprevention of high risk patients. Conclusive evidence for the benefit of nutrients or vitamins is lacking.

Oncologic outcomes of robotic cystectomy have focused on pathology and not on survival endpoints. We compared pathology, recurrence, and survival in a single surgeon series of open and robotic cystectomy since the introduction of robotic cystectomy.We identified all patients treated by a single surgeon with radical cystectomy for urothelial cancer from June 2007 to June 2010. Clinical, demographic, and pathologic data was abstracted from chart review. Mortality was obtained from institutional cancer registry and chart review. Patients were excluded from analysis for a relative contraindication to robotic surgery. The remaining cohort of patients undergoing robotic (n = 36) vs. open (n = 29) cystectomy with median follow-up 12.2 months were evaluated.The robotic cohort was more likely to be older and male (P0.05). Obesity, comorbidity, preoperative pathology, and receipt of neoadjuvant chemotherapy were not different between groups. Three patients had conversion from robotic to open cystectomy because of difficult dissection. Mean surgical time was longer in robotic cystectomy (410 vs. 345 minutes, P0.01). Cystectomy pathology was not different for robotic vs. open surgery for stage, margin status, or mean node count (robotic: 17.0, open: 15.5). On survival analysis robotic and open cystectomy outcomes were similar with respect to recurrence-free, disease-specific, and overall survival (all log-rank P values0.05). The Kaplan-Meier estimate for 2-year outcome for recurrence-free, disease-specific, and overall survival was 67% (95% CI: 41-83), 75% (95% CI: 53-88), 68% (95% CI: 47-82) for robotic cystectomy and 58% (95% CI: 29-79), 63% (95% CI: 34-82), 63% (95% CI: 34-82) for open cystectomy.Short-term oncologic outcomes were similar for open and robotic cystectomy. Increased sample size and further follow-up are necessary before claiming equivalent long-term survival.

The unpredictable behavior of carcinoma in situ and its high potential for recurrence and progression make identifying patient characteristics predicting a poor prognosis a priority. We assessed which factors affect the response to bacillus Calmette-Guérin plus interferon-α therapy in patients with urothelial carcinoma in situ.We analyzed data on a subset of 231 patients with carcinoma in situ enrolled in a multicenter, phase II trial of bacillus Calmette-Guérin plus interferon-α therapy for nonmuscle invasive bladder cancer. Analysis included patients who were bacillus Calmette-Guérin naïve and those with previous exposure to failed bacillus Calmette-Guérin therapy. We evaluated factors potentially affecting the bacillus Calmette-Guérin plus interferon-α response, including patient age, gender, tumor stage, multifocality, prior tumor stage, the previous bacillus Calmette-Guérin failure pattern, courses and maintenance, and prior chemotherapy.The complete response rate at 3 and 6 months in naïve vs previously failed bacillus Calmette-Guérin cases was 76% and 70% vs 76% and 66%, respectively. The 24-month disease-free rate was decreased in the 53 patients with a history of 2 or more failed bacillus Calmette-Guérin courses vs that in the 71 with a history of 1 failed course and bacillus Calmette-Guérin naïve patients (23% vs 57% and 60%, respectively). The 22 patients with refractory carcinoma in situ had the worst outcome of a 23% disease-free rate at 24 months while the 59 with relapse within 1 year had an intermediate outcome of 42% vs 59% in the 33 with relapse after 1 year. Patients with a history of papillary disease did better than those without such a history (p=0.019).Factors associated with a poor response to bacillus Calmette-Guérin plus interferon-α therapy in patients with carcinoma in situ are prior tumor stage, 2 or more prior bacillus Calmette-Guérin failures and a bacillus Calmette-Guérin failure pattern.

Stage T1Hg bladder cancer should be considered an aggressive andpotentially lethal disease. The importance of initial re-resection toidentify unrecognized muscle-invasive disease is significant. Mostpatients with high-risk disease are candidates for initial bladder salvagewith intravesical bacillus Calmette-Guerin vaccine forimmunotherapy, a procedure with a high survival rate; however,failure of the procedure may result in a guarded prognosis. Evenafter apparent success, patients should be informed of the risks ofthe disease progressing to muscle-invasive or metastatic diseaseand the need for vigilant monitoring. Despite optimal management,a significant number of patients relapse or progress to invasive diseaserequiring cystectomy. This review provides insight into theoptimal management of T1 high-grade bladder cancer.

Introduction and Objectives: A phase II clinical trial of an adenovirus/PSA (Ad/PSA) vaccine was carried out in men with recurrent prostate cancer using two protocols. The objectives of the study were to determine whether the vaccine produced beneficial immune and clinical responses in men with a low burden of tumor. Methods: In Protocol #1 men with recurrent prostate cancer following definitive initial treatment for their disease were placed in one of two arms: Arm A; men received the vaccine alone at days 0, 30, and 60; Arm B; men received the vaccine 14 days after the initiation of androgen deprivation therapy (ADT). In Protocol #2 men with hormone refractory disease received the vaccine alone using the same 3 injection schedule. Each injection consists of 108 pfu of the Ad/PSA vaccine suspended in a collagen matrix. All patients returned at regular intervals for physical, chemical, radiologic, and immunologic evaluations. Results: We enrolled all of our targeted 82 patients, 50 in protocol 1 (25 Arm A, 25 Arm B) and 32 in protocol 2. All patients have been followed a minimum of 12 months with the longest being over 6 years. Eighty nine percent (89%) of all patients produced anti-PSA T cell immune responses; 71% in protocol 1 Arm A, 100% in protocol 1 Arm B, and 100% in protocol 2. Clinically, 58% of patients in protocol 1 Arm A and 75% of patients in protocol 2 demonstrated a decrease in serum PSA or an increase in PSA doubling times (PSADT). As of the submission date the PSA levels of 2 patients declined to 0.07 ng/ml and undetectable ( Conclusions: Preliminary results of patients thus far studied in a phase II clinical trial of the Ad/PSA vaccine are very encouraging, demonstrating both immunologic and clinical responses to the 3-vaccination therapy. PSA responses indicate at least a decline in the growth and perhaps a destruction of recurrent prostate tumors in men immunized in two separate protocols. Data collection continues that include completion of immune assays on all 82 patients as well as monitoring PSA levels, PSADT, and radiologic changes. Citation Format: David M. Lubaroff, Daniel Vaena, James Brown, Kenneth Nepple, Pamela Zehr, Karen Griffith, Erica Brown, Julie Eastman, Gideon Zamba, Richard Williams. Preliminary results of a phase II trial of an adenovirus/PSA vaccine in men with recurrent prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT208. doi:10.1158/1538-7445.AM2015-CT208

e16132 Background: AdPSA is an investigational replication-deficient adenovirus-based PSA vaccine. A prior phase I trial in patients with metastatic castrate-resistant prostate cancer (CRPC) showed...