NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024.

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

BTK inhibition potentiates anti-PD-L1 treatment in murine melanoma: potential role for MDSC modulation in immunotherapy.

Myeloid-derived suppressor cells (MDSC) have been linked to loss of immune effector cell function through a variety of mechanisms such as the generation of reactive oxygen and nitrogen species and the production of inhibitory cytokines. Our group has shown that signaling through Bruton's tyrosine kinase (BTK) is important for MDSC function. Ibrutinib is an orally administered targeted agent that inhibits BTK activation and is currently used for the treatment of B cell malignancies. Using a syngeneic murine model of melanoma, the effect of BTK inhibition with ibrutinib on the therapeutic response to systemic PD-L1 blockade was studied. BTK was expressed by murine MDSC and their activation was inhibited by ibrutinib. Ibrutinib was not directly cytotoxic to cancer cells in vitro, but it inhibited BTK activation in MDSC and reduced expression of inducible nitric oxide synthase (NOS2) and production of nitric oxide. Ibrutinib treatments decreased the levels of circulating MDSC in vivo and increased the therapeutic efficacy of anti-PD-L1 antibody treatment. Gene expression profiling showed that ibrutinib decreased Cybb (NOX2) signaling, and increased IL-17 signaling (upregulating downstream targets Mmp9, Ptgs2, and S100a8). These results suggest that further exploration of MDSC inhibition could enhance the immunotherapy of advanced melanoma.PrécisInhibition of Bruton's tyrosine kinase, a key enzyme in myeloid cellular function, improves therapeutic response to an anti-PD-L1 antibody in an otherwise fairly resistant murine melanoma model.

Oncologic outcomes among Black and White men with grade group 4 or 5 (Gleason score 8-10) prostate cancer treated primarily by radical prostatectomy.

BACKGROUND: The aim of this study was to describe pathologic and short-term oncologic outcomes among Black and White men with grade group 4 or 5 prostate cancer managed primarily by radical prostatectomy. METHODS: This was a multi-institutional, observational study (2005-2015) evaluating radical prostatectomy outcomes by self-identified race. Descriptive analysis was performed via nonparametric statistical testing to compare baseline clinicopathologic data. Univariable and multivariable time-to-event analyses were performed to assess biochemical recurrence (BCR), metastasis, cancer-specific mortality (CSM), and overall survival between Black and White men. RESULTS: In total, 1662 men were identified with grade group 4 or 5 prostate cancer initially managed by radical prostatectomy. Black men represented 11.3% of the cohort (n = 188). Black men were younger, demonstrated a longer time from diagnosis to surgery, and were at a lower clinical stage (all P < .05). Black men had lower rates of pT3/4 disease (49.5% vs 63.5%; P < .05) but higher rates of positive surgical margins (31.6% vs 26.5%; P = .14) on pathologic evaluation. There was no difference in BCR, CSM, or overall survival over a median follow-up of 40.7 months. Black men had a lower 5-year cumulative incidence of metastasis-free survival (93.6%; 95% confidence interval [CI], 86.5%-97.0%) in comparison with White men (85.8%; 95% CI, 83.1%-88.0%), which did not persist in an age-adjusted analysis. CONCLUSIONS: Black and White men with high-grade prostate cancer at diagnosis demonstrated similar oncologic outcomes when they were managed by primary radical prostatectomy. Our findings suggest that racial disparities in prostate cancer mortality are not related to differences in the efficacy of extirpative therapy.

Downgrading from Biopsy Grade Group 4 Prostate Cancer in Patients Undergoing Radical Prostatectomy for High or Very High Risk Prostate Cancer.

PURPOSE: We examined rates of Grade Group 4 downgrading at radical prostatectomy among men diagnosed with high and very high risk prostate cancer at biopsy. MATERIALS AND METHODS: A pooled cohort of 1,776 patients from 3 tertiary referral centers who underwent radical prostatectomy for National Comprehensive Cancer Network® high risk (prostate specific antigen greater than 20 ng/ml, or Grade Group 4-5, or clinical stage T3 or greater) or very high risk (primary Gleason pattern 5, or more than 4 biopsy cores with Grade Group 4-5, or 2 or more high risk features) disease from 2005 to 2015 were reviewed. Overall 893 patients with Grade Group 4 disease at biopsy were identified and 726 patients were available for analysis. Multivariable logistic regression models were fit to determine factors associated with downgrading to Grade Group 3 or less at radical prostatectomy. RESULTS: Overall 333 (45%) cases were downgraded to Grade Group 3 or less at radical prostatectomy. Of these cases 198 (27%) had concordant Grade Group 4 biopsy and radical prostatectomy pathology and 195 (27%) were upgraded at radical prostatectomy to Grade Group 5. Of high risk cases with biopsy Grade Group 4 disease 49% had any downgrading vs 29% of very high risk cases (p <0.0001). Downgrading to Grade Group 2 or less occurred in 16% (98 of 604) of high risk and 7% (8 of 122) of very high risk cases (p <0.01). Downgraded cases had a lower prostate specific antigen, fewer positive biopsy cores and lower clinical stage (p <0.01). On multivariable analysis fewer positive biopsy cores were significantly associated with downgrading at radical prostatectomy (p <0.01). CONCLUSIONS: In this cohort of patients with high risk/very high risk prostate cancer, downgrading from biopsy Grade Group 4 at radical prostatectomy occurred less frequently than in other published reports. Any downgrading was significantly less common in very high risk compared to high risk patients, and downgrading to Grade Group 2 or less occurred in a minority of cases in high risk and very high risk patients.

Outcomes of very high-risk prostate cancer after radical prostatectomy: Validation study from 3 centers.

BACKGROUND: Among men with localized high-risk prostate cancer (PCa), patients who meet very high-risk (VHR) criteria have been shown to experience worse outcomes after radical prostatectomy (RP) in a previous study. Variations of VHR criteria have been suggested to be prognostic in other single-center cohorts, but multicenter outcomes validating VHR criteria have not been described. This study was designed to validate VHR criteria for identifying which PCa patients are at greatest risk for cancer progression. METHODS: Patients with high-risk PCa undergoing RP (2005-2015) at 3 tertiary centers were pooled. The outcomes of men with VHR PCa were compared with the outcomes of those who did not meet VHR criteria. The high-risk criteria were a clinical stage of T3 to T4, a prostate-specific antigen level > 20 ng/mL, or a biopsy Gleason grade sum of 8 to 10. The VHR criteria were multiple high-risk features, >4 biopsy cores with a Gleason grade sum of 8 to 10, or primary Gleason grade pattern 5. Biochemical recurrence, metastasis (METS), and cancer-specific mortality (CSM) were assessed with competing risks regressions. Overall mortality was assessed with Cox survival models. RESULTS: Among 1981 patients with high-risk PCa, men with VHR PCa (n = 602) had adverse pathologic outcomes: 37% versus 25% for positive margins and 37% versus 15% for positive lymph nodes (P < .001 for both comparisons). Patients with VHR PCa also had higher adjusted hazard ratios for METS (2.78; 95% confidence interval [CI], 2.08-3.72), CSM (6.77; 95% CI, 2.91-15.7), and overall mortality (2.44; 95% CI, 1.56-3.80; P < .001 for all comparisons). CONCLUSIONS: In a validation study of patients who underwent treatment for high-risk PCa, VHR criteria were strongly associated with adverse pathologic and oncologic outcomes.

Does time from diagnosis to treatment of high- or very-high-risk prostate cancer affect outcome?

OBJECTIVE: To determine whether time from diagnosis to treatment impacted outcomes in a multicentre cohort of high- and very-high-risk (VHR) patients with prostate cancer undergoing radical prostatectomy (RP). PATIENTS AND METHODS: In all, 1392 patients from three tertiary centres who underwent RP for either high-risk or VHR disease, from 2005 to 2015, were identified. The cohort was divided into tertiles based on time from diagnostic biopsy to RP. Cumulative incidence of biochemical recurrence (BCR), metastasis, and prostate cancer-specific mortality (PCSM) were calculated for each tertile. The Kaplan-Meier method was used to evaluate for differences in all-cause mortality (ACM) amongst tertiles. Competing risks regression models, as well as Cox proportional hazards regression models, were fitted to assess the association between time-to-event outcomes and patient characteristics. RESULTS: The median (interquartile range [IQR]) time from biopsy to RP was 68 (50-94) days. The median (IQR) follow-up was 31 (12.1-55.7) months. The cumulative incidence of BCR (P = 0.14), metastasis (P = 0.15), and PCSM (P = 0.69) did not differ amongst time-to-treatment tertiles of VHR patients. Also, Kaplan-Meier estimates of ACM (P = 0.53) did not differ amongst time-to-treatment tertiles. Similarly, BCR, metastasis, PCSM, and ACM did not significantly differ amongst time-to-treatment tertiles in multivariable modelling. CONCLUSION: In this pooled meta-dataset of patients with high-risk or VHR prostate cancer, time from diagnosis to RP did not appear to significantly contribute to differences in clinical outcomes. This finding supports the safety of enrollment of such patients into neoadjuvant clinical trials.

Risk of Pathological Upgrading and Up Staging among Men with Low Risk Prostate Cancer Varies by Race: Results from the National Cancer Database.

PURPOSE: The impact of African-American race on oncologic outcomes for low risk prostate cancer is unclear due to conflicting data. We investigated the effect of African-American race on pathological upgrading and/or up staging at prostatectomy in men with clinically low risk prostate cancer. MATERIALS AND METHODS: We queried the National Cancer Database for men with low risk prostate cancer (clinical stage T2a or less, Gleason score 6 or less, prostate specific antigen less than 10 ng/ml) treated with radical prostatectomy between 2010 and 2013. The outcomes were pathological upgrading to Gleason score greater than 6 (primary) or Gleason score greater than 3+4=7 (secondary) and/or up staging (pathological T3-4 or N1 disease). The association between race and the end points was assessed using multivariable logistic regression. To further adjust for potential confounders, stratification by urban residence and comorbidity score, and subgroup analyses were performed. RESULTS: With adjustment for age, comorbidity, income, urban residence, T stage, prostate specific antigen and percentage of positive biopsy cores, African-American race conferred 1.2-fold higher odds of pathological upgrading to Gleason score greater than 6 and/or up staging (OR 1.2, 95% CI 1.1-1.3, p <0.01). African-American race also was an independent predictor of pathological upgrading to Gleason score greater than 3+4=7 and/or up staging (p=0.03). CONCLUSIONS: African-American men with low risk prostate cancer are more likely to harbor higher risk disease, which may lead to adverse outcomes. This finding alone does not preclude active surveillance. However, race should be considered as men weigh the risks and benefits of active surveillance vs treatment.

Establishment of a new prostate cancer multidisciplinary clinic: Format and initial experience.

BACKGROUND: The use of multidisciplinary clinics (MDCs) for outpatient cancer evaluation is increasing. MDCs may vary in format, and data on whether MDCs change prostate cancer (PCa) care are limited. Here we report on the setup and design of a relatively new PCa MDC clinic. Because MDC evaluation was associated with a comprehensive re-evaluation of all patients' staging and risk stratification data, we studied the frequency of changes in PCa grade and stage upon MDC evaluation, which provides a unique estimate of the magnitude of pathology, radiology, and exam-based risk stratification in a modern tertiary setting. METHODS: In 2008-2012, 887 patients underwent consultation for newly diagnosed PCa at the Johns Hopkins Hospital (JHH) weekly MDC. In a same-day process, patients are interviewed and examined in a morning clinic. Examination findings, radiology studies, and biopsy slides are then reviewed during a noon conference that involves real-time collaboration among JHH attending specialty physicians: urologists, radiation oncologists, medical oncologists, pathologists, and radiologists. During afternoon consultations, attending physicians appropriate to each patient's eligible treatment options individually meet with patients to discuss management strategies and/or clinical trials. Retrospective chart review identified presenting tumor characteristics based on outside assessment, which was compared with stage and grade as determined at MDC evaluation. RESULTS: Overall, 186/647 (28.7%) had a change in their risk category or stage. For example, 2.9% of men were down-classified as very-low-risk, rendering them eligible for active surveillance. 5.7% of men thought to have localized cancer were up-classified as metastatic, thus prompting systemic management approaches. Using NCCN guidelines as a benchmark, many men were found to have undergone non-indicated imaging (bone scan 23.9%, CT/MRI 47.4%). The three most chosen treatments after MDC evaluation were external beam radiotherapy ± androgen deprivation (39.3%), radical prostatectomy (32.0%), and active surveillance/expectant management (12.9%). CONCLUSIONS: A once-weekly same-day evaluation that involves simultaneous data evaluation, management discussion, and patient consultations from a multidisciplinary team of PCa specialists is feasible. Comprehensive evaluation at a tertiary referral center, as demonstrated in a modern MDC setting, is associated with critical changes in presenting disease classification in over one in four men.

Identification of men with the highest risk of early disease recurrence after radical prostatectomy.

BACKGROUND: Men destined to have early biochemical recurrence (BCR) following radical prostatectomy (RP) may be optimal candidates for multimodal treatment. Here we identified pre-operative predictors of early BCR within a surgical cohort who recurred. METHODS: An institutional prostate cancer (PCa) database containing over 20,000 patients was queried to identify 1,471 men who had BCR after RP, and pre-operative predictors of early versus late BCR were assessed. Early BCR was defined as recurrence within 1 year after RP. Within the recurrence cohort, those with National Comprehensive Cancer Network (NCCN) high-risk features were more likely to experience early BCR. Therefore, in all NCCN high-risk men in the database, we abstracted detailed pathologic biopsy data. Among 753 high-risk men, 41 alternate multivariable criteria were assessed for their ability to predict early BCR in crude and adjusted logistic regression models. RESULTS: The criteria that best identified those likely to experience early BCR are primary Gleason pattern 5 on biopsy or ≥4 cores containing pattern 4 (odds ratio 3.17, P < 0.001). These criteria included 26.7% of NCCN high-risk men. Additionally, these criteria selected for men within the high-risk classification who were at significantly higher risk of subsequent metastasis (adjusted hazard ratio 3.04, P < 0.001) and cancer-specific death (adjusted hazard ratio 3.27, P < 0.001). CONCLUSIONS: In men with PCa who present with high-risk features, pre-operative criteria have the ability to discriminate the subgroup most likely to experience early BCR after RP. Men at risk for early disease recurrence may be the most suitable candidates for multimodal therapy.

Pathological examination of radical prostatectomy specimens in men with very low risk disease at biopsy reveals distinct zonal distribution of cancer in black American men.

PURPOSE: Of men with very low risk prostate cancer at biopsy recent evidence shows that black American men are at greater risk for adverse oncologic outcomes after radical prostatectomy. We studied radical prostatectomy specimens from black and white men at very low risk to determine whether there are systematic pathological differences. MATERIALS AND METHODS: Radical prostatectomy specimens were evaluated in men with National Comprehensive Cancer Network® (NCCN) very low risk prostate cancer. At diagnosis all men underwent extended biopsy sampling (10 or more cores) and were treated in the modern Gleason grade era. We analyzed tumor volume, grade and location in 87 black and 89 white men. For each specimen the dominant nodule was defined as the largest tumor with the highest grade. RESULTS: Compared to white men, black men were more likely to have significant prostate cancer (61% vs 29%), Gleason 7 or greater (37% vs 11%, each p <0.001) and a volume of greater than 0.5 cm(3) (45% vs 21%, p = 0.001). Dominant nodules in black men were larger (median 0.28 vs 0.13 cm(3), p = 0.002) and more often anterior (51% vs 29%, p = 0.003). In men who underwent pathological upgrading the dominant nodule was also more frequently anterior in black than in white men (59% vs 0%, p = 0.001). CONCLUSIONS: Black men with very low risk prostate cancer at diagnosis have a significantly higher prevalence of anterior cancer foci that are of higher grade and larger volume. Enhanced imaging or anterior zone sampling may detect these significant anterior tumors, improving the outcome in black men considering active surveillance.

Outcomes of men with an elevated prostate-specific antigen (PSA) level as their sole preoperative intermediate- or high-risk feature.

OBJECTIVE: To investigate the post-prostatectomy and long-term outcomes of men presenting with an elevated pretreatment prostate-specific antigen (PSA) level (>10 ng/mL), but otherwise low-risk features (biopsy Gleason score ≤6 and clinical stage ≤T2a). PATIENTS AND METHODS: PSA-incongruent intermediate-risk (PII) cases were defined as those patients with preoperative PSA >10 and ≤20 ng/mL but otherwise low-risk features, and PSA-incongruent high-risk (PIH) cases were defined as men with PSA >20 ng/mL but otherwise low-risk features. Our institutional radical prostatectomy database (1992-2012) was queried and the results were stratified into D'Amico low-, intermediate- and high risk, PSA-incongruent intermediate-risk and PSA-incongruent high-risk cases. Prostate cancer (PCa) features and outcomes were evaluated using appropriate comparative tests. Multivariable analyses were adjusted for age, race and year of surgery. RESULTS: Of the total cohort of 17 608 men, 1132 (6.4%) had PII-risk disease and 183 (1.0%) had PIH-risk disease. Compared with the low-risk group, the odds of upgrading at radical prostatectomy (RP) were 2.20 (95% CI 1.93-2.52; P < 0.001) for the PII group and 3.58 (95% CI 2.64-4.85; P < 0.001) for the PIH group, the odds of extraprostatic disease at RP were 2.35 (95% CI 2.05-2.68; P < 0.001) for the PII group and 6.68 (95% CI 4.89-9.15; P < 0.001) for the PIH group, and the odds of positive surgical margins were 1.97 (95% CI 1.67-2.33; P < 0.001) for the PII group and 3.54 (95% CI 2.50-4.95, P < 0.001) for the PIH group. Compared with low-risk disease, PII-risk disease was associated with a 2.85-, 2.99- and 3.32-fold greater risk of biochemical recurrence (BCR), metastasis and PCa-specific mortality, respectively, and PIH-risk disease was associated with a 5.32-, 6.14- and 7.07-fold greater risk of BCR, metastasis and PCa-specific mortality, respectively (P ≤ 0.001 for all comparisons). For the PII group, the higher risks of positive surgical margins, upgrading, upstaging and BCR were dependent on PSA density (PSAD): men in the PII group who had a PSAD <0.15 ng/mL/g were not at higher risk compared with those in the low-risk group. Men in the PII group with a PSAD ≥0.15 ng/mL/g and men in the PIH group were more likely to have an anterior component of the dominant tumour (59 and 64%, respectively) compared with those in the low- (35%) and intermediate-risk group (39%) and those in the PII-risk group with PSAD <0.15 ng/mL/g (29%). CONCLUSIONS: Men with PSA >20 ng/mL or men with PSA >10 and ≤20 ng/mL with a PSAD ≥0.15 ng/mL/g, but otherwise low-risk PCa, are at greater risk of adverse pathological and oncological outcomes and may be inappropriate candidates for active surveillance. These men are at greater risk of having anterior tumours that are undersampled at biopsy, so if treatment is deferred, ancillary testing such as anterior zone sampling or magnetic resonance imaging should be strongly encouraged. Men with elevated PSA levels >10 and ≤20 ng/mL but low PSAD have outcomes similar to those in the low-risk group, and consideration of surveillance is appropriate in these cases.

Melanoma Antigen Family A (MAGE A) as Promising Biomarkers and Therapeutic Targets in Bladder Cancer.

The Melanoma Antigen Gene (MAGE) is a large family of highly conserved proteins that share a common MAGE homology domain. Interestingly, many MAGE family members exhibit restricted expression in reproductive tissues but are abnormally expressed in various human malignancies, including bladder cancer, which is a common urinary malignancy associated with high morbidity and mortality rates. The recent literature suggests a more prominent role for MAGEA family members in driving bladder tumorigenesis. This review highlights the role of MAGEA proteins, the potential for them to serve as diagnostic or prognostic biomarker(s), and as therapeutic targets for bladder cancer.

A Comprehensive Review of Immunotherapy Clinical Trials for Metastatic Urothelial Carcinoma: Immune Checkpoint Inhibitors Alone or in Combination, Novel Antibodies, Cellular Therapies, and Vaccines.

Urothelial cancer is an immune-responsive cancer, but only a subset of patients benefits from immune checkpoint inhibition. Currently, single-agent immune checkpoint inhibitors (ICIs) and the combination of pembrolizumab with the antibody-drug conjugate enfortumab vedotin are approved to treat patients with metastatic UC (mUC). Approval of first-line nivolumab in combination with gemcitabine and cisplatin is expected imminently. Many treatment approaches are being investigated to better harness the immune system to fight mUC. In this review, we summarize the landmark clinical trials of ICIs that led to their incorporation into the current standard of care for mUC. We further discuss recent and ongoing clinical trials in mUC, which are investigating ICIs in combination with other agents, including chemotherapy, antibody-drug conjugates, tyrosine kinase inhibitors, and novel antibodies. Lastly, we review novel approaches utilizing bispecific antibodies, cellular therapies, and vaccines. The landscape of immunotherapy for mUC is rapidly evolving and will hopefully lead to better outcomes for patients.

PrECOG PrE0807: A Phase 1b Feasibility Trial of Neoadjuvant Nivolumab Without and with Lirilumab in Patients with Muscle-invasive Bladder Cancer Ineligible for or Refusing Cisplatin-based Neoadjuvant Chemotherapy.

BACKGROUND AND OBJECTIVE: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility. METHODS: Patients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC. Cohorts were enrolled sequentially. The key eligibility criteria were cT2-4aN0-1M0 stage and cisplatin ineligibility/refusal. The primary endpoint was the rate of grade (G) ≥3 treatment-related adverse events (TRAEs) as per Common Terminology Criteria for Adverse Events version 5.0. The key secondary endpoints included the proportion of patients who underwent RC >6 wk after the last dose, CD8+ T-cell density change between pretreatment transurethral resection of bladder tumor (TURBT) and post-treatment RC, ypT0N0, 6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%,

Roles of Androgen Receptor Signaling in Urothelial Carcinoma.

Preclinical and clinical data suggest that androgen receptor signaling strongly contributes to bladder cancer development. The roles of the androgen receptor in bladder carcinogenesis have obvious implications for understanding the strong male sex bias in this disease and for potential therapeutic strategies as well. In this review, we summarize what is known about androgen receptor signaling in urothelial carcinoma as well as in tumor-infiltrating immune cells, reviewing preclinical and clinical data. We also highlight clinical trial efforts in this area.

Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals.