Tyler F. Stewart

Urothelial carcinoma (UC) remains a common cancer with significant morbidity and mortality worldwide. Immune checkpoint inhibitors (ICIs) have helped revolutionize the treatment of UC, and there is growing evidence suggesting the crucial role of the gut microbiome in immune system function influences immunotherapy outcomes in this disease. Herein, we review the preclinical basis for how manipulation of the gut microbiome may alter the efficacy of immunotherapy for patients with cancer, highlight interventions optimizing gut microbiome diversity currently in use, review recent and ongoing clinical trials supporting the role of the gut microbiome in improving immunotherapy outcomes, and discuss clinical implications to improve outcomes for UC patients with immunotherapy in the real world. There is growing evidence that suggests that specific gut microbiome compositions significantly modulate the host immune system and response to ICIs. Early studies have shown that certain microbial taxa enhance antitumor immunity by influencing T cell priming, dendritic cell activation, and cytokine production. Fecal microbiota transplantation (FMT), probiotic supplementation, and dietary modulation have emerged as promising methods to alter microbiomes to improve immunotherapy outcomes. Taxa from positive immunotherapy responders across a variety of cancers demonstrate beneficial effects when transplanted into both treatment-naive or prior nonresponders. Increasing evidence suggests that the gut microbiome plays a crucial role in cancer care, particularly when patients are treated with immunotherapy. Future studies are needed to better understand the underlying mechanisms. While some studies are currently underway to explore gut manipulation for patients with UC, more studies are needed to investigate the potential to convert nonresponders into responders through microbiome manipulation.

PURPOSE: Molecular characterization of anatomically distinct urothelial carcinoma in the upper tract (UTUC) and bladder (UCB) has been challenging because of the rarity of UTUC. However, recent advances in real-world data curation have facilitated the generation of larger UTUC cohorts. In this study, we investigated the somatic, germline, and immunologic landscapes of UTUC compared with UCB. METHODS: From the Tempus Database, we retrospectively analyzed 505 UTUC and 2,416 UCB cases. Tumors were sequenced using Tempus xT DNA and xR RNA assays. Pathogenic somatic mutations, immune cell infiltration, tumor mutational burden (TMB), PD-L1, microsatellite instability (MSI), and mismatch repair (MMR) were evaluated. Potential germline alterations were assessed in 46 genes for patients with tumor/normal matched sequencing (UTUC, n = 285; UCB, n = 1,359). RESULTS: Alterations in TERT, TP53, RB1, ERBB2, and CDKN1A were more frequent in UCB, whereas KMT2D, FGFR3, CDKN2B, KRAS , and MYC were more frequent in UTUC. Germline variants were found in 4.8% of UCB and 5.6% of UTUC, with trends toward higher Lynch syndrome–associated gene alterations ( MLH1, MSH2, MSH6, PMS2 ) in UTUC (0.6% v 1.8%, P = .059). The prevalence of TMB ≥10 mut/Mb was higher in UCB (17% v 11%, P < .001). UCB had higher PD-L1 positivity ( P = .013), whereas UTUC had more MSI-high (UTUC = 3.2% v UCB = 1%, P = .001) and MMR-deficient ( P = .020) cases. CD4 ⁺ and regulatory T-cell infiltrates were similar in both. CONCLUSION: By comprehensive molecular characterization of UC, we observed distinct genomic alterations and tumor microenvironment patterns in UTUC and UCB. Further research is warranted to elucidate the clinical implications of these findings. We compared the genetic and immune features of upper tract and bladder cancers. Our study found key differences that could affect treatment decisions, such as specific gene changes and immune markers. These insights may help doctors personalize therapies and improve patient care.

Muscle-invasive bladder cancer represents a potentially curable disease, yet often disease recurs and is ultimately fatal. Outcomes for patients with localized urothelial carcinoma are heterogeneous with some patients cured with surgery alone, deriving no benefit from perioperative systemic therapy, while others are left with residual disease and may benefit from additional therapy. Neoadjuvant chemotherapy increases cure rates but comes with significant toxicity. Recently, adjuvant nivolumab has demonstrated significant improvement in disease free survival (DFS), and overall survival analysis is pending. With more therapies approved for urothelial cancer within the last 5 years than ever before, there is incredible potential to improve clinical outcomes and potentially cure more patients with integrated multimodal therapy. Biomarkers are needed to dichotomize those most likely to benefit from perioperative systemic therapy for residual disease, and de-escalate therapy for those likely to be cured with surgery alone. Ultrasensitive assays for circulating tumor DNA (ctDNA) have emerged as a method to identify patients at high risk of recurrence after definitive therapy and may benefit from escalated therapy, while also identifying those least likely to benefit from systemic therapy. Studies have demonstrated that the presence of ctDNA after surgery is prognostic of disease recurrence across multiple cancer types, including bladder cancer, but questions remain as to the utility of these tests, and whether they can be predictive of benefit of adjuvant therapy. Although these liquid biopsies hold significant promise to transform perioperative treatment, prospective studies are needed to validate their utility as prognostic and predictive biomarkers. To bridge this knowledge gap, contemporary clinical trials are incorporating ctDNA as an integral biomarker to guide therapy for MIBC.

With the advent of new therapeutic modalities, management of metastatic castrate-sensitive prostate cancer (mCSPC) has been in flux. From androgen-deprivation therapy to docetaxel to androgen receptor–signaling inhibitors, each agent has heralded a new treatment paradigm. As such, the optimal first-line therapy for mCSPC remains incompletely defined. This review provides a narrative of recent advances to systemic therapy within the mCSPC treatment space, particularly with regard to expansion to triplet therapy.

As the indications for the use of immunotherapy in genitourinary malignancies expand, its role in combination with standard or conventional therapies has become the subject of contemporary studies. Radiotherapy has multiple immunomodulating effects on anti-tumor immune response, which highlights potential synergistic role with immunotherapy agents. We sought to review the body of published data studying the combination of immunotherapy and radiotherapy as well as the rationale for combination therapy. Trial information and primary articles were obtained using the following terms “immunotherapy”, “radiotherapy”, “prostate cancer”, and “bladder cancer.” All articles and trials were screened to ensure they included combination radiotherapy and immunotherapy. The effects of radiation on the immune system, including both immunogenic and immunosuppressive effects, have been reported. There is a potential for combinatorial or synergistic effects between radiation therapy and immunotherapy in treating bladder and prostate cancers. However, results from ongoing and future clinical trials are needed to best integrate immunotherapy into current standard of care treatments for GU cancers.

Importance: Primary care physicians (PCPs) are significant contributors of early cancer detection, yet few studies have investigated whether consistent primary care translates to improved downstream outcomes.Objective: To evaluate the association of prediagnostic primary care use with metastatic disease at diagnosis and cancer-specific mortality (CSM).Design, Setting, and Participants: This cohort study used databases with primary care and referral linkage from multiple Veterans’ Affairs centers from 2004 to 2017 and had a 68-month median follow-up. Analysis was completed between July 2021 and September 2022. Participants included veterans older than 39 years who had been diagnosed with 1 of 12 cancers. Inclusion criteria included known clinical staging, survival follow-up, cause of death, and receiving care at the Veterans Affairs health system (VA).Exposures: Prediagnostic PCP use, measured in the 5 years prior to diagnosis. PCP visits were binned into none (0 visits), some (1-4 visits), and annual (5 visits).Main Outcomes and Measures: Metastatic disease at diagnosis, cancer-specific mortality (CSM) for entire cohort and stratified by tumor subtype.Results: Among 245 425 patients representing 12 tumor subtypes, mean age was 65.8 (9.3) years, and the cohort skewed male (97.6%), and White (76.1%), with higher levels of comorbidity (58.6% with Charlson Comorbidity Index scores ≥2). Compared with no prior visit, some PCP use was associated with 26% decreased odds of metastatic disease at diagnosis (odds ratio [OR], 0.74; 95% CI, 0.71-0.76; P < .001) and 12% reduced risk of CSM (subdistribution hazard ratio [SHR], 0.88; 95% CI, 0.86-0.89; P < .001). Annual PCP use was associated with 39% decreased odds of metastatic disease (OR, 0.61; 95% CI, 0.59-0.63; P < .001) and 21% reduced risk of CSM (SHR, 0.79; 95% CI, 0.77-0.81; P < .001). Among tumor subtypes, prostate cancer had the largest effect size for prior PCP use on metastatic disease at diagnosis (OR for annual use, 0.32; 95% CI, 0.30-0.35; P < .001) and CSM (SHRfor annual use, 0.51; 95% CI, 0.48-0.55; P < .001).Conclusions and Relevance: In this cohort study, increased primary care use before cancer diagnosis was associated with significant decreases in metastatic disease at diagnosis and cancer-related death, with potentially the greatest difference from annual use. PCPs play a vital role in cancer prevention, and additional resources should be allocated to assist these physicians.