Therapeutic Opportunities in the Intrinsic Subtypes of Muscle-Invasive Bladder Cancer

Evidence is limited on whether fibroblast growth factor receptor gene alterations (FGFRalt) impact clinical outcomes in patients with locally advanced or metastatic urothelial cancer (mUC). This study evaluated progression-free survival (PFS) in patients with mUC based on FGFRalt status in the first-line setting (1L).

Data on mUC patients were retrieved via convenience sampling of oncologists/urologists surveyed between August and September 2020 who treated at least 1 FGFRalt patient between July 2017 and June 2019. The questionnaire included information on patient demographics, FGFR status, treatment, and clinical and radiographic measures of progression.

Primary endpoint was time from metastatic diagnosis to disease progression from initial treatment for FGFRalt and FGFRwt (wild-type) mUC. Cox proportional hazards models quantified adjusted risk of FGFR status relating to PFS.

A total of 414 patients were analyzed. Mean age was 64.5 years, 73.9% were male, and 52.7% had an FGFRalt. Among FGFRalt, 47.2% received chemotherapy, 27.5% immune checkpoint inhibition (ICI), 11.5% chemotherapy+ICI, and 13.8% other treatments in 1L. FGFR status did not influence PFS from time of mUC diagnosis or among 224 stratified patients receiving either chemotherapy or chemotherapy+ICI. However, among 97 patients with an FGFRalt receiving 1L ICI therapy only, adjusted risk of progression was twice that of FGFRwt (HR: 2.12; 95% CI: 1.13-4.00).

Although FGFRalt did not predict outcomes in the overall cohort, for patients treated with 1L ICI, FGFRalt had significantly higher rates of progression than FGFRwt patients. Further validation is needed to determine whether FGFRalt has a decreased benefit from ICI therapy.

Recent targeted therapies for advanced and metastatic urothelial cancer have generated enthusiasm, but the actionable genomic landscape of early-stage disease remains largely unknown. Here, we utilized a large, real-world cohort to comprehensively investigate the incidence of genetic alterations with potential therapeutic implications at all stages of bladder cancer.

We retrospectively analyzed next-generation sequencing (NGS) data from 1,562 bladder cancer patients (stages I-IV) with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus xT solid tumor assay. Incidence of genetic alterations, tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 status were assessed and stratified by bladder cancer stage. For patients with tumor-normal match sequencing (n=966), incidental germline alterations in 50 genes were assessed.

The cohort was composed of 165 stage I-II, 211 stage III, and 1,186 stage IV tumors. TMB-high, PD-L1 positive, and MSI-high status were noted in 14%, 33%, and 0.7% of tumors, respectively, and were similar across stages. Alterations in fibroblast growth factor receptor (FGFR)2/3, homologous recombination repair genes, additional DNA repair gene mutations (ERCC2, RB1, FANCC), and NTRK fusions were detected at similar frequencies across disease stages. We identified a low rate of incidental germline mutations in all tumors (5.2%) and in specific genes: MUTYH (1.9%), BRCA2 (0.5%), and ATM (0.8%).

Important subsets of patients demonstrate genetic alterations in potentially actionable molecular pathways at all stages. This analysis found minimal variability in these alterations across stages, providing rationale for early identification of genetic alterations and personalization of therapies at all stages for patients with bladder cancer.

Non–muscle-invasive bladder cancer is one of the most common malignancies. Patients with intermediate-risk or high-risk disease can be treated with intravesical Bacillus Calmette-Guerin, a vaccine against tuberculosis. However, many of these patients will experience tumor recurrence, despite appropriate treatment. 1 The standard of care in these patients is radical cystectomy (RC) with urinary diversion. 2 Patients diagnosed with muscle-invasive bladder cancer (MIBC) have traditionally faced 2 main treatment options: RC and urinary diversion, as in Bacillus Calmette-Guerin-unresponsive Non–muscle-invasive bladder cancer, or alternatively, trimodal therapy comprising maximal transurethral resection of bladder tumor plus chemoradiation. 3 For patients with MIBC and clinical (c)T2–T4a, neoadjuvant chemotherapy (NAC) preceding RC is supported by Level 1 evidence with a modest 5-year overall survival benefit of 5% with cisplatin-based regimens. 4–9 A number of factors preclude MIBC patients from standard treatment options. For example, patients with serious comorbidities might be unable to tolerate general anesthesia, while others might be unwilling to adapt to the lifestyle changes after RC. 10-12 Likewise, patients with extensive carcinoma in situ or poor bladder function might not be optimal candidates for trimodal therapy or be prepared for the ongoing risk that salvage RC might be ultimately required. Reasons for the underuse of NAC range from the fear of delaying potentially curative surgery in nonresponders to patient ineligibility to cisplatin-based NAC. 13,14 Despite best efforts, in both surgical and bladder-sparing approaches, the 5-year overall survival in treated patients with MIBC is only 35% to 50%. 3,15 Strategies to improve overall prognosis as well as to reduce the indications of RC are desperately needed. Trial results have demonstrated the unprecedented ability of immune-checkpoint inhibitors to induce durable remissions in some patients with metastatic urothelial carcinoma. 16-20 Furthermore, immune-checkpoint inhibitors have shown to be better tolerated than traditional chemotherapy. 16 These successful results have spearheaded the research on these agents in earlier curative settings, with the shared goal of improving overall outcomes, and potentially avoid surgery in patients who show complete response (pT0). Strategies to enhance the immune response by combining immunotherapy with immune sensitizers such as chemotherapy, immunotherapy, targeted therapy or radiation are on the rise.

Bladder cancer (BCa) is the fourth most common malignancy of the urinary system in the United States. Most patients with BCa present with non-muscle invasive bladder cancer (NMIBC) that is responsive to local treatment and surveillance. However, despite initial response of NMIBC, recurrence and progression to muscle-invasive bladder cancer (MIBC) invariably occur. Patients who present with MIBC, or progress to it from NMIBC, harbor occult metastases, that eventually progress to distant overt metastases within 2 years of diagnosis and 5-year survival is exceedingly poor, with limited treatment options. BCa treatment requires life-long surveillance with expensive imaging and cystoscopy, thus BCa is the most expensive cancers to treat over the course of patient’s lifetime. Despite latest advances in diagnosis, genetic and molecular profiling, limited advances have been made in BCa therapy with only a few new FDA-approved treatments for locally advanced, metastatic, or platinum-resistant disease since 2016. The major challenges in BCa include the development of effective second-line therapies for both NMIBC and MIBC as well as the development of effective biomarkers for cost-effective surveillance and assessment of treatment efficacy. Understanding the pathophysiology of this heterogeneous disease is critical to solving these issues and overcoming treatment resistance.

Urothelial carcinoma is one of the most common carcinomas of the genitourinary system and can develop at multiple sites along the urothelium, from the pyelocaliceal system to the prostatic urethra. Imaging is therefore of paramount importance for the evaluation and detection of upper tract lesions and staging of the lower tract. CT and MRI are the predominant modalities to evaluate the entire urothelium and staging the tumor, lymph nodes, and solid organs for distant metastasis. Additional imaging. It is most common in white men and predominant risk factors include heavy smoking, exposure to chemicals, chronic infections, and inflammation, among others. The bladder is most frequently affected, and the tumors may present as polypoid or sessile lesions, that correspond to non-muscle invasive or muscle invasive tumors respectively, and carry different prognoses, the latter much worse. Patients present classically with painless hematuria, dysuria, or frequency. The tumor spreads through lymphatics and bloodstreams with an increased chance of spreading directly proportional to the tumor size and depth of invasion.The introduction of blue light cystoscopy, which takes advantage of the fluorescent properties of the urothelial carcinoma, has improved accuracy during diagnostic cystoscopy and has allowed noninvasive tumors to be resected earlier by transurethral resection of bladder tumors. Certain patients are at higher risk of recurrence (high grade tumors, > 3 cm, multifocal, early recurrence) and can benefit from intravesical immunotherapy or chemotherapy. Muscle invasive tumors are treated more aggressively, and treatment involves cystectomy with urinary diversions, plus adjuvant or neoadjuvant chemotherapy.In the setting of metastatic disease, immunotherapy has been recently adopted and approved as a second line treatment after the standard chemotherapy regimen.Monitoring tumor response depends largely on cystoscopy for the lower tract and imaging for the upper tract, with CT Urogram being the workhorse of our practice to evaluate the urothelium as well as lymph nodes and solid organs. MRI is frequently used on patients with renal insufficiency or in patients with iodine allergy. Several urinary markers are also used for surveillance in urine samples.

Systemic therapy is the mainstay of treatment for metastatic urothelial carcinoma (UC). Responses to first-line platinum-based therapy tend to be short-lived with potential toxicity. Despite the approval of checkpoint inhibitors, the long-term prognosis for patients with metastatic UC remains dismal. Herein we report the case of a patient with a solitary pulmonary metastatic lesion of urothelial origin as the only site of metastatic disease who remained free of disease for more than 2 years without systemic therapy after metastasectomy. We review the literature discussing the role of combined surgical and medical management of oligometastatic UC. As our case illustrates, a growing body of evidence suggests a potential role for a multimodal approach in patients with oligometastatic UC.