A 57-year-old man presented with a 30-pack year smoking history and high grade non-invasive bladder cancer. He initially underwent resection followed by a course of BCG, but developed a low-grade recurrence. He required further resection and a subsequent course of BCG + Interferon. He was kept on surveillance, but is again found to have T1 high-grade bladder cancer. He is strongly opposed to radical cystectomy and seeks alternative "bladder-sparing" options. Molecular analysis of his tumor was performed and showed FGFR3 mutation.
DISCUSSIONOne of the most challenging dilemmas in urologic oncology is the patient with BCG-refractory and recurrent high-grade, non-muscle invasive urothelial cancer of the bladder. These patients are at an extremely high risk of progression to muscle-invasive, dangerous or fatal disease; however, justifying a major extirpative surgery is difficult when no invasive disease is present. This blog will review immunotherapy as a cutting edge therapy for such patients.
At initial diagnosis of bladder cancer, 75% of disease is locally confined, while 25% has advanced to regional/metastatic disease. Of localized disease, 70% is found to be non-muscle invasive. Indeed, molecular analyses of numerous bladder tumors demonstrate that there are two alternative processes that occur in the development of bladder cancer (Figure 1). A hyperplastic process that is associated with mutations in HRAS and FGFR3 genes can occur, leading to a low-grade non-invasive papillary tumor phenotype. Alternatively, a dysplastic process that is associated with loss of tumor suppressors p53 and RB can also occur, leading to an invasive tumor phenotype.
|Figure 1. Diagram of alternative processes occurring in urothelial carcinoma. Xu WR. 2005.|
|Figure 2. FGFR3 is mutated more frequently in lower stage and grade tumors. Knowles. 2007.|
FGFR3 belongs to the Fibroblast Growth Factor Receptor family and includes 18 different proteins (ligands) and 4 different FGF receptors that control functions such as cell differentiation, proliferation, angiogenesis, and invasion. There is a wealth of pre-clinical and laboratory literature that suggests FGFR3 may be an effective therapeutic target in bladder cancer. For instance, a mouse model of bladder tumors demonstrated an 84% reduction in UM-UC1 (a tumor cell line that overexpresses FGFR3), shrinking tumor size and reduced cell proliferation on microscopic examination (Figure 3).
There is also clinical data to support the use of Dovitinib. Andre et al. analyzed the effectiveness of Dovitinib in treating women with metastatic breast cancer with FGFR1 mutation. This trial was in a patient population with very advanced disease – 78% of women had liver metastases and had received prior treatment with up to 3 hormone and chemotherapeutic agents or up to 3 chemotherapeutic agents, depending on their hormone receptor status. Nevertheless, there were a greater proportion of the patients treated with Dovitinib that had a partial clinical response or stable disease at ≥ 24 weeks follow up. Furthermore, tumors with large amounts of FGFR1 (amplification greater than 6 copies) showed a 20.2% reduction in tumor burden from baseline compared to tumors with less than 6 copies that had a mean 8.3% increase from baseline. The authors also showed in a waterfall plot that patients with FGF pathway mutation trended toward reduction in tumor burden as compared to increase in tumor burden in those that did not have FGF amplification (Figure 4). Because of its effects against multiple tyrosine kinases, toxicity is a concern for Dovitinib and safety data from the trial showed that nausea, vomiting, diarrhea, and asthenia were common complications. Less common, but more serious complications included: hypertriglyceridemia, pulmonary embolism, and myocardial infarction.
|Figure 4. Dovitinib was more effective in reducing tumor burden in tumors with FGF pathway amplification. |
From Andre et al 2013.
In conclusion, FGFR3 is a potential therapeutic target in non-invasive urothelial carcinoma and Dovitinib is a multi-kinase inhibitor that may be effective for treatment in this setting. The Dovitinib trial at Hopkins is currently enrolling patients and offers bladder sparing treatment for patients with non-invasive BCG-refractory disease and FGFR3 mutation.
This blog was written by Matthew Lee, a medical student at Columbia University, College of Physicians & Surgeons in New York, New York. Matthew recently finished a four-week sub-internship at the Brady Urological Institute and gave a presentation to the department on "A Phase II Clinical Trial of Dovitinib in BCG Refractory Bladder Cancer" from which this blog is inspired. Matthew is looking forward to a career in urology.