The development of multiple bladder tumour recurrences in relation to the FGFR3 mutation status of the primary tumour

Abstract

Non-muscle invasive bladder cancers (NMI-BCs) represent 75% of bladder cancers upon presentation. After removal of the primary tumour by transurethral resection, multiple recurrences continue to develop in 70% of patients. Consequently, prolonged and costly surveillance by cystoscopy is required. Mutations in the FGFR3 oncogene are common in NMI-BCs and are associated with a lower chance of progression to muscle-invasive disease. Here we analysed the consistency of FGFR3 mutations in primary and recurrent tumours. This knowledge is of crucial importance if FGFR3 mutation analysis on urinary cells is to be used as an alternative for cystoscopical surveillance. To this end, we monitored the disease process and FGFR3 mutation status of primary and recurrent tumours in 118 patients with NMI-BC. During median follow-up of 8.8 years, these patients underwent 2133 cystoscopies and 80 patients developed 414 recurrences. FGFR3 mutations were equally prevalent in primary and recurrent tumours (63%). Patients can have different types of FGFR3 mutations in different tumours. Recurrence risk was not significantly different for patients with a mutant or wild-type primary tumour. Recurrence rates varied widely between patients but were constant for a patient and were unrelated to FGFR3 status. In the mutant patient group, in contrast to the wild-type group, recurrences continued to develop after 10 years. In 81% of the recurrences of patients with a mutant primary tumour, a mutation was found. Moreover, recurrences in this patient group were of lower stage and grade than those of patients with a wild-type primary tumour (p < 0.001). These results suggest that surveillance by FGFR3 mutation analysis on voided urine in combination with a reduced cystoscopy frequency of patients presenting with an FGFR3 mutant tumour is worth investigating.

Fibroblast Growth Factor Receptor 3 Mutation Analysis on Voided Urine for Surveillance of Patients with Low-Grade Non-Muscle–Invasive Bladder Cancer

“…Because this problem of urine sampling concerns all urinary tests that depend on the presence of tumor cells in the urine, this is an important issue and it would be of interest to determine the optimal time point and frequency of urine collection to improve the number of urinary tumor cells. Secondly, FGFR3 WT recurrences are sometimes found in patients with a primary FGFR3-mutant tumor (22). Whether this is the reason why some recurrences were missed here is not known at present because tumor material from the recurrences was not available for FGFR3 mutation analysis.…”

“…Whether this is the reason why some recurrences were missed here is not known at present because tumor material from the recurrences was not available for FGFR3 mutation analysis. We have previously shown that the stage and grade of these recurrences do not differ from mutant recurrences (22). Therefore, the absence of a mutation cannot be correlated with progression to a more severe phenotype.…”

“…Thus, repeated urine testing should circumvent this potential problem. Thirdly, although cystoscopy is considered the golden standard, it is known that cystoscopy does not detect all tumors (22)(23)(24)(25). Urine cytology was not routinely done in the participating centers due to the low sensitivity in tumors of low stage and grade (G1 tumors: range, 7-38%; G2 tumors: range, 18-46%), and this is considered a limitation of the study (26)(27)(28)(29).…”

A 3-Plex Methylation Assay Combined with the FGFR3 Mutation Assay Sensitively Detects Recurrent Bladder Cancer in Voided Urine

“…A major problem in the management of patients presenting with NMIBC is that 70% will develop one or more recurrences and that recurrences can keep on developing for up to 25 years (9). Surveillance of these patients by cystoscopy is warranted (32).…”

“…Somatic mutations in the FGFR3 gene accompanied with losses of chromosome 9 are more frequent in NMIBC, whereas TP53 mutations are associated with muscle-invasive bladder cancer (MIBC) (4)(5)(6). Unfortunately, 70% of patients with NMIBC will have one or more recurrence after transurethral resection (TUR) and 10% to 20% of patients will eventually have progression to MIBC (7)(8)(9). Patients with NMIBC are currently stratified into low/intermediate and high-risk groups regarding progression and recurrence based on clinicopathologic parameters (10,11).…”