Clinical and genomic profiling of early-onset bladder cancer identifies key alterations and therapeutic targets.

PURPOSE: Younger patients with bladder cancer typically have fewer environmental exposures or risk factors, suggesting that the molecular pathways implicated in early-onset disease differ from those in older patients. Dissecting the genomic profiles of early-onset tumors may inform targeted treatment strategies for young patients. We compared the frequency of somatic mutations in early-onset bladder cancer, defined as a diagnosis before the age of 55 years, which encompasses the youngest patients in about 1 in 10 diagnoses based on national registries.

MATERIAL AND

METHODS

We assessed two institutional cohorts: the Mass General Brigham Young Cystectomy Cohort (MGB-YCC, n=134 patients) from 2008-2023 and the Memorial Sloan-Kettering-IMPACT bladder cancer cohort (MSK-IMPACT, n=1271) from 2014-2021. Clinical outcomes of MGB-YCC were also compared with published data from patients undergoing cystectomy in the National Surgical Quality Improvement Program (NSQIP, n=10,848) from 2008-2013.

RESULTS

Both the MGB-YCC and MSK-IMPACT cohorts were predominantly male (>76%), and younger patients were less likely to have a history of smoking or muscle-invasive disease. MGB-YCC demonstrated more patients with continent diversions (51.5% vs 14.9%) than the older population in NSQIP, although complication rates were similar. Genomic characterization of MGB-YCC demonstrated KMT2D mutations almost exclusively in the youngest patients (83% <45-years-old, p=0.008). MSK-IMPACT revealed a significant increase in FGFR3 mutations in younger patients (p<0.001).

CONCLUSIONS

Our results indicate that early-onset bladder cancer is a distinct patient population that has disease driven by specific somatic mutations, some of which represent therapeutic targets. This suggests potential benefits of genomic tumor profiling in guiding personalized treatment.