Clinical and genomic profiling of early-onset bladder cancer identifies key alterations and therapeutic targets
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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 including n=207 cystectomy and n=811 transurethral resection (TUR) specimens 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 (>75%), and younger patients had lower rates of smoking history 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 enrichment in younger patients of TP53 (65% overall, 83% <50-year-old, p=0.045) and KMT2D mutations almost exclusively in the youngest patients (35% overall, 83% <45-years-old, p=0.008). MSK-IMPACT revealed a significant increase in FGFR3 mutations in younger patients in both cystectomy (33% vs 13%, p=0.014) and TUR (45% vs 27%, 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.
