Integrative Clinical and Genomic Characterization of MTAP-deficient Metastatic Urothelial Cancer

Deficiency of MTAP (MTAP) mainly occurs because of homozygous loss of chromosome 9p21, which is the most common copy-number loss in metastatic urothelial cancer (mUC). We characterized the clinical and genomic features of MTAP mUC in 193 patients treated at MD Anderson Cancer Center (MDACC) and 298 patients from the phase 2 IMvigor210 trial, which investigated atezolizumab in cisplatin-ineligible and platinum-refractory disease. In the MDACC cohort, visceral metastases were significantly more common for MTAP (n = 48) than for MTAP-proficient (MTAP; n = 145) patients (75% vs 55.2%; p = 0.02). MTAP was associated with poor prognosis (median overall survival [mOS] 12.3 vs 20.2 mo; p = 0.007) with an adjusted hazard ratio of 1.93 (95% confidence interval 1.35-2.98). Similarly, IMvigor210 patients with MTAP (n = 29) had a higher incidence of visceral metastases than those with MTAP tumors (n = 269; 86.2% vs 72.5%; p = 0.021) and worse prognosis (mOS 8.0 vs 11.3 mo; p = 0.042). Hyperplasia-associated genes were more frequently mutated in MTAP tumors (FGFR3: 31% vs 8%; PI3KCA: 31% vs 19%), while alterations in dysplasia-associated genes were less common in MTAP tumors (TP53: 41% vs 67%; RB1: 0% vs 16%). Our findings support a distinct biology in MTAP mUC that is associated with early visceral disease and worse prognosis. PATIENT SUMMARY: We investigated the outcomes for patients with the most common gene loss (MTAP gene) in metastatic cancer of the urinary tract. We found that this loss correlates with worse prognosis and a higher risk of metastasis in internal organs. There seems to be distinct tumor biology for urinary tract cancer with MTAP gene loss and this could be a potential target for treatment.