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

Deficiency of MTAP (MTAP^def) 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^def 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^def (n = 48) than for MTAP-proficient (MTAP^prof; n = 145) patients (75% vs 55.2%; p = 0.02). MTAP^def 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^lo (n = 29) had a higher incidence of visceral metastases than those with MTAP^hi 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^def tumors (FGFR3: 31% vs 8%; PI3KCA: 31% vs 19%), while alterations in dysplasia-associated genes were less common in MTAP^def tumors (TP53: 41% vs 67%; RB1: 0% vs 16%). Our findings support a distinct biology in MTAP^def 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.