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

Abstract

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.

Keywords: Chemotherapy; FGFR; Immunotherapy; MTAP; PIK3CA; Urothelial carcinoma.

Fig. 1 –

MTAP^def was associated with poor OS and FPS, metastatic status, and genomic alteration. (A) OS for patients stratified by MTAP status. (B) PFS for patients stratified by MTAP status. Only 172 patients who received chemotherapy or immunotherapy as front-line therapy were analyzed for PFS. (C) Proportion of patients by site of metastasis involvement at baseline. Created using a licensed version of biorender.com. (D) CONSORT diagram for patients with available target sequencing data and genomic alterations. (E) Oncoplot showing the most common genomic alterations in our patient cohorts. Patients without genomic alterations and genes with an alteration frequency of <5% in each group were excluded. The right bar plot showed the alteration frequency for each gene. OS = overall survival; PFS = progression-free survival; UC = urothelial cancer; MTAP>^def = MTAP-deficient; MTAP^prof = MTAP-proficient; NGS = next-generation sequencing.

Fig. 2 –

Correlation between MTAP RNA expression, survival, and visceral disease for the validation cohort from the Imvigor210 trial (NCT02951767). (A) MTAP mRNA expression status by number of patients plotted on the x-axis. (B) Metastatic disease in patients with MTAP^lo, MTAP^hi, and the overall cohort; (C) OS for all patients stratified by MTAP expression. (D) OS for all patients stratified by metastatic sites. OS = overall survival; MTAP^lo = MTAP-low; MTAP^hi = MTAP-high; LN = lymph node; NA = not available.