Characterization of MTAP-Deleted Bladder Cancers - Expert Commentary
The study sample consisted of 61 patients with a median age of 68 years, of whom 29% were female. Patients had received between one and four lines of treatment. Out of 61 patients, 19 harbored a deletion in MTAP. Squamous differentiation and bone metastases were significantly associated with MTAP deletion. In addition, patients with MTAP deletion tended to develop tumors in the bladder instead of the upper urinary tract. In terms of genomic characteristics, TERT promoter missense mutations and alterations in the PI3K pathway were more prevalent among patients with MTAP depletion. Regarding changes in expression, MTAP-depleted patients exhibited a significant increase in mRNA of genes in the MAPK pathway relative to controls. Researchers also identified the top 50 downregulated genes in MTAP-depleted tumors. Many differentially expressed genes in patients with MTAP depletion were linked to methylation, circadian rhythm, cell adhesion, apoptosis channels, and vesicle trafficking. Interestingly, the link between squamous differentiation and MTAP depletion may be partly mediated by the upregulation of genes that induce keratinization.
Among control patients without MTAP deletion, 35.7% had received chemotherapy, and the overall response rate (ORR) was 53%, while the disease control rate (DCR) was 60%. Among patients with MTAP deletion, 47.3% received chemotherapy, and the best response was one patient exhibiting stable disease, whereas most patients did not respond to treatment. Most control patients received immune checkpoint inhibitors (73.8%), among whom the ORR was 19% while the DCR was 41.9%. Similarly, 63.1% of patients with MTAP deletion received immune checkpoint inhibitors, among whom the ORR was 8%, while the DCR was 33.3%. Finally, among control patients who received enfortumab (14.2%), the ORR was 33.3%, and DCR was 50%. For patients with MTAP depletion who received enfortumab (36.8%), the ORR was 42.8%, while the DCR was 57.1%. Most patients with wild-type or deleted MTAP developed progression (87.5% versus 93.3%, respectively). Median progression-free survival after first-line treatment was significantly longer in control patients (6 months) versus MTAP deletion patients (4 months).
Patients with MTAP deletion also exhibited a mortality rate of 78.9%, while control patients exhibited a mortality rate of 59%. Median overall survival was significantly higher in control patients (43 months) than in MTAP deletion patients (26 months). These differences were still present after researchers performed a Cox regression analysis on propensity-matched scores.
These findings reveal the prognostic impact of MTAP deletion among patients with urothelial carcinoma. As MTAP-deleted tumors show differential alteration of specific signaling pathways, developing biomarker-driven targeted therapeutic approaches for this subgroup is a promising future treatment strategy.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
References:
Read the Abstract