Variant allele frequency as a potential marker in response to frontline systemic therapy for patients with locally advanced and metastatic urothelial carcinoma.

Patients with locally advanced and metastatic urothelial cancer (la/mUC) have a poor prognosis. Some patients have tumors that are refractory to frontline systemic treatment and progress rapidly, while other patients' tumors have a sustained response for months. We describe the clinicogenomic patterns observed between these two groups, with a particular interest in the variant allele frequency (VAF) of the gene alterations. This study evaluated the impact of VAF of gene alterations on treatment outcomes for patients with la/mUC. This was a single-institution retrospective cohort study of patients who received standard of care (SoC) frontline systemic therapies and had available next-generation sequencing (NGS) data from 2013-2023. Patients were categorized into rapid progressors (RP) if they had radiographic progression on the first restaging scan after starting therapy or clinical progression resulting in change of therapy or death if beforehand, or sustained responders (SR) if they had a response for at least 180 days. Statistical methods used include Fisher's exact test, Kruskal-Wallis test, Kaplan-Meier analysis with log-rank test, and Cox proportional hazards model. There were 317 patients with la/mUC on SoC frontline therapies identified in the database. From 82 eligible patients with NGS testing, there were 33 RP and 37 SR, with 12 patients in neither cohort. The most common genetic alterations found on NGS of tumor tissue samples were TP53, TERT promoter, and PIK3CA, with no statistical difference in any alteration frequency between the cohorts. Amongst patients with sustained response to frontline platinum-based regimens, the VAF was significantly higher for patients with alterations in TP53 (P=0.04). The P value remained significant when analyzing all patients in the SR cohort. Our findings demonstrate the value of the VAF when interpreting the tumor NGS panel for patients with la/mUC receiving frontline systemic therapy. These findings are hypothesis-generating and must be validated in larger cohorts and prospective studies.