Molecular Determinants of Clinical Outcomes in Patients with Upper Tract Urothelial Carcinoma - Expert Commentary
The investigators performed targeted DNA and whole transcriptome RNA sequencing on 100 UTUC tumors from patients undergoing nephroureterectomy. They identified five distinct molecular clusters (C1-C5) associated with different clinical outcomes using consensus non-negative matrix factorization. The analysis revealed that favorable subtypes (C1 and C2) showed luminal-like signatures with immunologically depleted tumor microenvironment. Subtype C3 was characterized by FGFR3 alterations and higher tumor mutational burden (p < 0.071), including all microsatellite instability cases. Despite higher recurrence rates and inferior survival, subtypes C4 and C5 demonstrated an immunologically rich tumor microenvironment favoring ICB response.
The study identified significant associations between molecular features and clinical outcomes. Patients with FGFR3 gene alterations showed favorable cancer-specific survival (p < 0.014), while TP53 mutations correlated with worse outcomes (p < 0.002). Among ICB-treated patients (n=31), complete responses were observed only in C3 and C5 subtypes, with no objective responses in C1/C2 tumors.
This study identifies UTUC subtypes that are more likely to respond to immunotherapy. Identifying patients with the highest metastatic recurrence risk and highest likelihood of benefit could lead to new approaches for perioperative immunotherapy in patients with UTUC.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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