Upper tract urothelial cancer (UTUC): Role of sequencing, molecular subtyping and treatment outcomes.

Abstract

e16578 Background: Upper tract urothelial cancers (UTUCs) are rare forms of urothelial cancer that behave in a more aggressive manner. Treatment response to immunotherapy may be less impactful in the adjuvant setting. Studies suggest molecular subtyping might predict survival outcomes. We seek to determine whether genomic sequencing, molecular subtype signatures can be used to predict patient response to chemotherapy in upper tract urothelial cancers. Methods: UTUC patients seen consecutively at a single institution during a 4-year period were evaluated with IRB approval. Analyses of NGS (next-generation sequencing) using Foundation Medicine or TEMPUS platforms were compiled. Decipher Bladder assay (research use only for UTUC) using a transcriptome microarray to characterize tumor specimens as luminal vs. non-luminal and 4 non-luminal subtypes. Retrospective and descriptive analyses were used to identify predictors of response and survival and therapeutic options patients (pts) underwent. Additional phenotypic factors such as initial staging, tumor location, response to neoadjuvant chemotherapy (NAC), and responses to treatment for localized or metastatic disease were determined. Results: UTUC patients whose clinical and demographic features were available for 23 patients (Male = 7; Female = 16); locally advanced = 9; metastatic = 14. Tumor samples were obtained with Decipher bladder assay (n=4); next-generation sequencing assay (n = 9). Neoadjuvant chemotherapy (NAC) was given in all pts with localized disease and for metastatic disease (n=11 pts). Platinum-based chemotherapy (PBC) resulted in median overall survival (mOS) of 36.6 mos compared to no chemotherapy 22.8 mos at the time of data cut-off. Decipher bladder assay showed basal subtype and mixed basal/claudin-low in 4 patients of whom one achieved stable disease though residual ypT3 after NAC and the 3 achieved progressive disease as best response, all with metastatic disease. NGS showed LOH - 21.01% and ATM truncation in 2 patients with prolonged responses to avelumab maintenance immunotherapy and 2 patients with CDK2A/2B loss with prolonged survival (mOS = 16.8 mos). Additionally, 5 patients were identified as having a TERT promoter variant, though this does not appear to have a significant relationship with survival or disease progression when compared to those without the variant. Conclusions: Results do not identify a specific NGS signature or subtype signature that predicts response to chemotherapy in the neoadjuvant or metastatic setting though receipt of chemotherapy appears to clinically affect outcomes in this small sample of UTUC patients. Further studies are needed to identify specific molecular signatures that would predict responses to therapy.