Tumor mutation burden to predict progression in high-risk non-muscle invasive bladder cancer.

Abstract

397 Background: The genetic mechanisms associated with progression of high-risk non-muscle-invasive bladder cancer (HR-NMIBC) have not been described. We conducted next-generation sequencing (NGS) of HR-NMIBC and compared the genomic profiles of cancers that responded to intravesical therapy and those that progressed to muscle-invasive or advanced disease. Methods: DNA was extracted from formalin-fixed paraffin-embedded sections of tumor from 25 patients with HR-NMIBC (23 with T1HG; 3 with TaHG and carcinoma in situ). Ten patients with HR-NMIBC developed progression (pT2+ or N+) (“progressors”). Fifteen patients had no progression (“non-progressors”). Tissue from 11 patients with metastatic bladder cancer (BC) were analyzed for comparison. Results: We identified no difference in the frequency of mutations of TP53, PIK3CA, or KMT2D between the primary tumors of progressors compared to non-progressors and metastatic tumors. An increased frequency of mutations and deletions causing loss of function of CDKN2A and CDKN2B was identified in tumors at progression (37%) compared to non-progressors (6%) (p=0.10). We found a significant decrease in total mutational burden (TMB) comparing non-progressors, progressors and metastatic tumors at 15, 10.1 and 5.1 mutations/MB respectively (p=0.02). This association suggests more advanced tumors have decreased neoantigen burden and may potentially explain the mechanism of BCG response in non-progressors. Conclusions: TMB was significantly greater in non-progressors compared to progressors. We found no novel genetic drivers in tumors that progressed and HR-NMIBC had many genetic features similar to metastatic BC. The loss of CDKN2A appears to occur late in the process of invasion of BC and may represent an important step in progression. Further research is necessary to evaluate loss of CDKN2A as a biomarker for progression of NMIBC.