Germline mutational profile in metastatic urothelial malignancy.

Abstract

550 Background: 24% of patients with high-risk urothelial carcinoma have pathogenic germline mutations (Nassar, Genetics in Medicine 2020). In that study, demographics, metachronous/synchronous tumors, and family history did not differ between germline and sporadic cases of bladder cancer. We report herein the prevalence of actionable mutations and de novo metastatic disease in patients with germline mutations who developed metastatic urothelial carcinoma. Methods: We retrospectively analyzed a database of 90 patients with metastatic urothelial carcinoma (urethral, bladder, and upper tract disease) at our institution who had genetic testing performed on tumor specimens. T-student test was performed to calculate statistical significance for the distribution of age, while Chi-square test evaluated the frequency distribution of gender, actionable mutations, and de novo metastatic disease. Patients’ tumors were sequenced by a 700 gene panel for both somatic and germline mutations. Comprehensive chart review was performed to extract clinical data. Results: Out of the 90 patients reviewed, 11 (11.1%) had germline mutations. Of these patients, 5 had upper tract urothelial carcinoma, 5 had bladder cancer, and 1 had urethral cancer. Nine patients had pathogenic germline mutations: MUTYH, BRCA2 (each representing 1.8% of patients); APC, BRCA1, CDKN2A, FH, MSH2 (each representing 0.9% of patients). Two patients had germline mutations of unknown significance ( APC, CHEK2). Age (T-value 1.62053, p=1.08453), gender (Chi-square 0.0024, p=0.961037) or de novo metastatic presentation (Chi-square 0.5, p=0.4795) were not statistically significant between patients with germline and sporadic mutations. Somatic actionable mutations included ATR, BRCA2, BRAF, CDK12, ERBB2, FBXW7, FGFR3, HRAS, MTAP, and PIK3CA. Microsatellite instability high (MSI-H) status was only present in the patient with germline MSH2 mutation. PD-L1 expression was high (CPS ≥10) in 4 patients with germline mutations. Tumor mutational burden ranged from 1.1 to 28.4 mutations per Megabase. Conclusions: Our findings further define the clinical and genomic characteristics of patients with metastatic urothelial carcinoma and germline mutations in a tertiary center. Further investigation is warranted to validate these findings in national sequencing databases.