Abstract 1596: Genomic heterogeneity as a barrier to precision oncology in urothelial cancer
Authors: Chen Ziyu , Clinton Timothy N. , Park Soonbum , Lenis Andrew T. , Donoghue Mark , Rosenberg Jonathan E. , Dean Bajorin F. , Teo Min Y. , Bochner Bernard H. , Ostrovnaya Irina , Pietzak Eugene J. , Iyer Gopakumar V. , Gao Sizhi , Hu Wenhuo , Shen Michael M. , Berger Michael F. , Al-Ahmadie Hikmat A. , Abate-Shen Corinne T. , Solit David B. 
Published: June 2022

Abstract
Background: Precision oncology relies on the accurate molecular characterization of individual cancer patients at the time of treatment initiation. However, tumor molecular profiles are not static, and cancers continually evolve because of ongoing mutagenesis and clonal selection, with actionable genomic alterations potentially gained or lost during disease progression.
Methods: To define the concordance of potentially actionable genomic alterations between primary and metastatic disease sites in patients with urothelial cancer and to identify drivers of metastatic disease progression, we performed an integrated analysis of clinical and genomic data from 2,199 urothelial carcinoma patients (2,732 tumor and 331 plasma cfDNA samples) prospectively profiled at Memorial Sloan Kettering Cancer Center (MSKCC) from 2014 to 2021. Paired primary and metastatic tumor samples from individual patients were sequenced with MSK-IMPACT and/or whole-exome sequencing (WES). Plasma samples were analyzed using the MSK-ACCESS cfDNA platform.
Results: Among potentially actionable mutations (defined as OncoKB level 1-4), ERBB2 and ARID1A were associated with higher tumor grade and stage (p-value &lt;0.001, p-value = 0.03 respectively). WES analysis of primary and metastatic tumor sites was consistent with early branched evolution with on average 42% of mutations shared between disease sites. Among chromatin-modifying genes, ARID1A has a discordant rate of 15.8%. In the 6 discordant cases, ARID1A mutation was seen exclusively in the metastatic tumor samples. This suggests a role for ARID1A mutations in metastatic disease progression. While known and likely oncogenic mutations were more likely to be concordant than variants of unknown functional significance, we observed a high degree of mutational discordance among potentially actionable genomic alterations with 23% discordant between primary and metastatic disease sites. 24% of mutations were exclusively identified by plasma cell-free DNA sequencing. Actionable mutations in cell-free DNA were more likely to be concordant with metastatic tumor biopsies than tumor tissue collected from the primary tumor site.
Conclusions: In sum, our analysis of patient-matched primary and metastatic urothelial carcinomas revealed a high degree of lesion-to-lesion genomic heterogeneity that may be a barrier to precision oncology approaches for this disease. Our data also provide a rationale for the use of cell-free DNA sequencing to guide targeted therapy selection in patients with metastatic urothelial cancer.
Citation Format: Ziyu Chen, Timothy N. Clinton, Soonbum Park, Andrew T. Lenis, Mark Donoghue, Jonathan E. Rosenberg, Bajorin F. Dean, Min Y. Teo, Bernard H. Bochner, Irina Ostrovnaya, Eugene J. Pietzak, Gopakumar V. Iyer, Sizhi Gao, Wenhuo Hu, Michael M. Shen, Michael F. Berger, Hikmat A. Al-Ahmadie, Corinne T. Abate-Shen, David B. Solit. Genomic heterogeneity as a barrier to precision oncology in urothelial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1596.