Does Longitudinal Targeted Panel Sequencing Provide Clinically Relevant Information in Translocation-Associated Sarcomas?
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PURPOSE: Translocation-associated sarcomas (TAS) represent a heterogeneous group of pathologic entities characterized by specific gene fusions and a low tumor mutational burden (TMB). Although RNA sequencing remains the hallmark molecular platform to establish the fusion type, targeted panel DNA next-generation sequencing (NGS) has been increasingly used in TAS to identify actionable alterations as well as potential mechanisms of resistance to therapy. MATERIALS AND METHODS: We herein investigate sequential targeted DNA sequencing (Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets) in a large cohort of 108 TAS, spanning six most common subtypes, with available longitudinal sequencing. RESULTS: Overall, 53% of cases acquired alterations (n = 122) compared with the initial testing, of which 33 (27%) were oncogenic/likely oncogenic. Only two of the five patients with >3 tests/each acquired oncogenic mutations. Overall, 21% of cases did not acquire alterations in any assay. Subsequent NGS was initiated after systemic treatment (93%) and disease progression (83%). The number of oncogenic acquired alterations did not correlate with histotype (mean 0.4/case). In sequential NGS, the mean mutation count, TMB, and fraction of genome altered were significantly higher (P < .001, .04, and .03, respectively) compared with baseline. TP53 alteration was the most common acquired mutation (10%), being detected mostly in the subsequent assay. By contrast, other common alterations, such as STAG2 in Ewing sarcoma and gene amplifications in alveolar rhabdomyosarcoma, were detected at diagnosis. Although 27% of pathogenic alterations in the initial and 9% in the subsequent NGS were deemed as OncoKB levels 1-2 for other cancers, none were relevant for sarcomas. CONCLUSION: The role of multiple NGS testing in the context of TAS remains undetermined.