Abstract 2862: Evolution of clinically relevant variants in advanced pediatric sarcomas
Authors: Comeau Hannah Y. , Vega Lorena Lazo De La , Church Alanna J. , Maese Luke D. , Pinto Navin , Macy Margaret E. , Applebaum Mark A. , Sabnis Amit J. , Kim AeRang , Colace Susan I. , Dela Cruz Filemon , DuBois Steven G. , Collins Natalie B. , Janeway Katherine A. 
Published: March 2024

Abstract
Objective Few pediatric sarcoma studies have investigated how gene alterations detected by targeted sequencing change in the same patient over time. We leveraged targeted somatic DNA next-generation sequencing (NGS) data from a large cohort of young patients with osteosarcoma (OS), Ewing sarcoma (EWS), or rhabdomyosarcoma (RMS) to identify changes in known oncogenic variants with the aim of addressing the clinical utility of resequencing at recurrence.
Methods The iCat2/GAIN Consortium Study is a cohort study involving 13 US institutions evaluating outcomes after receipt of matched targeted therapy (MTT) in young patients with advanced extra-cranial solid tumors. Tumors are sequenced using OncoPanel, a targeted DNA NGS test performed in a CLIA/CAP certified laboratory assessing single nucleotide variants (SNV), copy number variants (CNV) and structural variants (SV) in up to 447 cancer genes and rearrangements in up to 60 cancer genes. In 2 cases, similar targeted NGS tests were performed. For OS, EWS, or RMS patients with at least 2 OncoPanels from different timepoints (initial diagnosis or relapse) and/or tumor sites (metastatic or primary), we assessed oncogenic variants in genes previously known to be recurrently altered in the respective diagnosis. For each variant, we assigned patterns of change as emergence, disappearance, or persistence.
Results Of 784 iCat2/GAIN patients, there were 157, 107, and 100 patients with OS, EWS, and RMS respectively. The analytic cohort consisted of 34, 20, and 15 OS, EWS, and RMS patients respectively with at least 2 tumor sequenced samples. The median number of sequenced samples per patient was 2 (range 2 to 6). In EWS, 9 (45%) patients had an oncogenic variant (other than an expected fusion) in at least one sample. In 4 patients, the predominant pattern of change was emergence. Specifically, a new pathogenic SNV in STAG2 (N=1) or TP53 (N=3) were observed. In OS, all 34 patients had an oncogenic variant in at least one sample. In RMS, 12 (80%) patients had an oncogenic variant in at least one sample. There was no predominant pattern of change in OS and RMS. In OS, 41% percent of variants persisted in all samples; 32% of variants disappeared in subsequent samples; 22% of variants emerged in subsequent samples; 5% of variants were variably present over time. Interestingly, while TP53 was most often persistent over time, there were also 7 cases with emergence of TP53 variants and 8 cases with disappearance of TP53 variants. In RMS, 26% percent of variants persisted in all samples; 31% of variants disappeared in subsequent samples; 43% of variants emerged in subsequent samples. Interestingly, in three cases there was emergence of a new variant activating the RAF/MAPK or AKT pathway.
Conclusion Pediatric sarcomas display a range of genomic changes over time. Given the observed changes in oncogenic alterations, there may be utility to repeat sequencing of relapsed tumor biopsies to understand these changes.
Citation Format: Hannah Y. Comeau, Lorena Lazo De La Vega, Alanna J. Church, Luke D. Maese, Navin Pinto, Margaret E. Macy, Mark A. Applebaum, Amit J. Sabnis, AeRang Kim, Susan I. Colace, Filemon Dela Cruz, Steven G. DuBois, Natalie B. Collins, Katherine A. Janeway. Evolution of clinically relevant variants in advanced pediatric sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2862.