Abstract A003: The clinical impact of targeted next-generation sequencing for advanced pediatric and AYA sarcoma patients in the iCat2/GAIN Consortium Study

Abstract Next generation sequencing (NGS) assays are standard clinical care for most adult and some pediatric solid cancers. The significance of molecular tumor profiling for the care of children, adolescents and young adults with sarcomas is not well understood. We aimed to determine the clinical impact of identifying genomic alterations by NGS for relapsed, refractory, high-risk sarcoma patients (pts) enrolled on the GAIN/iCat2 study. Eligible participants had an extracranial solid tumor diagnosed at age 30 years and recurrent/refractory (R/R), or newly diagnosed high-risk disease (NDHR). Each pt had targeted DNA NGS performed on tumor samples. Selected pt tumors had targeted and bulk RNA sequencing (RNAseq). Test results were returned to the oncologist and follow-up treatment and response data were collected. Identified genomic alterations were classified according to evidence of impact on diagnosis, prognosis or response to matched targeted therapy (MTT) using established guidelines. Therapeutic relevance was defined as a variant with preclinical, clinical evidence, or FDA approval suggesting potential benefit of MTT. Response to MTT was defined as a radiographic response according to RECIST or duration of therapy 4 months in pts with evaluable or measurable disease at treatment start. Pts receiving chemotherapy combined with MTT were ineligible for response. Between 11/1/2015 and 1/31/2025, 825 pts were accrued; 512 (62%) had a sarcoma diagnosis and an NGS result. 486/512 (95%) sarcoma pts were eligible for assessment of MTT. The median age at enrollment for sarcoma pts was 14. 9 years (0-32). 57% were male, 70% were white, and 88% were non-Hispanic. The most common diagnoses were osteosarcoma (OS, n=151, 30%), Ewing (n=101, 20%), and rhabdomyosarcoma (RMS, n=77, 15%), though 35% had less common sarcoma diagnoses. 332 (65%) pts were R/R and 180 (35%) pts were NDHR at enrollment. 694 somatic DNA NGS tests were performed for 512 pts, 86 targeted fusion RNAseq tests were done for 72 pts (14%), and 35 bulk RNAseq tests were done for 32 pts (6%). Diagnostically significant variants were present in 428/512 (84%) pts. For 26 (5%) pts, the diagnostic variant clarified the diagnosis beyond routine site clinical testing. Variants with prognostic significance were identified in 192/329 (58%) of pts with OS, Ewing and RMS. Common prognostically significant variants for these diagnoses were the PAX/FOXO fusion, TP53 and STAG2 mutations, and MYC amplification. 369/512 (72%) pts had at least one variant identified with therapeutic relevance. 30/486 (6%) pts received matched MTT. Three pts responded to MTT for a response rate of 10%. In a study enrolling R/R and NDHR pts 30 years of age at diagnosis from 12 pediatric oncology practices, 62% of enrolling pts had a sarcoma diagnosis associated with poor outcome. NGS frequently identifies diagnostic and prognostic variants in sarcoma pts. The low proportion of pts receiving MTT and even lower proportion with responses to MTT speaks to lagging drug development for advanced sarcomas impacting young people. Citation Format: Hannah Y Comeau, Lorena Lazo de la Vega, Pei-Chi Kao, Catherine M Albert, Navin Pinto, Luke D. Maese, Rochelle Bagatell, AeRang Kim, Laura J Klesse, Theodore W Laetsch, Margaret E Macy, Mark A Applebaum, Susan I Colace, Amit J Sabnis, Daniel A Weiser, Filemon Dela Cruz, Darrell J Yamashiro, Steven G DuBois, Natalie B Collins, Wendy B London, Alanna J Church, Katherine A Janeway. The clinical impact of targeted next-generation sequencing for advanced pediatric and AYA sarcoma patients in the iCat2/GAIN Consortium Study abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₂): Abstract nr A003.