Abstract 2249: Molecular landscape and actionable alterations in Chinese soft-tissue sarcoma patients

Abstract

Abstract Background: Soft-tissue sarcoma (STS) is a rare solid malignant tumor. It has numerous histological subtypes that originate from all over the human body. It has been difficult to perform generic large-scale clinical trials on STS patients due to limited populations in each subtype and various pathological situations. Current studies on targeted therapy in STS are still in preclinical and early-phase trials. No research on targeted therapy in Asian STS patients has been published so far. To investigate the potential of targeted therapy in STS, we analyzed the genomic landscape, the actionable genomic alterations (GAs) along with TMB, MSI and HRD in Chinese STS patients. Methods: Targeted sequencing covering 425 genes was performed, from which we obtained the sequencing results of tissue samples from 351 Chinese STS patients with various histological subtypes. The mean sequencing depth of tumors was ~800X. Bioinformatics analysis of altered genes with nonsynonymous mutations, copy-number variations (CNVs) and gene fusions were performed. OncoKB actionable gene alterations (GAs) and relevant biomarkers including tumor mutational burden (TMB), microsatellite instability (MSI) and homologous recombination deficiency (HRD) were further examined for potential targeted therapy. Results: In the 351 Chinese STS patients with various subtypes, 45% were women and 55% were men, with an age range from 2 to 99 years and a median age of 54 years. 2743 GAs in tumor tissue samples were identified in 330 genes with a median of 6 (1-38) per case, including 979 CNVs, 982 single nucleotide variations (SNVs), 182 indels and 151 gene fusions. The top 10 frequently altered genes in GAs of STS were: TP53, MCL1, MDM2, CDK4, MYC, CDKN2A, GNAS, RB1, ATRX, CDKN2B, FGFR1. RTKRAS (59%), TP53(53%), Cell cycle(39%) and PI3K(38%) were the most frequently affected pathways in the 351 patients. 9.40% of the cohort were TMB-high, 2.85% were MSI-high and 13.68% were HRD-positive. Based on the 4 levels of actionable genes defined by OncoKB, actionable GAs were found in 43% of the patients. 242 Actionable GAs (187 CNVs, 40 SNVs and indels, and 15 gene fusions) were found in 23 genes. Actionable CNVs were mostly found in CDK4 (13%), MDM2 (13%), CDKN2A (7%) and FGFR1 (7%). The two most frequent genes with actionable SNVs and indels were KRAS (3%) and PIK3CA (2%). Taking TMB, MSI, HRD and OncoKB definition altogether into consideration, 54% of the patients had the potential to respond to targeted therapy. Conclusions: Comprehensive genetic landscape can provide new treatment insight in STS. OncoKB actionable GAs were observed in up to 41% of STS patients. Considering other relevant biomarkers together, 54% of the patients were potentially responsive to targeted therapy or immunotherapy. Citation Format: Hua Bao, Yue Wang, Rui Liu, Xue Wu, Yang Shao. Molecular landscape and actionable alterations in Chinese soft-tissue sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2249.