1660P The promising role of the extracellular matrix in the activity of trabectedin in soft tissue sarcoma: A prospective study on a UPS and L-sarcoma patient-derived primary culture case series using 3D and zebrafish models

Abstract

Background: NTRK gene fusions resulting in the elevated expression of TRK kinases were discovered in a wide variety of tumor types but generally at a low frequency. FDA approved TRK inhibitors such as larotrectinib and entrectinib in patients with TRK fusion positive cancers, regardless of age or the tumor type.Methods: Formalin Fixed Paraffin Embedded (FFPE) samples of 599 Chinese sarcoma patients were collected from nearly 58 kinds of subtype of sarcoma for next-generation sequencing (NGS) assay with 638-gene panel. The testing was carried out by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, Shanghai, China.Results: We analyzed 170 children (age 19 years) and 429 adults (age＞19 years). 24 patients were identified as NTRK fusion positive, with 12 children and 12 adults, which accounted to approximately 4.1% of the Chinese sarcoma patients in our cohort. NTRK fusions were found in 7.1% of children, including rhabdomyosarcoma (3%) and fibrosarcoma (50%), and 2.8% in adults, including rhabdomyosarcoma (14.3%), synovial sarcoma (3.7%), undifferentiated pleomorphic sarcoma (3.5%) and osteosarcoma (3.4%). 13 out of 24 patients harbored NTRK1 fusions, 2 with NTRK2 fusions, and the remained ones were NTRK3 fusions with 9 partners. LMNA (8/24), ETV6 (4/24), TPM3 (2/24) were the most common partners of NTRK fusion in this cohort. Moreover, we identified uncommon partner genes by NGS, including CHTOP, SLC28A3, LOXL1, LRRC28, ZNF704, SH2D2A and TPR. Based on the NGS results, several actionable genomic alterations including CDKN2A, BRCA2, and CDK4 were found in this study. We also found 10 patients harbored NTRK amplification in our cohort, who may also benefit from TRK kinases.