1940P - Deep molecular profiling of advanced synovial sarcoma as a basis for interventional clinical trials

Background

Synovial sarcoma (SySa) is a rare soft-tissue malignancy occurring predominantly in the lower extremities of young adults. It is driven by a unique SS18::SSX fusion gene. In locally advanced/metastatic SySa, treatment options are limited, and it is of high interest to identify targetable molecular alterations.

Methods

Within the MASTER precision oncology program of DKFZ, NCT Heidelberg/Dresden, and DKTK (ClinicalTrials.gov Identifier: NCT05852522), patients with advanced SySa were analyzed by whole-genome/exome (WGS/WES) and RNA sequencing to inform the care of individual patients and provide starting points for interventional clinical trials in adolescents and young adults. Median age at the time of molecular analysis was 37 years (range, 22–65 years), and 45% of patients were female. Median time between diagnosis and molecular analysis was 29 months (range, 2–288 months). Median follow-up for survival was 89 months.

Results

Between 2013 and 2022, 69 patients were studied. Median survival and 3-year survival rate after molecular analysis were 14 months (95% confidence interval [CI], 12–19 months) and 8% (95% CI, 3–22%), respectively. Molecular profiling included WES (n=33) or WGS (n=32) as well as RNA sequencing (n=56). Beyond SS18::SSX fusions, the most common somatic and germline single-nucleotide variants and small insertions/deletions affected TTN (17%), NIPBL (9%), CTNNB1 (8%), ATM, TAF1L, TP53, MADD, and COL7A1 (each 6%). Based on the presence of a significant single-base substitution signature 3 (SBS3), two patient groups could be distinguished (group 1, SBS3 present, 28 patients; group 2, SBS3 absent, 37 patients). The most frequent genomic gains involved chromosomes 8 and 12; the most frequent deletions involved chromosomes 3 and 11. Comparative analysis of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 expression between the SySa cases (n=56) and the entire MASTER cohort (n=3,023) revealed significant differences for SSTR2, SSTR4, and SSTR5, with top 10% expression in 13, 31, and 22 patients, respectively.

Conclusions

Our study demonstrates the utility of broad molecular profiling in patients with advanced SySa for identifying subgroups of patients, whose molecular profiles may inform the design of future clinical trials.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

National Center for Tumor Diseases, German Cancer Research Center and Heidelberg University Hospital.

Funding

NCT Molecular Precision Oncology Program, German Cancer Consortium.

Disclosure

R.F. Schlenk: Financial Interests, Personal, Advisory Board: AbbVie, Daiichi Sankyo, Jazz Pharma, Pfizer; Financial Interests, Institutional, Research Funding: AstraZeneca, Boehringer Ingelheim, Pfizer, PharmaMar, Roche, Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Daiichi Sankyo. S. Bauer: Financial Interests, Institutional, Research Funding: Blueprint Medicines, Incyte, Novartis; Financial Interests, Personal, Advisory Role: PharmaMar, Eli Lilly & Co, Novartis; Financial Interests, Personal, Advisory Board: Adcendo, Bayer, Blueprint Medicines, Böhringer Ingelheim, Cogant, Daiichi Sankyo, Deciphera, GSK, Exelixis, Nanobiotix, Novartis, Roche; Financial Interests, Personal, Other, Travel support: PharmaMar. D.T. Rieke: Financial Interests, Personal, Advisory Board: Bayer, Alacris Theranostics; Financial Interests, Personal, Invited Speaker: Roche, BMS, Lilly; Non-Financial Interests, Principal Investigator: Bayer. C. Heining: Financial Interests, Institutional, Research Funding: Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Roche, Novartis; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim. P. Horak: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Platomics, Varsome. S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illumina, PharmaMar, Roche. All other authors have declared no conflicts of interest.