(P 269) LANDSCAPE OF GENOMIC ALTERATIONS IN 115 PATIENTS WITH DESMOID FIBROMATOSIS IN THE AACR GENIE REAL WORLD DATABASE: CLINICAL IMPLICATIONS

Objective: Desmoid fibromatosis is a rare, locally aggressive soft tissue tumor with an unpredictable clinical course. The genomics of desmoid fibromatosis is characterized by CTNNB1 mutations in most of the tumors, however, other genes and pathways are poorly elucidated. Identifying targetable genomic alterations is important to improve treatment options.

Methods: We reviewed the AACR project Genomics Evidence Neoplasia Information Exchange (GENIE) database which contains CLIA-/ISO-certified genomic data. We also searched the literature to identify additional datasets, genes and pathways involved in this malignancy, and currently used treatment options.

Results: Among the 115 patients analyzed median age was 39 in 89 patients older than 18 (range 18-81, 27 pts < 18), 44 were male (38 %). 95 patients had a sample from the primary tumor. Copy number alterations available for 79 patients included copy number gains in NRG1 (n=10), MAFB (n=5), ID3 (n=4), TMPRSS2 (n=3), and NOTCH3 (n=1). Mutations were available for 105 patients and included CTNNB1 (n=85), APC (n=14), PRKDC (n=5), FAT1 (n=5), NOTCH3 (4), SETD2 (n=3), PTCH1 (n=3), NRG1 (n=1), and TMPRSS2 (n=1). Pre-clinical studies reveal that NRG1 (Neuregulin 1) signals inhibition through Notch1 and inhibition of NRG1 signaling reduced melanoma cell growth. Furthermore, MAFB (MAF BZIP Transcription Factor B) was found to enhance oncogenic Notch signaling in T cell acute lymphoblastic leukemia. As Notch pathway is emerging as a therapeutic target in desmoid fibromatosis, NRG1 and MAFB may be relevant biomarkers. Current treatments include surgery, tyrosine kinase inhibitors (e.g. sorafenib, pazopanib, sunitinib), and NSAIDs while gamma secretase inhibitors are under study. A large cohort of 204 desmoid-type fibromatosis samples analysed by targeted next-generation sequencing at the University Munster revealed imatinib sensitive KIT V559D in addition to AKT1, ALK, EGFR and ERBB2, however, NRG1 and MAFB were not included in the gene panel.

Conclusion: Copy number alterations and mutations in NRG1 and MAFB may be relevant to the pathogenesis and a potential targeted therapy of desmoid fibromatosis. Further analyses will be needed to confirm the relevance of these genes. Larger studies that include copy number analysis, whole exome and RNA sequencing are warranted.