Genetic landscape of soft-tissue sarcomas: Moving toward personalized medicine.

• DOI: 10.1200/jco.2017.35.15_suppl.11002
• Publication Date: 2018-09-06T15:58:12Z
• Authors: Antoine Italiano; Emmanuel Khalifa; Yec'han Laizet; Maud Toulmonde; Sophie Cousin; Carlo Lucchesi
• Keywords: 03 medical and health sciences; 0302 clinical medicine; 3. Good health

11002 Background: Patients with advanced soft-tissue sarcomas have a very poor outcome with a median overall survival of less than 18 months. Identification of molecular abnormalities for which targeted therapies are available or can be developed is critical for improving their outcomes. Methods: We have analyzed the mutational and copy number profiles of patients with sarcoma sequenced through the AACR Project GENIE Consortium in order to identify the proportion of cases bearing actionable mutation. Results: 587 patients (pts) were included in the study (295 males). 331 pts (56%) had complex genomics sarcomas, 144 (25%) translocation-related sarcomas and 112 (19%) others sarcomas (inactivating mutation, simple amplicon). The five most frequent histology were: Leiomyosarcoma (n = 112; 19.1%); Undifferentiated Pleomorphic Sarcomas (n = 74, 12.6%), dedifferentiated liposarcoma (n = 55, 9.4 %), angiosarcoma (n = 43, 7.3%), synovial sarcoma (n = 38, 6.5%). 430 pts (73%) had at least one mutation. The ten most frequently mutated genes were: TP53 (34.7%); ATRX (9.1%), RB1 (8.4%), KMT2D (5.8%), NF1 (5.3%), ATM (5.1%), PI3KCA (4.9%), ERBB4 (4.2%), PTEN (4%), and ARID1A (3.7%). 504 patients (85.9%) presented at least one copy number alteration. The 5 five most frequently amplified genes were: MDM2 (20%), CDK4 (16.7%), GLI1, MAP2KA, and TERT (3.2% for each gene), and the most frequently deleted were RB1 (12.7%), CDKN2A (10.3%), CDKN2B (9.7%), TP53(9.5%), PTEN (8.5). 92.5% of pts had at least one targetable mutation, copy number alteration and/or fusion gene ( Leiomyosarcoma n = 100/17%, UPS n = 74/12%, dedifferentiated diposarcoma n = 54/9%, angiosarcoma n = 41/7%, synovial Sarcoma n = 36/6%), with incidences reported that will be reported in details at the meeting. Conclusions: This is the first large report of genomic landscape including mutation and copy number profiling through NGS of soft-tissue sarcomas. Our results indicate a significant proportion of actionable mutations and represent a rationale for the MULTISARC study: the first study implementing Exome Seq and RNA Seq for clinical decision making in patients with advanced STS. The design of this study supported by the French government and launched in 09/2017 will be presented at the meeting.