(P 157) MOLECULAR SCREENING OF ADVANCED SARCOMAS THROUGH NEXT-GENERATION SEQUENCING IN A TERTIARY UNIVERSITY HOSPITAL

Objective: Bone and soft tissue sarcomas are rare and heterogeneous neoplasms. Due to the histological diversity and the low incidence of these tumors, current chemotherapy regimens often come from small non-randomized clinical trials and retrospective studies. Furthermore, some subtypes of sarcomas are intrinsically resistant to chemotherapy, thus being orphan tumors that lack a standard therapy. In the recent years, there has been an increasing interest in the molecular characterization of these tumors. Massive parallel sequencing may allow clinicians to better understand the tumorigenesis of these neoplasms and to identify driver mutations that may be triggered by tailored drugs.

Methods: From 2019 to 2022, patients with advanced sarcomas diagnosed in our facility underwent genomic profiling with Foundation One Medicine next-generation sequencing (NGS). Sixty-two patients were analyzed, including 3 Ewing sarcomas, 10 osteosarcomas, 4 chondrosarcomas, 10 leiomyosarcomas, 6 liposarcomas, 7 undifferentiated pleomorphic sarcomas (UPS), 5 malignant peripheral nerve sheath tumor (MPNST), 4 angiosarcomas, 3 solitary fibrous tumors, 2 chordomas, 1 fibrosarcoma, 1 phyllodes tumor, 1 epithelioid hemangioendothelioma (EHE), 1 myxofibrosarcoma, 1 primitive neuroectodermal tumor (PNET) of the uterus, 1 rhabdomyosarcoma, 1 alveolar soft part sarcoma (ASPS) and 1 synovial sarcoma.

Results: A total of 232 pathogenic mutations and 407 variants of unknown significance were found (figure 1). Almost every patient (60/62, 97%) harbored a pathogenic mutation. Most mutations occurred in genes involved in cell cycle control (34%), tyrosine kinase molecular pathways (29%), transcription regulation (16%), chromatin remodeling (7%) and DNA damage repair (4%). Up to 36 patients (58%) bore a potentially actionable mutation. Three patients (2 MPNST and 1 osteosarcoma) had a mutation in BRAF, two of them being the characteristic BRAF V600E mutation. One patient with a BRAF-mutated MPNST was treated with BRAF/MEK inhibitors encorafenib and binimetinib, reaching partial response and a progression free survival of 7 months. Two patients, 1 UPS and 1 liposarcoma, harbored a ROS1 amplification and rearrangement, respectively. Crizotinib was used in two heavily pretreated patients (one ROS1-rearranged liposarcoma and one ALK-rearranged liposarcoma), with disappointing outcomes. Two patients (1 UPS and 1 myxofibrosarcoma) carried MET amplifications. One patient with MPNST had a RET-rearranged tumor. Three tumors had mutations in PIK3CA, including 1 chondrosarcoma, 1 UPS and 1 PNET of the uterus. Interestingly, genetic alterations of cyclin-dependent kinases (CDK) pathway genes were consistently observed throughout our cohort. Particularly, loss of CDKN2A/B was identified in up to 3 osteosarcomas (33%) and 3 MPNST (60%), suggesting that aberrant CDK activity may play a role in sarcoma tumorigenesis, hence stablishing a molecular rationale for the use of cyclin inhibitors.

Conclusion: Nowadays, cytotoxic chemotherapy still remains the front-line therapy in most locally advanced and metastatic unresectable sarcomas. Considering the low response rates to standard treatment, the fact that effective therapeutic alternatives are scarce, and the young age of many of these patients, there is an urgent need for the development of novel therapies. A profound understanding of the molecular mechanisms of sarcomagenesis is essential to propel the era of personalized medicine in advanced sarcomas. It is of vital importance to treat these patients in highly specialized facilities that allow a multidisciplinary approach and to include them in phase I tumor-agnostic basket trials.