Intimal sarcomas (ISarc) of the cardiac chambers (CC) of the heart and great vessels (GV): a comprehensive genomic profiling (CGP) study.

BACKGROUND: ISarc of the CC and GV are extremely rare primary tumors of the cardiac chambers (CC), aortic root (AO) and pulmonary artery (PA). These tumors are rarely resectable and are associated with rapid progression and poor clinical outcome. We queried whether CGP could uncover new routes to targeted therapies for this aggressive form of malignancy. METHODS: 27 cases of ISarc were centrally reviewed and required direct association with the intimal surfaces of the CC and GV with supporting routine histologic features and immunohistochemical staining patterns. DNA and RNA extracted from the ISarc cases were both sequenced using a hybrid-capture based CGP to study all classes of genomic alterations (GA) and determine MSI status, TMB level, HRD score, genomic ancestry, cosmic trinucleotide signature (Signature) and germline status. PD-L1 expression was measured by IHC (Dako 22C3 and TPS scoring). RESULTS: Among 27 ISarc cases (15 CC, 12 GV—11 pulmonary artery, 1 aortic root), most were high-grade tumors (89% grade 3, 11% grade 2). Median age was 45–46 years across groups. CC ISarc patients were more often female (73% vs 50%; P=0.26). Genomic alterations relevant to targeted therapy included MDM2 (67% CC, 50% GV), PDGFRA (53% CC, 42% GV), CDK4 (60% CC, 33% GV), and KIT (40% CC, 33% GV), though differences were not significant. CDKN2A deletions were more common in GV (67% vs 27%, P=0.055). PIK3CA mutations were significantly more frequent in CC (20% vs 0%, P=0.007); ERBB3 mutations were infrequent and not significant. EUR ancestry was seen in just over 50% of cases. Of four ISarc cases analyzed for mutational signatures, three had MMR and one APOBEC; none were MSI-high. Median TMB was similar (4.3–4.7 mut/Mb), with one CC case >10 mut/Mb. One GV case had germline VHL and KEAP1 mutations. Low PD-L1 expression was found in 1/5 (20%) of tested ISarc cases. CONCLUSIONS: CGP of ISarc cases reveals that these tumors do feature a modest number of GA potentially associated with benefit for targeted therapies but low and absent biomarkers predictive of immunotherapy benefit. Further study of ISarc in a setting of rare tumor clinical trials appears warranted.