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: The 27 ISarc cases included 15 CC and 12 GV (11 pulmonary artery ISarc and 1 aortic root Isarc). There were 24 (88.9%) histologic grade 3 and 3 (11.1%) grade 2 tumors. Median ages for all ISarc ranged from 45 to 46 years and were similar in both groups. The CC ISarc pts tended to be female when compared with the GV pts (73% vs 50%; P=.26). GA potentially impacting targeted therapy selection in clinical trials for rare tumors included amplifications of MDM2 in 66.7% of CC ISarc and 50% of GV ISarc, PDGFRA in 53.3% CC and 41.7% of GV; homozygous deletions in CDKN2A in 26.7% in CC vs 66.7% of GV was near significant (p=0.055) and significantly more frequent point mutations in PIK3CAin CC at 20% vs 0% in GV (p=.007) and ERBB3 in 13.3% of CV and 8.3% of GV which was not significant. EUR ancestry was present in slightly more than 50% of ISarc cases and similar in both sub-groups. Median TMB was similar and ranged from 4.3 to 4.7 mutations/Mb with 1 (6.7%) CC ISarc having a TMB of > 10 mut/Mb. 1/5 (20%) tested ISarc cases stained for low level PD-L1 expression. 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.