Comprehensive genomic profiling of intimal sarcomas identified recurrent alterations in MDM2, PDGFRA, and CDK4, with PIK3CA mutations significantly enriched in cardiac chamber tumors.
Observational (n=27)
Yes
Does comprehensive genomic profiling uncover new routes to targeted therapies in intimal sarcomas of the cardiac chambers and great vessels?
Comprehensive genomic profiling of intimal sarcomas reveals a modest number of genomic alterations potentially targetable by therapies, but low biomarkers for immunotherapy benefit.
Absolute Event Rate: 20% vs 0%
p-value: p=0.007
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.
Zerdan et al. (2026) conducted an observational in Intimal sarcomas of the cardiac chambers and great vessels (n=27). Comprehensive genomic profiling (CGP) was evaluated on PIK3CA point mutations (Cardiac Chamber vs Great Vessel) (p=0.007). Comprehensive genomic profiling of intimal sarcomas identified recurrent alterations in MDM2, PDGFRA, and CDK4, with PIK3CA mutations significantly enriched in cardiac chamber tumors.