Genomic Landscape of Angiosarcoma: A Targeted and Immunotherapy Biomarker Analysis

SIMPLE SUMMARY: Angiosarcomas (AS) are rare, highly aggressive sarcomas with limited therapeutic options. Genomic sequencing techniques have identified recurrent genetic abnormalities. Nevertheless, the association of these findings with etiology, site of origin, prognosis, and therapeutic implications is not well understood. We analyzed Next Generation Sequencing (NGS) and Whole Transcriptome Sequencing (WTS) data in a cohort of 143 AS cases. We identified distinct genomic biology according to the AS primary site. Head and neck AS cases primarily have Immunotherapy (IO) response markers and mutations in TP53 and POT1. On the other hand, breast AS is enriched for cell cycle alterations, predominately MYC amplification. Additionally, a microenvironment with abundant immune cells is present in a minority of cases but distributed evenly among primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS according to its biology at different primary sites. ABSTRACT: We performed a retrospective analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin in a cohort of 143 cases. Primary sites were head and neck (31%), breast (22%), extremity (11%), viscera (20%), skin at other locations (8%), and unknown (9%). All cases had Next Generation Sequencing (NGS) data with a 592 gene panel, and 53 cases had Whole Exome Sequencing (WES) data, which we used to study the microenvironment phenotype. The immunotherapy (IO) response biomarkers Tumor Mutation Burden (TMB), Microsatellite Instability (MSI), and PD-L1 status were the most frequently encountered alteration, present in 36.4% of the cohort and 65% of head and neck AS (H/N-AS) (p < 0.0001). In H/N-AS, TMB-High was seen in 63.4% of cases (p < 0.0001) and PDL-1 positivity in 33% of cases. The most common genetic alterations were TP53 (29%), MYC amplification (23%), ARID1A (17%), POT1 (16%), and ATRX (13%). H/N-AS cases had predominantly mutations in TP53 (50.0%, p = 0.0004), POT1 (40.5%, p < 0.0001), and ARID1A (33.3%, p = 0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p < 0.0001), HRAS (16.1%, p = 0.0377), and PIK3CA (16.1%, p = 0.2352). At other sites, conclusions are difficult to generate due to the small number of cases. A microenvironment with a high immune signature, previously associated with IO response, was evenly distributed in 13% of the cases at different primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS.