Genomic Landscape of Angiosarcoma: A Targeted and Immunotherapy Biomarker Analysis

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.

Clinical, genomic, and transcriptomic correlates of response to immune checkpoint blockade-based therapy in a cohort of patients with angiosarcoma treated at a single center

“…This analysis is constrained by a limited number of samples for analysis; yet, we identified the same number of immune clusters (four) as the recent report by Espejo-Freire et al . 55 Cancer-associated fibroblasts, a stromal population not included in the Petitprez et al sarcoma immune classification, 47 are upregulated in a subset of angiosarcomas. 55 We identified a trend toward inferior PFS in these patients, potentially indicating a mechanism of resistance to ICB, a finding confirmed in select carcinomas.…”

“… 55 Cancer-associated fibroblasts, a stromal population not included in the Petitprez et al sarcoma immune classification, 47 are upregulated in a subset of angiosarcomas. 55 We identified a trend toward inferior PFS in these patients, potentially indicating a mechanism of resistance to ICB, a finding confirmed in select carcinomas. 56 Additionally, gene set enrichment analysis found that upregulated KRAS signaling, a pathway that we found to be significantly altered in CHN angiosarcoma, was associated with PFS ≥16 weeks after ICB.…”

In vitro anticancer effects of alpelisib against PIK3CA‑mutated canine hemangiosarcoma cell lines

“…HSA occurs in ~50,000 canines per year in the United States ( 16 ), and its frequency is higher than that in humans, rendering this a useful model for the study of human intractable disease that requires early detection and effective therapeutic strategy. Developments in genome-wide approaches have enabled the comprehensive analysis of disease-related gene mutations in humans and animals ( 17 , 18 ). Mutated canine genes related to HSA have been searched using exome sequencing, and the 1047th histidine residue (H1047) of p110α phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) was found to be highly mutated ( 19 ).…”

Differences in potential key genes and pathways between primary and radiation-associated angiosarcoma of the breast

“…Angiosarcoma is a high-grade malignant soft tissue tumor, originating from lymphatic or vascular endothelial cells, which exhibit rapid proliferation and invasion capacity that is associated with a poor prognosis [ 1 , 2 ]. Angiosarcoma may arise in any location of the body, such as bone, liver, heart or breast; it occurs most frequently in the skin and soft tissues [3] .…”