Abstract LB140: The genomic landscape of primary and secondary angiosarcomas, a rare heterogenous group of soft tissue sarcomas
Authors: van Ravensteijn Stefan G. , Versleijen-Jonkers Yvonne M. , Hillebrandt-Roeffen Melissa H. , Nederkoorn Maikel , Gorris Mark A. , Verrijp Kiek , Kroeze Leonie I. , de Bitter Tessa J. , de Voer Richarda M. , Flucke Uta E. , Desar Ingrid M. 
Published: June 2022

Abstract
Background: Angiosarcomas (AS) are a rare heterogenous group of soft tissue sarcomas (STS) that form in the lining of blood vessels or lymphatic vessels. They comprise of primary (de novo) AS and secondary AS. The etiology of primary AS is unknown. Secondary AS arise due to DNA damaging factors like prior radiotherapy (RT), ultraviolet (UV) light exposure or chronic lymphedema (Stewart Treves syndrome). Treatment options are limited and their prognosis is poor. Development of new treatment strategies is difficult due to the rarity of these subgroups of STS. Genomic profiling of primary and secondary AS may provide a rationale for targeted treatment strategies.
Method: Tumor samples were retrospectively collected from patients diagnosed with AS in the Netherlands. Patients were categorized as primary/secondary AS. Genomic profiles were analyzed using “TruSight Oncology 500”, a Next Generation Sequencing panel that analyzes variants in 523 cancer relevant genes.
Results: Tumor DNA from 51 treatment naive AS patients was analyzed. The cohort comprised of 26 patients with a primary AS, divided in 5 subgroups: Heart (n=5, 10%), primary breast (n=5, 10%), skin not UV associated (n=4, 8%), soft tissue (n=5, 10%) and visceral (n=7, 14%) AS. The other 25 patients had a secondary AS, subdivided in RT-associated (n=13, 25%), Stewart Treves (n=5, 10%) and UV-associated (n=7, 14%) AS. Mean Tumor Mutational Burden (TMB) was 7.1 mutations per Mb for all patients (4.2 mut/Mb in primary AS vs 10.1 in secondary AS, p = 0.91). High TMB (≥10 mut/Mb) was found in 6 patients (12%) divided over 3 subgroups: UV associated AS (n=3/7 (43%)), visceral AS (n=2/7 (28%)) and skin not UV associated AS (n=1/4 (25%)). No patients were microsatellite instable. A pathogenic mutation, amplification or deletion was identified in 82% of all patients (n=42, 70% of primary AS vs 100% of secondary AS (p=&lt;0.01)). In 36 patients (71%) at least one (likely) pathogenic mutation was detected (54% primary vs 88% secondary AS, (p=0,013)). In 20 patients (39%) a mutation in the DNA damage response (DDR) pathway was detected (12% primary vs 68% secondary AS (p=&lt;0.01)). The most frequently found mutations were TP53 (10%), BRAF (6%), ERCC4 (6%), PTPRD (6%), WETD2 (6%), SETD2 (6%) and PIK3CA (4%). Amplifications were found in 49% (n=25) of all patients (15% primary vs 84% secondary AS, (p=&lt;0,01)). MYC amplifications were detected in 41% of all patients (15% of primary vs 68% of secondary AS), including 100% of Stewart Treves AS, 92% of RT associated AS and 75% of skin not UV associated AS. FLT4 (20%) and CRKL (12%) amplifications occurred only in secondary AS. FLT4 was seen in 31% of RT-associated AS.
Conclusion: We showed a clear distinction in genomic profiles of AS subgroups with specific pathogenic alterations. Especially secondary AS may benefit from treatment with ICI based on frequent MYC amplifications, DDR mutations, and high TMB. These data show clear evidence for the development of future treatment strategies with targeted therapy and ICI for this rare heterogeneous group of STS.
Citation Format: Stefan G. van Ravensteijn, Yvonne M. Versleijen-Jonkers, Melissa H. Hillebrandt-Roeffen, Maikel Nederkoorn, Mark A. Gorris, Kiek Verrijp, Leonie I. Kroeze, Tessa J. de Bitter, Richarda M. de Voer, Uta E. Flucke, Ingrid M. Desar. The genomic landscape of primary and secondary angiosarcomas, a rare heterogenous group of soft tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB140.