Abstract 1622: Characterization of the phylogenetic relationships in bilateral breast angiosarcoma
Authors: Kim Minju , Youk Jeonghwan , Kim Soyeon , Kim Miso , Keam Bhumsuk , Kim Tae Min , Kim Dong-Wan , Song Myung Geun , Koh Jiwon , Bae Jeong Mo , Moon Hyeong-Gon , Im Seock-Ah 
Published: March 2024

Background: Breast angiosarcoma represents around 20% of all angiosarcomas, and often spread to lung, liver, and bones. Driver mutations of angiosarcoma, specifically PTPRB, and PLCG1, are well-known as reported previously. Notably, contralateral breast is another metastatic site of the breast angiosarcoma, where an unusual location for other soft tissue sarcomas. However, it remains uncertain whether the contralateral disease originates from the primary tumor or emerges independently. Here, we present a 75-year-old woman with bilateral breast angiosarcomas to investigate the genetic relationship between the tumors.

Methods: Irregular and heterogeneous masses were synchronously detected through breast sonography. Whole genome sequencing (WGS) was conducted at 60X coverage using bilateral total mastectomies, along with a matched normal blood sample (n=1). Single nucleotide variants (SNVs) and small indels were identified using Strelka2 and Varscan2. Subsequent filtering was performed using custom Python scripts to establish high-confidence variants. A phylogenetic tree was then reconstructed based on SNVs to trace clonal evolution and distinguish between de novo primary and metastasis. Following this, COSMIC mutational signatures were analyzed to characterize the genomic profile.

Results: For the left breast angiosarcoma, we found 1,086 SNVs and 101 indels, while the right breast angiosarcoma had 921 SNVs and 92 indels. Despite their small size (&lt;1.0 cm) and low FNCLCC grade (G1), these two cancers shared 600 SNVs and 135 indels as “truncal events”, indicating that one side metastasized from the other. According to the phylogenetic tree and the molecular clock of the two angiosarcomas, we estimated that the metastasis occurred during the middle stages of cancer evolution. Additionally, we identified 7 nonsynonymous SNVs (ADAMTS7, RPS15, CYP2A6, OR1S2, ARHGAP23, GNAQ, UGT2B7), five of which were shared. Remarkably, the GNAQ driver mutation exhibited a mutation at codon 209, a hotspot mutation not previously reported in breast angiosarcoma. The dominant Cosmic mutational signatures were SBS1/5 and ID1/2, all of which were associated with aging.

Conclusion: Our findings demonstrate that bilateral breast angiosarcomas metastasized from one side to the other, as evidenced by the WGS data. This study underscores that the capability of WGS to distinguish between oligometastatic disease and multiple primary cancers, which has implications for predicting patients’ prognosis.

Citation Format: Minju Kim, Jeonghwan Youk, Soyeon Kim, Miso Kim, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Myung Geun Song, Jiwon Koh, Jeong Mo Bae, Hyeong-Gon Moon, Seock-Ah Im. Characterization of the phylogenetic relationships in bilateral breast angiosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1622.