Primary mammary angiosarcomas harbor frequent mutations in KDR and PIK3CA and show evidence of distinct pathogenesis

• Published in: Modern pathology Vol. 33; no. 8; pp. 1518 - 1526
• Main Authors: Beca, Francisco, Krings, Gregor, Chen, Yunn-Yi, Hosfield, Elizabeth M., Vohra, Poonam, Sibley, Richard K., Troxell, Megan L., West, Robert B., Allison, Kimberly H., Bean, Gregory R.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2020; Elsevier Limited
• Subjects: 1-Phosphatidylinositol 3-kinase; 45/23; 631/208/514/2254; 631/67/1347; 631/67/1798; 631/67/395; 631/67/68; Adult; Angiogenesis; Breast cancer; Breast Neoplasms - genetics; Class I Phosphatidylinositol 3-Kinases - genetics; Female; Genomics; Hemangiosarcoma - genetics; Heterozygosity; Humans; Immunohistochemistry; Laboratory Medicine; Loss of heterozygosity; MAP kinase; Medicine; Medicine & Public Health; Metastases; Middle Aged; Mutants; Mutation; Mutation hot spots; Myc protein; p53 Protein; Pathogenesis; Pathology; Radiation therapy; Sarcoma; Tumors; Vascular Endothelial Growth Factor Receptor-2 - genetics
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/s41379-020-0511-6

Angiosarcoma (AS) is the most frequent primary sarcoma of the breast but nevertheless remains uncommon, accounting for <0.05% of breast malignancies. Secondary mammary AS arise following radiation therapy for breast cancer, in contrast to primary AS which occur sporadically. Essentially all show aggressive clinical behavior independent of histologic grade and most are treated by mastectomy. MYC amplification is frequently identified in radiation-induced AS but only rarely in primary mammary AS (PMAS). As a heterogeneous group, AS from various anatomic sites have been shown to harbor recurrent alterations in TP53 , MAP kinase pathway genes, and genes involved in angiogenic signaling including KDR (VEGFR2) and PTPRB . In part due to its rarity, the pathogenesis of PMAS has not been fully characterized. In this study, we examined the clinical, pathologic, and genomic features of ten cases of PMAS, including one patient with bilateral disease. Recurrent genomic alterations were identified in KDR (70%), PIK3CA/PIK3R1 (70%), and PTPRB (30%), each at higher frequencies than reported in AS across all sites. Six tumors harbored a KDR p.T771R hotspot mutation, and all seven KDR -mutant cases showed evidence suggestive of biallelism (four with loss of heterozygosity and three with two aberrations). Of the seven tumors with PI3K alterations, six harbored pathogenic mutations other than in the canonical PIK3 CA residues which are most frequent in breast cancer. Three AS were hypermutated (≥10 mutations/megabase (Mb)); hypermutation was seen concurrent with KDR or PIK3CA mutations. The patient with bilateral disease demonstrated shared alterations, indicative of contralateral metastasis. No MYC or TP53 aberrations were detected in this series. Immunohistochemistry for VEGFR2 was unable to discriminate between KDR -mutant tumors and benign vascular lesions of the breast. These findings highlight the underrecognized frequency of KDR and PIK3CA mutation in PMAS, and a significant subset with hypermutation, suggesting a pathogenesis distinct from other AS.