Cutaneous Angiosarcomas: Molecular Pathogenesis Guides Novel Therapeutic Approaches

Abstract

Summary Cutaneous angiosarcoma (CAS) is a highly aggressive cancer with a poor prognosis. Primary, spontaneous CAS (pCAS) and secondary, post‐irradiation‐ or lymphedema‐associated CAS (sCAS) are clinically, but also molecularly distinct. Myc amplification/overexpression is a characteristic, although not exclusive feature of sCAS, while loss of TP53 selectively occurs in pCAS. Detailed molecular analyses with modern multi‐omics approaches have revealed that both pCAS and sCAS exhibit considerable molecular heterogeneity. Affected genes and their molecular regulators including a plethora of microRNAs may serve as future drug targets. Furthermore, pCAS could be subdivided into clusters with high tumor mutational burden and/or high tumor inflammation signatures providing a rationale for the stratification of pCAS patients in future immunotherapeutic clinical studies. Development of novel treatment regimens guided by these molecular alterations, however, cannot fully keep up with the pace of their discovery due to the low incidence of the disease. Nevertheless, beyond conventional surgery and chemoradiotherapy, clinical trials investigating novel treatment options have been initiated including targeted therapies against VEGF and VEGFR1–3 such as bevacizumab and pazopanib, and β‐adrenoreceptor blockers such as propranolol. Finally, immunotherapies are being developed including immune checkpoint inhibitors pembrolizumab and nivolumab as well as anti‐RANKL antibody denosumab.

Cutaneous Angiosarcoma of the Head and Neck—A Retrospective Analysis of 47 Patients

“…About 50% of cases in both cluster 1 and cluster 3 displayed UV mutational signals and high tumor mutational burden (TMB). Cluster 3 patients with high TMB and TIS scores represent the population with highest probability for efficacious response rates from immune checkpoint inhibitor treatments [ 36 ]. Moreover, immunotherapy has shown promise as a treatment modality in several studies.…”

Plasminogen activating inhibitor‐1 promotes angiogenesis in cutaneous angiosarcomas

“…Cutaneous angiosarcoma (CAS) is a vascular tumor histologically characterized by detachment of EC‐derived tumor cells 3 . Since CAS expresses multiple angiogenic growth factors and has increased expressions of angiogenic receptor tyrosine kinase transcripts including VEGFR1/2/3, VEGF and VEGFR inhibitors or multi‐tyrosine kinase inhibitors (TKIs) are potential drug targets in CAS 5–8 . Indeed, several phase II trials of antiangiogenic tyrosine kinase inhibitors (TKIs) for AS have been reported, although the results were not satisfactory 8 .…”

“…3 Since CAS expresses multiple angiogenic growth factors and has increased expressions of angiogenic receptor tyrosine kinase transcripts including VEGFR1/2/3, VEGF and VEGFR inhibitors or multi-tyrosine kinase inhibitors (TKIs) are potential drug targets in CAS. [5][6][7][8] Indeed,…”

“…several phase II trials of antiangiogenic tyrosine kinase inhibitors (TKIs) for AS have been reported, although the results were not satisfactory. 8 For example, the objective response rate (ORR) of bevacizumab monotherapy was 8%, and median progression-free survival (PFS) was 3 months. 9 Moreover, even bevacizumab in combination with paclitaxel, a standard drug for the treatment of CAS, did not improve the ORR of paclitaxel monotherapy (28% combination vs. 46% paclitaxel), PFS (6.6 vs. 6.6 months) or overall survival (19.5 vs. 15.9 months).…”

Case report: Unique FLT4 variants associated with differential response to anlotinib in angiosarcoma

“…Surgical resection with wide excisional margins is the main therapy for R0 resection cASs, but due to insufficient surgical excision and the infiltrative growth pattern, local recurrences or metastases are common, particularly in head and neck locations, with 5-year overall survival of 10%–15% ( 11 , 12 ). Several studies revealed that age, tumor size, tumor location, resection with positive margins, and advanced stage are the poor prognosis factors for cASs ( 13 – 15 ).…”