Angiosarcoma treatment often includes combined radical surgical excision and radiotherapy. However, over 60% of patients ultimately develop distant metastases. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is an unmet clinical need for more effective therapies to induce durable responses. In the last 2 years, the advent of immunotherapy has provided a promising alternative for classical cytotoxic chemotherapy. Sensitivity to immunotherapy is thought to be secondary to higher DNA mutation rates, for example those found in melanoma and non-small cell lung cancer. While in comparison the mutation rate in acute leukemia is low. The genetic aberrations involved in the development of angiosarcoma are still poorly understood. Until recently, most of the genetic alterations were identified mostly in secondary but not in primary angiosarcomas. The most frequent chromosomal abnormalities were on chromosome 8q, 10p and 5q . Additonally, MYC amplification is a recurrent genetic mutation in secondary angiosarcoma. Recently, Shon and his colleagues confirmed the presence of both MYC amplification and MYC overexpression in a minority of primary angiosarcomas . In their study, by IHC analysis, MYC overexpression was present in 9 of 38 (24%) cases. Six of the nine positive cases were from the head and neck region . Therefore, in comparison to other tumor types, angiosarcoma would appear to have an intermediate mutation frequency.
The anti-CTLA4 antibody ipilimumab has been given to six patients with synovial sarcoma without a response . Current data using PD-1 inhibitors for the treatment of sarcoma is limited. PD-1 and PD-L1 expression has been reported in a variety of sarcomas, although the limited number of angiosarcomas tested have been negative for this marker. One study reviewed PD-1 and PD-L1 expression in 105 patients with multiple subtypes of sarcoma and found that intratumoral infiltration of PD-1 positive lymphocytes was seen in 65% of cases and PD-L1 tumor expression in 58% . PD-1 and PD-L1 expression was correlated with higher tumor grade, advanced stage of disease, presence of metastasis, and poor clinical outcome . Another study evaluated various subtypes of soft tissue in 50 sarcoma patients, and pathologic expression revealed lower levels of PD-L1 expression on tumor cells and infiltrating lymphocytes (12% and 30%, respectively) . In this study, there was no association between clinical features and overall survival with PD-L1 expression in tumor or immune infiltrates. The authors proposed that the reason for the differing results could be due to the small heterogeneous cohort and the use of a differing PD-L1 assay in these studies.
Despite the lack of a large clinical trial data showing definitive efficacy in sarcomas, there is data from smaller trials that show that immunotherapy has activity against certain sarcomas. Tawbi and colleagues evaluated the use of pembrolizumab in soft tissue sarcoma and bone sarcoma in a phase II study . Five of the 76 patients had a partial response after 20 weeks of treatment suggesting that the use of PD-1 and PD-L1 blockade does show efficacy in the treatment of sarcomas and may provide a viable treatment option for patients . Another retrospective analysis included 23 metastatic soft tissue sarcoma or bone sarcoma patients treated with nivolumab . Thirteen of these patients also received concomitant treatment with the tyrosine kinase inhibitor, pazopanib. Patients had baseline imaging and then restaging imaging after 6 cycles of treatment and 9/23 patients were found to have clinical benefit, with either a partial response or stable disease .