Background Angiosarcomas are rare and aggressive tumors with high risk of recurrence and metastasis that lack effective long-term therapy standards. Growing evidence suggests that immune checkpoint inhibitors (ICI) hold promise as therapeutic options for angiosarcomas.^{1 2} Moreover, the tumor microenvironment (TME) landscape in angiosarcomas may contribute to the prediction of tumor response to ICI.³ Here, we investigated genomic and TME features of angiosarcomas using comprehensive genomic profiling to reveal their potential predictive values for treatment strategies.

Methods Retrospective analysis of BostonGene Tumor Portrait™ test reports, which included data from whole exome and whole transcriptome sequencing and comprehensive profiling,³ was performed for 39 samples from angiosarcoma patients. Genomic alterations were identified, and tumors were classified into TME subtypes to define immune and stromal characteristics. For 4 patients with available data on response to prior immunotherapy regimens, associations between TME profiles and the response to ICI and its duration were assessed.

Results Samples of primary angiosarcoma (31/39) and radiation-induced angiosarcoma (8/39) patients with cutaneous (13/39) and non-cutaneous (26/39) subtypes were studied. Importantly, genetic alterations critical for targeted therapy selection were uncovered (table 1). Transcriptomic-based TME classification revealed 67% of angiosarcoma samples (26/39) with immune-enriched (IE) microenvironments, as characterized by high levels of immune infiltration (including cytotoxic effector cells), low to high prevalence of stromal and fibrotic elements, and medium levels of cancer-associated fibroblasts. These features may be associated with potential benefits from ICI therapy. The remaining 33% of samples (13/39) demonstrated a fibrotic (F) TME subtype with minimal immune infiltration and high prevalence of stromal elements. Only 35% of samples (14/39) had high PD-L1 mRNA expression (relative expression at ≥90th percentile according to internal sarcoma cohort). Moreover, 4 samples exhibited high tumor mutational burden (TMB). Response data to prior immunotherapy showed that patients with partial response (PR, N=1) and stable disease (SD, N=1) had an IE TME subtype. Progressive disease (PD) was observed in 2 angiosarcoma patients (IE subtype N=1, F subtype N=1, table 2).

Conclusions The BostoneGene Tumor Portrait™ test revealed possible associations between TME subtypes and immunotherapy response in angiosarcomas. Particularly, immune-enriched tumors may be conducive to more targeted and efficient treatment selection, pending future validation. Angiosarcoma tumor profiling also uncovered potentially targetable and clinically relevant alterations in these tumors, which may expand treatment options.

References

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2. Florou V, Rosenberg AE, Wieder E, Komanduri KV, Kolonias D, Uduman M, Castle JC, Buell JS, Trent JC, Wilky BA. Angiosarcoma patients treated with immune checkpoint inhibitors: a case series of seven patients from a single institution. J Immunother Cancer 2019;8;7(1):213. Erratum in: J Immunother Cancer 2019;6;7(1):285.

3. Loh JW, Lee JY, Lim AH, Guan P, Lim BY, Kannan B, Lee ECY, Gu NX, Ko TK, Ng CC, Lim JCT, Yeong J, Lim JQ, Ong CK, Teh BT, Chan JY. Spatial transcriptomics reveal topological immune landscapes of Asian head and neck angiosarcoma. Commun Biol 2023;27;6(1):461.

Ethics Approval The use of clinical samples was conducted in accordance with the Declaration of Helsinki and has been granted exemption from ethics approval by the Biomedical Research Alliance of New York (BRANY) Institutional Review Board (BRANY study #22-12-938-853).