Clinical, genomic, and transcriptomic correlates of response to immune checkpoint blockade-based therapy in a cohort of patients with angiosarcoma treated at a single center

• Published in: Journal for immunotherapy of cancer 2022-04, Vol.10 (4), p.e004149
• Main Authors: Rosenbaum, Evan, Antonescu, Cristina R, Smith, Shaleigh, Bradic, Martina, Kashani, Daniel, Richards, Allison L, Donoghue, Mark, Kelly, Ciara M, Nacev, Benjamin, Chan, Jason E, Chi, Ping, Dickson, Mark A, Keohan, Mary L, Gounder, Mrinal M, Movva, Sujana, Avutu, Viswatej, Thornton, Katherine, Zehir, Ahmet, Bowman, Anita S, Singer, Samuel, Tap, William, D’Angelo, Sandra
• Format: Article
• Language: English
• Subjects: Antibodies; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Biomarkers; Biomarkers, Tumor; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Clinical trials; Cloning; Genomes; Genomics; Hemangiosarcoma - drug therapy; Hemangiosarcoma - genetics; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Immunotherapy Biomarkers; Laboratories; Lung Neoplasms - drug therapy; Lymphedema; Lymphocytes; Metastasis; Mutation; Patients; Quality control; Radiation; Retrospective Studies; Sarcoma; Signatures; Software; Transcriptome
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-004149

BackgroundAngiosarcoma is a histologically and molecularly heterogeneous vascular neoplasm with aggressive clinical behavior. Emerging data suggests that immune checkpoint blockade (ICB) is efficacious against some angiosarcomas, particularly cutaneous angiosarcoma of the head and neck (CHN).MethodsPatients with histologically confirmed angiosarcoma treated with ICB-based therapy at a comprehensive cancer center were retrospectively identified. Clinical characteristics and the results of targeted exome sequencing, transcriptome sequencing, and immunohistochemistry analyses were examined for correlation with clinical benefit. Durable clinical benefit was defined as a progression-free survival (PFS) of ≥16 weeks.ResultsFor the 35 patients included in the analyses, median PFS and median overall survival (OS) from the time of first ICB-based treatment were 11.9 (95% CI 7.4 to 31.9) and 42.5 (95% CI 19.6 to 114.2) weeks, respectively. Thirteen patients (37%) had PFS ≥16 weeks. Clinical factors associated with longer PFS and longer OS in multivariate analyses were ICB plus other therapy regimens, CHN disease, and white race. Three of 10 patients with CHN angiosarcoma evaluable for tumor mutational burden (TMB) had a TMB ≥10. Five of six patients with CHN angiosarcoma evaluable for mutational signature analysis had a dominant mutational signature associated with ultraviolet (UV) light. No individual gene or genomic pathway was significantly associated with PFS or OS; neither were TMB or UV signature status. Analyses of whole transcriptomes from nine patient tumor samples found upregulation of angiogenesis, inflammatory response, and KRAS signaling pathways, among others, in patients with PFS ≥16 weeks, as well as higher levels of cytotoxic T cells, dendritic cells, and natural killer cells. Patients with PFS