Angiosarcomas are rare, clinically aggressive tumors with limited treatment options and a dismal prognosis. We analyzed angiosarcomas from 68 patients, integrating information from multiomic sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence for tumor-infiltrating immune cells. Through whole-genome sequencing (n = 18), 50% of the cutaneous head and neck angiosarcomas exhibited higher tumor mutation burden (TMB) and UV mutational signatures; others were mutationally quiet and non-UV driven. NanoString profiling revealed 3 distinct patient clusters represented by lack (clusters 1 and 2) or enrichment (cluster 3) of immune-related signaling and immune cells. Neutrophils (CD15 +), macrophages (CD68 +), cytotoxic T cells (CD8 +), Tregs (FOXP3 +), and PD-L1 + cells were enriched in cluster 3 relative to clusters 2 and 1. Likewise, tumor inflammation signature (TIS) scores were highest in cluster 3 (7.54 vs. 6.71 vs. 5.75, respectively; P < 0.0001). Head and neck angiosarcomas were predominant in clusters 1 and 3, providing the rationale for checkpoint immunotherapy, especially in the latter subgroup with both high TMB and TIS scores. Cluster 2 was enriched for secondary angiosarcomas and exhibited higher expression of DNMT1, BRD3/4, MYC, HRAS, and PDGFRB, in keeping with the upregulation of epigenetic and oncogenic signaling pathways amenable to targeted therapies. Molecular and immunological dissection of angiosarcomas may provide insights into opportunities for precision medicine.
The role of programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) in triple negative breast cancer (TNBC) remains to be fully understood. In this study, we investigated the role of PD-1 as a prognostic marker for TNBC in an Asian cohort (n = 269). Samples from patients with TNBC were labeled with antibodies against PD-L1 and PD-1, and subjected to NanoString assays to measure the expression of immune-related genes. Associations between disease-free survival (DFS), overall survival (OS) and biomarker expression were investigated. Multivariate analysis showed that tumors with high PD-1+ immune infiltrates harbored significantly increased DFS, and this increase was significant even after controlling for clinicopathological parameters (HR 0.95; P = 0.030). In addition, the density of cells expressing both CD8 and PD-1, but not the density of CD8−PD-1+ immune infiltrates, was associated with improved DFS. Notably, this prognostic significance was independent of clinicopathological parameters and the densities of total CD8+ cell (HR 0.43, P = 0.011). At the transcriptional level, high expression of PDCD1 within the tumor was significantly associated with improved DFS (HR 0.38; P = 0.027). In line with these findings, high expression of IFNG (HR 0.38; P = 0.001) and IFN signaling genes (HR 0.46; p = 0.027) was also associated with favorable DFS. Inclusion of PD-1 immune infiltrates and PDCD1 gene expression added significant prognostic value for DFS (ΔLRχ2 = 6.35; P = 0.041) and OS (ΔLRχ2 = 9.53; P = 0.008), beyond that provided by classical clinicopathological variables. Thus, PD-1 mRNA and protein expression status represent a promising, independent indicator of prognosis in TNBC.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0499-y) contains supplementary material, which is available to authorized users.
Context.— The role of liquid biopsy in cancer management has been gaining increased prominence in the past decade, with well-defined clinical applications now being established in lung cancer. Recently, the US Food and Drug Administration also approved the Therascreen PIK3CA RGQ polymerase chain reaction assay as a companion diagnostic assay to detect PIK3CA mutations in breast cancer for both tissue and liquid biopsies, bringing the role of liquid biopsy in breast cancer management to the fore. Its utility in other aspects of breast cancer, however, is yet to be clearly defined. Objective.— To review the studies that looked at liquid biopsies in breast cancer and examine their potential for clinical application in the areas of early diagnosis, prognostication, monitoring disease response, detecting minimal residual disease, and predicting risk of progression or relapse. We focus mainly on circulating tumor cells and circulating tumor DNA. Data sources.— Peer-reviewed articles in PubMed. Conclusions.— Liquid biopsies in breast cancers have yielded promising results, especially in the areas of monitoring treatment response and predicting disease progression or relapse. With further study, and hopefully coupled with continued improvements in technologies that isolate tumor-derived materials, liquid biopsies may go on to play a greater role in the breast cancer clinic.
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