The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research

Nat Med. 2020 Feb;26(2):181-187. doi: 10.1038/s41591-019-0749-z. Epub 2020 Feb 10.

Abstract

Despite rare cancers accounting for 25% of adult tumors1, they are difficult to study due to the low disease incidence and geographically dispersed patient populations, which has resulted in significant unmet clinical needs for patients with rare cancers. We assessed whether a patient-partnered research approach using online engagement can overcome these challenges, focusing on angiosarcoma, a sarcoma with an annual incidence of 300 cases in the United States. Here we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling US and Canadian patients to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 patients registered for the ASCproject, which comprises a large proportion of all patients with angiosarcoma. Whole-exome sequencing (WES) of 47 tumors revealed recurrently mutated genes that included KDR, TP53, and PIK3CA. PIK3CA-activating mutations were observed predominantly in primary breast angiosarcoma, which suggested a therapeutic rationale. Angiosarcoma of the head, neck, face and scalp (HNFS) was associated with a high tumor mutation burden (TMB) and a dominant ultraviolet damage mutational signature, which suggested that for the subset of patients with angiosarcoma of HNFS, ultraviolet damage may be a causative factor and that immune checkpoint inhibition may be beneficial. Medical record review revealed that two patients with HNFS angiosarcoma had received off-label therapeutic use of antibody to the programmed death-1 protein (anti-PD-1) and had experienced exceptional responses, which highlights immune checkpoint inhibition as a therapeutic avenue for HNFS angiosarcoma. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for patients with angiosarcoma. Collectively, this proof-of-concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and can enable discoveries.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / therapy*
  • Canada
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • DNA Mutational Analysis
  • Exome
  • Female
  • Genome, Human
  • Genomics
  • Hemangiosarcoma / genetics*
  • Hemangiosarcoma / therapy*
  • Humans
  • Middle Aged
  • Mutation
  • Patient Participation*
  • Program Development
  • Rare Diseases / genetics*
  • Rare Diseases / therapy*
  • Tumor Suppressor Protein p53 / genetics
  • United States
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Whole Exome Sequencing
  • Young Adult

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2

Supplementary concepts

  • Angiosarcoma of the breast