Predictive biomarker profiling of > 1,900 sarcomas: Identification of potential novel treatment modalities

Authors:

Sujana Movva, Wenhsiang Wen, Wangjuh Chen, Sherri Z. Millis, Margaret von Mehren, Zoran Gatalica, Brian A. Van Tine

Introduction:

  • Sarcomas are rare, heterogeneous tumors
  • Predictive biomarkers may help direct the optimal selection of therapy
  • Identification of new therapeutic targets is needed

Methods:

  • Multiplatform profiling at Caris Life Sciences, CLIA certified, specimen reviewed by Board certified pathologists
  • Formalin-fixed paraffin-embedded samples
    • Immunohistochemistry
      • 21 protein panel
      • Standard thresholds specific to each antibody
    • Fluorescence/Chromogenic in situ hybridization (FISH/CISH)
      • Detect gene amplifications
      • 7 gene panel
      • Standard scoring systems applied
    • DNA Sequencing (Next generation sequencing or Sanger)
      • Somatic mutations
      • 45 genes
      • Next generation sequencing
      • Illumina MiSeq platform (Illumina TruSeq Amplicon Cancer Hotspot panel)

Results – Sequencing Summary:

  • Mutations with frequency ≥ 5%
    • Synovial sarcoma and ATM, cKIT
    • Angiosarcoma and BRAF, APC, NRAS, ATM, cMET, KRAS, PTEN
    • Chondrosarcoma and IDH1, PTEN
    • Liposarcoma and PIK3CA
    • LMS and PTEN, RB1

Limitations:

  • Subtype of sarcoma extracted from paperwork submitted by treating physician
    • “Sarcoma, NOS”
  • Limited clinical information regarding:
    • Site of tumor (primary vs. metastatic)
    • Treatment history

Conclusions:

  • TOPO2A is overexpressed in approximately 50% of sarcomas, without associated gene amplification
    – Most commonly in angiosarcoma, LMS, UPS
  • SPARC is overexpressed in angiosarcoma, chondrosarcoma, EHE and osteosarcoma
  • PTEN loss was found in up to 80% of sarcomas, without a high frequency of PTEN mutations noted
  • Concordance between EGFR overexpression and EGFR gene amplification was low
    • Gene amplification was highest in LMS, MPNST, osteosarcoma and UPS
  • PD-L1 expression was noted in 100% of liposarcomas (mostly dedifferentiated) and 100% of chondrosarcomas
  • Profiling through protein expression, gene copy variations and mutations identified alterations in 99% of sarcoma samples
  • Future clinical trials are needed to determine the predictive and/or prognostic nature of these findings

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