Genomic and Immunological Tumor Profiling Identifies Targetable Pathways and Extensive CD8+/PDL1+ Immune Infiltration in Inflammatory Breast Cancer Tumors

Mol Cancer Ther. 2016 Jul;15(7):1746-56. doi: 10.1158/1535-7163.MCT-15-0353. Epub 2016 Apr 19.

Abstract

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that remains poorly understood at the molecular level. Comprehensive tumor profiling was performed to understand clinically actionable alterations in IBC. Targeted next-generation sequencing (NGS) and IHC were performed to identify activated pathways in IBC tumor tissues. siRNA studies examined the impact of IBC genomic variants in cellular models. IBC tumor tissues were further characterized for immune infiltration and immune checkpoint expression by IHC. Genomic analysis identified recurrent alterations in core biologic pathways, including activating and targetable variants in HER/PI3K/mTOR signaling. High rates of activating HER3 point mutations were discovered in IBC tumors. Cell line studies confirmed a role for mutant HER3 in IBC cell proliferation. Immunologic analysis revealed a subset of IBC tumors associated with high CD8(+)/PD-L1(+) lymphocyte infiltration. Immune infiltration positively correlated with an NGS-based estimate of neoantigen exposure derived from the somatic mutation rate and mutant allele frequency, iScore. Additionally, DNA mismatch repair alterations, which may contribute to higher iScores, occurred at greater frequency in tumors with higher immune infiltration. Our study identifies genomic alterations that mechanistically contribute to oncogenic signaling in IBC and provides a genetic basis for the selection of clinically relevant targeted and combination therapeutic strategies. Furthermore, an NGS-based estimate of neoantigen exposure developed in this study (iScore) may be a useful biomarker to predict immune infiltration in IBC and other cancers. The iScore may be associated with greater levels of response to immunotherapies, such as PD-L1/PD-1-targeted therapies. Mol Cancer Ther; 15(7); 1746-56. ©2016 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Line, Tumor
  • Cluster Analysis
  • Computational Biology / methods
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genomics* / methods
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Inflammatory Breast Neoplasms / genetics*
  • Inflammatory Breast Neoplasms / immunology
  • Inflammatory Breast Neoplasms / metabolism*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Models, Biological
  • Mutation
  • Mutation Rate
  • Phosphatidylinositol 3-Kinases / metabolism
  • RNA, Small Interfering / genetics
  • Receptor, ErbB-3 / genetics
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • B7-H1 Antigen
  • RNA, Small Interfering
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Receptor, ErbB-3