Genomic and immunological tumor profiling identifies targetable pathways and extensive CD8+/PDL1+ immune infiltration in inflammatory breast cancer tumors

Christopher A. Hamm, Diarmuid Moran, Kakuturu Rao, Patricia B. Trusk, Karen Pry, Mark Sausen, Siân Jones, Victor E Velculescu, Massimo Cristofanilli, Sarah Bacus

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1746-1756
Number of pages11
JournalMolecular Cancer Therapeutics
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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