Abstract 3887: Genomic analysis identifies drug targetable pathways and predicts immune infiltration in inflammatory breast cancer tumors
Authors: Moran Diarmuid , Hamm Christopher A. , Rao Kakuturu , Bacon-Trusk Patricia , Pry Karen , Velculescu Victor , Cristofanilli Massimo , Bacus Sarah S. 
Published: August 2015

Background

Inflammatory breast Cancer (IBC) is a rare aggressive breast cancer in which cancer cells block the lymph vessels in the skin of the breast. IBC tumors have a high rate of ERBB2 positivity and response to ERBB2 targeted therapies. Due to the rarity of this cancer, the molecular etiology of this disease is poorly understood.

Materials & Methods

A 208 gene next-generation sequencing (NGS) panel was used to analyze 20 IBC patient tumor and matched normal samples. Tissues were stained for cell signaling proteins and immune-markers. Cell line studies were performed to understand the impact of genomic variants on therapeutic selection.

Results

Common pathway alterations reoccur among IBC samples that influence genome stability, PI3K signaling, and ERBB signaling. NGS revealed alterations in both the ERBB/PI3K pathways, including: ERBB2 amplification, ERBB3 mutations, and activating PI3K mutations. Immunohistochemistry (IHC) staining for pS6 and pERBB3 identified ERBB/PI3K pathway activity in IBC samples. Cell line studies using siRNA and neutralizing antibodies demonstrate that mutant ERBB3 signaling contributes to IBC proliferation.

IBC tumors with high levels of CD8+ immune infiltrate have a significantly higher somatic mutation rate than other IBC tumors. A proposed score (iScore) based on the somatic mutation rate and the average mutant allele frequency, showed greater correlation with the level of CD8+ immune infiltration. Furthermore, tumors with high CD8+ infiltrating lymphocytes were associated with a higher frequency of alterations in DNA mismatch repair (MMR) genes. IHC revealed high levels of the immune checkpoint signaling molecule PD-L1 in the inflammatory infiltrate of IBC tumors.

Conclusions

This study identifies a higher level of ERBB3 mutations than reported in other cancers and an important role for ERBB3 mutation in IBC. ERBB3 targeted therapies in combination with ERBB/PI3K drugs may be important for IBC treatment. Furthermore, high somatic mutations rates in a subset of IBC tumors harboring MMR mutations lead to greater levels of PD-L1+ immune infiltrates, which suggests a possible benefit from immunotherapies such as anti-PD-L1 antibodies. iScore, a more predictive value of immune infiltration in tumors, may be indicative of the level of neoantigen exposure to the immune system. The utility of the newly proposed iScore is currently being investigated as a method to predict immune cell infiltrates and immunotherapy response in other tumor types.

Citation Format: Diarmuid Moran, Christopher A. Hamm, Kakuturu Rao, Patricia Bacon-Trusk, Karen Pry, Victor Velculescu, Massimo Cristofanilli, Sarah S. Bacus. Genomic analysis identifies drug targetable pathways and predicts immune infiltration in inflammatory breast cancer tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3887. doi:10.1158/1538-7445.AM2015-3887