Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419

Abstract

BackgroundTriple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease.MethodsWhole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC—Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed.ResultsPrimary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM.ConclusionsBrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted.

Immunotherapy: an emerging modality to checkmate brain metastasis

“…TNBC is considered a highly aggressive cancer that proliferates rapidly and is often initially diagnosed at advanced stages. Between 22% and 50% of TNBC patients develop BrM and have 4–5 months OS of patients [ 130 , 131 , 133 , 137 – 140 ]. Traditionally, treatment modalities for the treatment of BCs have depended on the receptor status of the tumor, thus, it is harder to treat a cancer like TNBC with no receptors to target.…”

“…Routh et al conducted a similar analysis of immune biomarkers in patients with TNBC. Compared to primary breast tumor tissue, BrM displayed a higher TMB, with tumor protein 53 (TP53) altered in 50% of patients [ 137 ]. Neoantigen prediction displayed high levels of endogenous retrovirus-derived MHC class I-binding peptides in both primary and BrM tumors and further predicted significantly higher single-nucleotide variant-derived peptides in BrM compared to primary tumors [ 137 ].…”

“…Compared to primary breast tumor tissue, BrM displayed a higher TMB, with tumor protein 53 (TP53) altered in 50% of patients [ 137 ]. Neoantigen prediction displayed high levels of endogenous retrovirus-derived MHC class I-binding peptides in both primary and BrM tumors and further predicted significantly higher single-nucleotide variant-derived peptides in BrM compared to primary tumors [ 137 ]. BrM also had decreased immune gene expression, with reduced T and B cell receptor diversity compared to pair-matched breast tumor tissue [ 137 ].…”

“…Neoantigen prediction displayed high levels of endogenous retrovirus-derived MHC class I-binding peptides in both primary and BrM tumors and further predicted significantly higher single-nucleotide variant-derived peptides in BrM compared to primary tumors [ 137 ]. BrM also had decreased immune gene expression, with reduced T and B cell receptor diversity compared to pair-matched breast tumor tissue [ 137 ]. These results proved the potential of IT vaccines or ICIs in the treatment of TNBC BrM, with further scope for investigation [ 137 ].…”

“…BrM also had decreased immune gene expression, with reduced T and B cell receptor diversity compared to pair-matched breast tumor tissue [ 137 ]. These results proved the potential of IT vaccines or ICIs in the treatment of TNBC BrM, with further scope for investigation [ 137 ].…”