Genomic Signatures Predict the Immunogenicity of BRCA-Deficient Breast Cancer.

Abstract

Breast cancers with <i>BRCA1/2</i> alterations have a relatively high mutational load, suggesting that immune checkpoint blockade may be a potential treatment option. However, the degree of immune cell infiltration varies widely, and molecular features contributing to this variability remain unknown. We hypothesized that genomic signatures might predict immunogenicity in <i>BRCA1/2</i> breast cancers. Using The Cancer Genome Atlas (TCGA) genomic data, we compared breast cancers with (89) and without (770) either germline or somatic <i>BRCA1/2</i> alterations. We also studied 35 breast cancers with germline <i>BRCA1/2</i> mutations from Penn using WES and IHC. We found that homologous recombination deficiency (HRD) scores were negatively associated with expression-based immune indices [cytolytic index (<i>P</i> = 0.04), immune ESTIMATE (<i>P</i> = 0.002), type II IFN signaling (<i>P</i> = 0.002)] despite being associated with a higher mutational/neoantigen burden, in <i>BRCA1/2</i> mutant breast cancers. Further, absence of allele-specific loss of heterozygosity (LOH negative; <i>P</i> = 0.01) or subclonality (<i>P</i> = 0.003) of germline and somatic <i>BRCA1/2</i> mutations, respectively, predicted for heightened cytolytic activity. Gene set analysis found that multiple innate and adaptive immune pathways that converge on NF-κB may contribute to this heightened immunogenicity. IHC of Penn breast cancers demonstrated increased CD45⁺ (<i>P</i> = 0.039) and CD8⁺ infiltrates (<i>P</i> = 0.037) and increased PDL1 expression (<i>P</i> = 0.012) in HRD-low or LOH-negative cancers. Triple-negative cancers with low HRD had far greater CD8⁺ T cells (<i>P</i> = 0.0011) and Perforin 1 expression (<i>P</i> = 0.014) compared with hormone receptor-positive HRD-high cancers. HRD scores and hormone receptor subtype are predictive of immunogenicity in <i>BRCA1/2</i> breast cancers and may inform the design of optimal immune therapeutic strategies.