Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer

Purpose: Breast cancers with BRCA1/2 alterations have a in BRCA1/2 mutant breast cancers. Further, absence of relatively high mutational load, suggesting that immune allele-specific loss of heterozygosity (LOH negative; P ¼ checkpoint blockade may be a potential treatment option. 0.01) or subclonality (P ¼ 0.003) of germline and somatic However, the degree of immune cell infiltration varies widely, BRCA1/2 mutations, respectively, predicted for heightened and molecular features contributing to this variability remain cytolytic activity. Gene set analysis found that multiple unknown. innate and adaptive immune pathways that converge on Experimental Design: We hypothesized that genomic sig-NF-kB may contribute to this heightened immunogenicity. natures might predict immunogenicity in BRCA1/2 breast IHC of Penn breast cancers demonstrated increased CD45^þ cancers. Using The Cancer Genome Atlas (TCGA) genomic (P ¼ 0.039) and CD8^þ infiltrates (P ¼ 0.037) and increased data, we compared breast cancers with (89) and without (770) PDL1 expression (P ¼ 0.012) in HRD-low or LOH-negative either germline or somatic BRCA1/2 alterations. We also cancers. Triple-negative cancers with low HRD had far studied 35 breast cancers with germline BRCA1/2 mutations greater CD8^þ T cells (P ¼ 0.0011) and Perforin 1 expression from Penn using WES and IHC. (P ¼ 0.014) compared with hormone receptor-positive Results: We found that homologous recombination defi-HRD-high cancers. ciency (HRD) scores were negatively associated with expression-Conclusions: HRD scores and hormone receptor subtype based immune indices [cytolytic index (P ¼ 0.04), immune are predictive of immunogenicity in BRCA1/2 breast cancers ESTIMATE (P ¼ 0.002), type II IFN signaling (P ¼ 0.002)] despite and may inform the design of optimal immune therapeutic being associated with a higher mutational/neoantigen burden, strategies.