Breast cancers with BRCA1/2 alterations have a relatively high mutational load, suggesting that immune checkpoint blockade may be a potential treatment option. However, opposite to this conventional wisdom, by using a set of The Cancer Genome Atlas (TCGA) genomic data the researchers reported in July 2019 issue of the Clinical Cancer Research that higher levels of genomic instability have been associated with lower immunogenicity, which means that immune checkpoint inhibitors are less effective in patients with such tumours.
The study team from the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, US wrote in the study background that the degree of immune cell infiltration varies widely, and molecular features contributing to this variability remain unknown. They hypothesized that genomic signatures might predict immunogenicity in BRCA1/2 breast cancers.
In this study, by using TCGA genomic data, they compared 89 breast cancers with and 770 without either germline or somatic BRCA1/2 alterations. They also studied 35 breast cancers with germline BRCA1/2 mutations from Penn using whole exome sequencing (WES) and immunohistochemistry (IHC).
The study team found that homologous recombination deficiency (HRD) scores were negatively associated with expression-based immune indices despite being associated with a higher mutational/neoantigen burden in BRCA1/2 mutated breast cancers.
Furthermore, absence of allele-specific loss of heterozygosity (LOH) or subclonality of germline and somatic BRCA1/2 mutations, 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.
The IHC of Penn breast cancers demonstrated increased CD45+ and CD8+ infiltrates and increased PD-L1 expression in HRD-low or LOH-negative cancers.
Triple-negative cancers with low HRD had greater CD8+ T cells and Perforin 1 expression compared with hormone receptor-positive, HRD-high cancers.
The authors concluded that HRD scores and hormone receptor subtype are predictive of immunogenicity in BRCA1/2 breast cancers and may inform the design of optimal immune therapeutic strategies. The findings may help in understanding whether immune checkpoint inhibitors may be effective in treating BRCA1/2-related breast cancers.
Although this study is one of the largest of such analyses to date, the authors suggested that a larger sample size would help to understand further how the molecular features of BRCA1/2 mutation associated breast cancers are linked to immune response.
Reference
Kraya AA, Maxwell KN, Wubbenhorst B, et al. Genomic Signatures Predict the Immunogenicity of BRCA-Deficient Breast Cancer. Clinical Cancer Research 2019; 25(14):4363-4374.