Your browser doesn't support javascript.

Biblioteca Virtual em Saúde

Brasil

Home > Pesquisa > ()
Imprimir Exportar

Formato de exportação:

Exportar

Email
Adicionar mais destinatários
| |

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

Kraya, Adam A; Maxwell, Kara N; Wubbenhorst, Bradley; Wenz, Brandon M; Pluta, John; Rech, Andrew J; Dorfman, Liza M; Lunceford, Nicole; Barrett, Amanda; Mitra, Nandita; Morrissette, Jennifer J D; Feldman, Michael; Nayak, Anupma; Domchek, Susan M; Vonderheide, Robert H; Nathanson, Katherine L.
Clin Cancer Res; 25(14): 4363-4374, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30914433

PURPOSE:

Breast cancers with BRCA1/2 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.

EXPERIMENTAL DESIGN:

We hypothesized that genomic signatures might predict immunogenicity in BRCA1/2 breast cancers. Using The Cancer Genome Atlas (TCGA) genomic data, we compared breast cancers with (89) and without (770) either germline or somatic BRCA1/2 alterations. We also studied 35 breast cancers with germline BRCA1/2 mutations from Penn using WES and IHC.

RESULTS:

We found that homologous recombination deficiency (HRD) scores were negatively associated with expression-based immune indices [cytolytic index (P = 0.04), immune ESTIMATE (P = 0.002), type II IFN signaling (P = 0.002)] despite being associated with a higher mutational/neoantigen burden, in BRCA1/2 mutant breast cancers. Further, absence of allele-specific loss of heterozygosity (LOH negative; P = 0.01) or subclonality (P = 0.003) of germline and somatic BRCA1/2 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+ (P = 0.039) and CD8+ infiltrates (P = 0.037) and increased PDL1 expression (P = 0.012) in HRD-low or LOH-negative cancers. Triple-negative cancers with low HRD had far greater CD8+ T cells (P = 0.0011) and Perforin 1 expression (P = 0.014) compared with hormone receptor-positive HRD-high cancers.

CONCLUSIONS:

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.
Selo DaSilva