Genomic Signatures Predict the Immunogenicity of BRCA-Deficient Breast Cancer

Abstract

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 expressionbased immune indices [cytolytic index (P ¼ 0.04), immune ESTIMATE (P ¼ 0.002), type II IFN signaling (P ¼ 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 ¼ 0.01) or subclonality (P ¼ 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-kB may contribute to this heightened immunogenicity. IHC of Penn breast cancers demonstrated increased CD45 þ (P ¼ 0.039) and CD8 þ infiltrates (P ¼ 0.037) and increased PDL1 expression (P ¼ 0.012) in HRD-low or LOH-negative cancers. Triple-negative cancers with low HRD had far greater CD8 þ T cells (P ¼ 0.0011) and Perforin 1 expression (P ¼ 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.

Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors

“…These analyses revealed that OXPHOS and four additional mitochondria‐related metabolic sets () are positively associated with the presence of the S3 signature (S3+), that is, with HR defects in breast tumors (gene set expression analysis [GSEA] nominal P = 0.019, Fig A, top panel). Moreover, we also complied BRCA1 / 2 mutation status of TCGA breast cancer datasets from different sources (cBioPortal and TCGA accessible data) (Kraya et al , ; Yost et al , ) and further analyzed the association with the KEGG oxidative phosphorylation pathway. In multivariate regression analyses including age at diagnosis and tumor stage, overexpression of this pathway was also detected significantly associated with BRCA1 / 2 mutations ( P = 0.013, Fig A, middle panel).…”

“…The BRCA1/2 mutation status in primary breast and ovarian tumors from TCGA studies was determined by annotations downloaded from the cBioPortal combined with curated information from two publications (Kraya et al , ; Yost et al , ).…”

Elevated tumor mutation burden and immunogenic activity in patients with hormone receptor‑negative or human epidermal growth factor receptor 2‑positive breast cancer

“…Previous studies have used genomic data from TCGA to characterize cytolytic activity estimated using the expression of two genes (15,17,18). Recently, marker gene expression was used to analyze infiltration of various immune cell types (16,19–21).…”

Role of Immunotherapy in Triple-Negative Breast Cancer

“…40 Translational studies of human breast cancers have also shown that BRCA1/2 mutations negatively associate with markers of immunogenicity, such as immune infiltration and T-cell-mediated cytolysis, the latter calculated as the summed expression of the CD8-positive T-cell effectors PRF1 and GZMA. 41 To evaluate the clinical efficacy of combining the PARP inhibitor niraparib with the PD-1 inhibitor pembrolizumab, the phase II TOPACIO trial (ClinicalTrials.gov identifier: NCT02657889) enrolled 55 patients with advanced or mTNBC and found an ORR of 47% and a median PFS of 8.3 months among the 15 patients with tumor BRCA mutations. 42 Within the limits of cross-trial comparisons, this ORR was slightly lower than the ORRs of 55% and 62% associated with single-agent PARP inhibitor therapy in patients with TNBC and germline BRCA mutations in the OlympiAD (NCT02000622) 43 and EMBRACA 44 (NCT01945775) trials, respectively.…”