Cancer immunotherapy has altered the management of human malignancies, improving outcomes in an expanding list of diseases. Breast cancer - presumably due to its perceived low immunogenicity - is a late addition to this list. Furthermore, most of the focus has been on the triple negative subtype because of its higher tumor mutational load and lymphocyte-enriched stroma, although emerging data show promise on the other breast cancer subtypes as well. To this point the clinical use of immunotherapy is limited to the inhibition of two immune checkpoints, Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4). Consistent with the complexity of the regulation of the tumor – host interactions and their lack of reliance on a single regulatory pathway, combinatory approaches have shown improved efficacy albeit at the cost of increased toxicity. Beyond those two checkpoints though, a large number of co-stimulatory or co-inhibitory molecules play major roles on tumor evasion from immunosurveillance. These molecules likely represent future targets of immunotherapy provided that the promise shown in early data is translated into improved patient survival in randomized trials. The biological role, prognostic and predictive implications regarding breast cancer and early clinical efforts on exploiting these immune-related therapeutic targets are herein reviewed.

Gene and protein expression of programmed death‐ligand 1 (PD‐L1) are prognostic in early breast cancer (BC), but their prognostic information is inconsistent at least in some biological subgroups. The validated prognostic gene signatures (GS) in BC are mainly based on proliferation and estrogen receptor (ER)‐related genes. Here, we aimed to explore the prognostic capacity of PD‐L1 expression at the protein vs mRNA levels and to investigate the prognostic information that PD‐L1 can potentially add to routinely used GS. Gene expression data were derived from two early BC cohorts (cohort 1: 562 patients; cohort 2: 1081 patients). Tissue microarrays from cohort 1 were immunohistochemically (IHC) stained for PD‐L1 using the SP263 clone. GS scores (21‐gene, 70‐gene) were calculated, and likelihood‐ratio (LR) tests and concordance indices were used to evaluate the additional prognostic information for each signature. The immune cell composition was also evaluated using the CIBERSORT in silico tool. PD‐L1 gene and protein expressions were independently associated with better prognosis. In ER+/HER2− patients, PD‐L1 gene expression provided significant additional prognostic information beyond that of both 21‐GS [LR‐Δχ2 = 15.289 and LR‐Δχ2 = 8.812, P < 0.01 for distant metastasis‐free interval (DMFI) in cohorts 1 and 2, respectively] and 70‐GS score alone (LR‐Δχ2 = 18.198 and LR‐Δχ2 = 8.467, P < 0.01 for DMFI in cohorts 1 and 2, respectively). PD‐L1 expression was correlated with IHC‐determined CD3+ cells (r = 0.41, P < 0.001) and with CD8+ (r = 0.62, P < 0.001) and CD4+ memory activated (r = 0.66, P < 0.001) but not with memory resting (r = −0.063, P = 0.14) or regulatory (r = −0.12, P < 0.01) T cells in silico. PD‐L1 gene expression represents a promising favorable prognostic marker and can provide additional prognostic value to 21‐ and 70‐gene scores in ER+/HER2− BC.

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Background: Detection of the human epidermal growth factor receptor 2 gene (HER2, also known as erbB2) expression is important to decide a treatment strategy for breast cancer patients. 20 to 30% of breast cancer patients overexpress HER2. The reference methods for determining HER2 protein expression are Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Although both methods are reliable, they are complex, time-consuming and expensive.

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