Immunotherapy in triple-negative breast cancer

Abstract

Breast cancer can be classified based on the expression or lack of expression of protein receptors including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor 2 (Her2). The basal molecular subtype is mostly made up of breast cancers that do not express ER/PR or Her2, triple-negative breast cancers (TNBC) (Bertucci et al. in Int J Cancer 123(1):236, 2008). TNBC tends to be more aggressive as there are no approved targeted treatments and the only treatment option currently is cytotoxic chemotherapy. Recent data show that some chemotherapies, specifically anthracyclines, not only have cytotoxic effects but also use the immune system by activating CD8+ T cell responses to kill cancer cells (Stagg et al. in Ther Adv Med Oncol 5(3):169-181, 2013), and thus, tumor-infiltrating lymphocytes respond well to chemotherapy. Currently, systemic immunotherapy which utilizes the patient's own immune system directly to eradicate and target neoplastic cells is being explored as treatment for TNBC as this type of breast cancer has been shown to be immunogenic (Yu et al. in Int J Environ Res Public Health 14:68, 2017). According to the Cancer Genome Atlas, TNBC has higher PD-L1 mRNA expression (Mittendorf et al. Cancer Immunol Res 2(4):361-370, 2014). Higher rates of CD8+ T cell infiltration were also found in TNBC according to a study by Liu et al. (Breast Cancer Res 14:R48, 2012). In TNBC patients, Pembrolizumab, a monoclonal antibody that targets programmed cell death protein 1 (PD-1), and Atezolizumab, a monoclonal antibody that targets its ligand, have been investigated to assess dose tolerability and side effects. Further studies involving vaccines, immunotherapy that targets cytotoxic T lymphocyte-associated protein-4 and PD-L1, are currently being investigated for treatment of TNBC. This review outlines the systemic immunotherapies that are currently being investigated for patients with TNBC.

PD-L1 Expression and Tumor-infiltrating Lymphocytes in Breast Cancer: Clinicopathological Analysis in Women Younger than 40 Years Old

“…Undeniable, the discovery of TILs as well as the PD1/PD-L1 axis has opened new horizons in understanding the response of the host immune system and the way it associates with tumor progression. Thus, established targeted therapy against ER and PR, as well as human epidermal growth factor receptor 2 (HER2), are already getting enriched with the introduction of immunotherapy, showing very promising results (64). Our opinion is that as in other age groups, stromal TILs and PDL1TC and PDL1IC could be used as prognostic factors and immunotherapy will complement the existent targeted therapies.…”

Epitherapy and immune checkpoint blockade: using epigenetic reinvigoration of exhausted and dysfunctional T cells to reimburse immunotherapy response

“…Snyder et al [13] discovered a peptide sequence that, when absent in melanomas, is associated with ipilimumab or tremelimumab resistance. Furthermore, there is a correlation between a high prevalence of somatic mutations (termed 'high mutational burden') and probability of response to checkpoint blockade, especially in melanoma [13], nonsmall cell lung carcinoma (NSCLC) [14], and triplenegative breast cancer (TNBC) [15]. This phenomenon occurs because a high mutational burden tumor expresses more neoantigens; that is, cancer antigens that can be recognized, marked, and attacked by the immune system [16].…”

The changing role of pathologists from morphologists to molecular pathologists in the era of precision medicine

“…Recent interest in the use of contemporary treatment options for triple‐negative breast cancer patients has resulted in new studies focused on systemic immunotherapy and possibly the use of vaccines . Based on the findings of Cancer Genome Atlas , triple‐negative breast cancer has higher PD‐L1 mRNA expression that can be studied by immunohistochemistry.…”