Immune-Based Therapy in Triple-Negative Breast Cancer: From Molecular Biology to Clinical Practice

Abstract

Triple-negative breast cancer (TNBC) has been considered for many years an orphan disease in terms of therapeutic options, with conventional chemotherapy (CT) still representing the mainstay of treatment in the majority of patients. Although breast cancer (BC) has been historically considered a “cold tumor”, exciting progress in the genomic field leading to the characterization of the molecular portrait and the immune profile of TNBC has opened the door to novel therapeutic strategies, including Immune Checkpoint Inhibitors (ICIs), Poly ADP-Ribose Polymerase (PARP) inhibitors and Antibody Drug Conjugates (ADCs). In particular, compared to standard CT, the immune-based approach has been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in metastatic PD-L1-positive TNBC and the pathological complete response rate in the early setting, regardless of PD-L1 expression. To date, PD-L1 has been widely used as a predictor of the response to ICIs; however, many patients do not benefit from the addition of immunotherapy. Therefore, PD-L1 is not a reliable predictive biomarker of the response, and its accuracy remains controversial due to the lack of a consensus about the assay, the antibody, and the scoring system to adopt, as well as the spatial and temporal heterogeneity of the PD-L1 status. In the precision medicine era, there is an urgent need to identify more sensitive biomarkers in the BC immune oncology field other than just PD-L1 expression. Through the characterization of the tumor microenvironment (TME), the analysis of peripheral blood and the evaluation of immune gene signatures, novel potential biomarkers have been explored, such as the Tumor Mutational Burden (TMB), Microsatellite Instability/Mismatch Repair Deficiency (MSI/dMMR) status, genomic and epigenomic alterations and tumor-infiltrating lymphocytes (TILs). This review aims to summarize the recent knowledge on BC immunograms and on the biomarkers proposed to support ICI-based therapy in TNBC, as well as to provide an overview of the potential strategies to enhance the immune response in order to overcome the mechanisms of resistance.

Mismatch repair protein deficiency in triple-negative breast carcinomas

“…Immunohistochemical analysis of MMRPs can help identify patients who are likely to respond to immunotherapy. 7 , 19 , 20 …”

“…Immune-based treatment has increased the pathological complete response rate in the early setting and progression-free survival and overall survival (OS) in metastatic programmed cell death ligand 1 (PD-L1)-positive TNBC. 7 , 8 Currently, one of the most promising immune checkpoint inhibitor targets involves blocking the actions of programmed cell death receptor 1 (PD-1) and PD-L1, which leads to an enhanced attack on tumor cells through an immune-mediated mechanism. 9 PD-L1 is frequently used to predict immune checkpoint inhibitor responses; nonetheless, many patients do not respond to immunotherapy.…”

Advances in Tumour-Infiltrating Lymphocytes for Triple-Negative Breast Cancer Management

“…23 When pembrolizumab was used as a monotherapy in second- or third-line treatment, however, it did not demonstrate superior OS compared to chemotherapy. 24 Lastly, olaparib and talazoparib were approved by the FDA in 2018 to treat patients with advanced stage HER2-negative breast cancer and a positive BRCA1 or BRCA2 mutation. Along with olaparib and talazoparib, the diagnostic test to identify germline BRCA-mutated (gBRCAm) breast cancers was also approved.…”

SBFI-26 enhances apoptosis in docetaxel-treated triple-negative breast cancer cells by increasing ROS levels

“…8 However, drug resistance, poor efficacy, and a lack of clear therapeutic targets remain significant challenges in TNBC clinical treatment. 9,10 Combining drugs can often achieve therapeutic effects that a single treatment cannot achieve. [11][12][13] Due to its therapeutic index, docetaxel, a microtubuletargeting agent, has garnered significant attention in cancer chemotherapy.…”

“…Numerous research reports have demonstrated that combination therapy effectively addresses this issue. [1][2][3][4]10,16,17 Fatty acid binding protein 5 (FABP5), a non-enzymatic protein, has been identified as an indispensable molecule in regulating cellular fatty acid transport, skin hemostasis, and metabolism. [18][19][20] Overexpression of FABP5 has been observed in various human cancers, including breast, skin, bladder, pancreatic, prostate, gastric, hepatocellular carcinoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), melanoma, and endometrial cancer.…”