Untangling Triple-Negative Breast Cancer Molecular Peculiarity and Chemo-Resistance: Trailing Towards Marker-Based Targeted Therapies.

Bushra Kanwal

doi:10.7759/cureus.16636

Abstract

Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor-2, affects nearly 15% of women with breast cancer. To date, the mainstay of treatment remains chemotherapy, with all the associated consequences, such as the significant toxicity and the suboptimal effect on the five-year survival rates. RNA-expression profiling showed that TNBC is biologically a heterogeneous malignancy. Therefore, predictive biomarkers matched with the diverse subtypes of TNBC could classify patients that would most benefit from a certain targeted treatment. Three biomarker-driven therapies are currently available: poly-adenosine diphosphate (ADP) ribose polymerase inhibitors for patients with germline BReast CAncer gene (BRCA) mutations, atezolizumab combined with nab-paclitaxel for patients expressing programmed death-ligand 1 (PD-L1) on tumor-infiltrating immune cells, and sacituzumab govitecan, an antibody-drug conjugate targeting human trophoblast cell-surface antigen 2 (TROP-2). Identifying predictive biomarkers is crucial for the optimum generation and implementation of targeted agents for TNBC, while further relevant treatments are in the pipeline given the promising results in clinical trials. Finally, newly developed immunotherapies and other targeted agents should also be investigated in earlier stages of the disease, especially in the neoadjuvant setting, broadening the therapeutic application of such regimens.

Highlights

BackgroundBreast cancer is the most prevalent malignancy in females worldwide, while metastatic breast cancers are the second leading cause of tumor-related deaths in American women
This type is characterized by the absence of estrogen and progesterone receptors and the lack of human epidermal growth factor receptor-2 amplification
Compared to other subtypes of breast cancer, patients with triple-negative breast cancer (TNBC) show a significant prevalence of germline BReast CAncer gene (BRCA) mutations, reaching up to 31% [24]

Summary

Introduction

Breast cancer is the most prevalent malignancy in females worldwide, while metastatic breast cancers are the second leading cause of tumor-related deaths in American women. The absence of those receptors, medications like tamoxifen (targeting ER) and trastuzumab (targeting HER-2) do not affect patients with this type of breast cancer Their variable response to chemotherapy and the high incidence of recurrences justifies the fact that TNBCs demonstrate poor clinical outcomes, overall poor prognosis, and shorter long-term survival. Several FDA-approved regimens targeting programmed cell death protein-1 (pembrolizumab) and programmed death ligand-1 (atezolizumab), poly adenosine diphosphate (ADP)-ribose polymerase (olaparib and talazoparib), and/or antibody-drug conjugates (sacituzumab govitecan) have provided promising clinical results for specific patients with TNBC These inhibitors targeting key genetic mutations and certain molecular signaling pathways that control carcinoma growth have been employed as single agents and/or in conjunction with typical chemotherapy drugs [23]. Sacituzumab govitecan demonstrated a less satisfactory safety profile regarding treatment-related adverse events of grade 3 or higher than chemotherapy, with neutropenia, leukopenia, diarrhea, anemia, and febrile neutropenia being the most common [37]

Conclusions

Findings

Disclosures