New and Emerging Targeted Therapies for Advanced Breast Cancer

Abstract

In the United States, breast cancer is among the most frequently diagnosed cancers in women. Breast cancer is classified into four major subtypes: human epidermal growth factor receptor 2 (HER2), Luminal-A, Luminal-B, and Basal-like or triple-negative, based on histopathological criteria including the expression of hormone receptors (estrogen receptor and/or progesterone receptor) and/or HER2. Primary breast cancer treatments can include surgery, radiation therapy, systemic chemotherapy, endocrine therapy, and/or targeted therapy. Endocrine therapy has been shown to be effective in hormone receptor-positive breast cancers and is a common choice for adjuvant therapy. However, due to the aggressive nature of triple-negative breast cancer, targeted therapy is becoming a noteworthy area of research in the search for non-endocrine-targets in breast cancer. In addition to HER2-targeted therapy, other emerging therapies include immunotherapy and targeted therapy against critical checkpoints and/or pathways in cell growth. This review summarizes novel targeted breast cancer treatments and explores the possible implications of combination therapy.

Keywords: HER2; breast cancer; breast cancer treatment; emerging therapies; targeted therapy.

Figure 1

The PI3K/Akt/mTOR pathway and mechanisms of inhibition. RTK: receptor tyrosine kinase; PI3K: phosphoinositide 3-kinase; PI3Ki: PI3K inhibitor; PIP₂: phosphatidylinositol-4,5-biphosphate; PIP₃: phosphatidylinositol-3,4,5-triphosphate; PTEN: phosphatase and tensin homolog; Akt: protein kinase B; LKB1: liver kinase B1; AMPK: adenosine monophosphate-activated protein kinase; mTOR: mammalian target of rapamycin; mTORi: mTOR inhibitor.

Figure 2

The HER2 signaling pathway and mechanisms of HER2 signaling inhibition. The left-most receptor signaling pathway depicts the mechanism and binding of trastuzumab monoclonal antibody. The receptor pathway second to the left depicts the mechanism and binding of the pertuzumab monoclonal antibody. The receptor pathway second to the right depicts the mechanism of TKIs. Finally, the right-most receptor pathway depicts a normal uninhibited HER2 signaling pathway upon ligand binding. HER2: human epidermal growth factor receptor 2; HER3: human epidermal growth factor receptor 3; TKIs: tyrosine kinase inhibitors; PI3K: Phosphoinositide 3-kinase; Akt: protein kinase B.

Figure 3

PARP proteins in DNA repair and PARP inhibitor mechanism of action. The top of the figure describes the normal DNA repair mechanism of a single-stranded break. The lower portion of the figure describes how PARP inhibitors alter normal DNA repair. ssDNA: single-stranded DNA; PARP1: poly-ADP-ribose polymerase 1; PARPi: PARP inhibitor; NAD+: nicotinamide adenine dinucleotide; PARylation: poly-ADP-ribosylation; dsDNA: double-stranded DNA; HRR: homologous recombination repair; NHEJ: non-homologous end joining; BRCA: breast cancer-associated protein.

Figure 4

Role of CDK4 and CDK6 in cell growth progression and CDK4/6 inhibitor mechanism of action. CDK: cyclin-dependent kinase; Rb: retinoblastoma protein.

Figure 5

Mechanism of immune checkpoint inhibitors pembrolizumab and atezolizumab on the PD-1/PD-L1 axis. PD-1: programmed cell death protein 1; PD-L1: programmed cell death ligand 1.