Moving Towards Targeted Therapies for Triple-Negative Breast Cancer

Abstract

Purpose of review: In this review, we discuss targets of interest in Triple-negative breast cancer (TNBC), approved targeted agents and the results of the clinical trials that led to their approval. Additionally, we review ongoing clinical trials evaluating the use of novel targeted agents in the treatment of TNBC.

Recent findings: TNBC accounts for 15-20% of all breast cancer cases and is associated with worse clinical outcomes. Patients have a higher risk of metastatic recurrence and inferior overall survival compared to other breast cancer subtypes. Cytotoxic chemotherapy has historically been the mainstay of treatment for TNBC. In recent years, we have seen a surge in clinical trials investigating the use of targeted agents in TNBC and now have approval for targeted therapies in select patients. Inhibitors of PARP (olaparib and talazoparib), PD-L1 (atezolizumab) and an antibody drug conjugate targeting Trop-2 (sacituzumab govitecan-hziy) are now approved for the use in select groups of patients with TNBC.

Summary: Various novel targeted agents as monotherapy, dual targeted combinations, and chemotherapy combinations are currently under investigation. The results are promising and may significantly improve patient outcomes in TNBC.

Keywords: immunotherapy; novel agents; targeted therapies; triple-negative breast cancer.

Figure 1.

Mechanism of action of PARP inhibitors and immune checkpoint inhibitors. (A) The PARP enzymes repair single-stranded DNA breaks which allow for cell survival. PARP inhibitors prevent PARP from repairing single-stranded DNA breaks which result in double-stranded DNA breaks. BRCA proteins repair double-stranded DNA breaks via homologous recombination and allow for cell survival however mutated BRCA proteins lose the ability repair double-stranded DNA breaks resulting in cell death. (B) Interaction between PD-L1 on tumor cells and PD-1 on T cells results in immune system inactivation and tumor cell survival. CTLA-4 on T cells competes with CD28 for B7 ligands on antigen presenting cells and when bound to B7 results in immune system inactivation. PD-L1, PD-1 and CTLA-4 blockade results in immune system activation and anti-tumor response. PARP: Poly ADP-ribose polymerase, BRCA: breast cancer gene, mBRCA: mutated BRCA gene, PD-L1: programmed-death ligand 1, PD-1: programmed cell death protein 1, CTLA-4: cytotoxic T-lymphocyte-associated antigen 4; MHC: major histocompatibility complex, TCR: T cell receptor.

Figure 2.

Mechanism of action of PI3K/AKT/mTOR (PAM) pathway inhibitors and androgen receptor blockers. (A) Growth factor binds to growth factor receptor in the tumor cell membrane resulting in activation of the PI3K, AKT, and mTOR. Activation of mTOR results in protein synthesis and cell growth. PTEN downregulates PI3K and results in decreased activation of the PAM pathway. PI3K, AKT, and mTOR inhibitors block the activation of this pathway and results in cell death. (B) Androgens bind to cytoplasmic androgen receptors resulting in activation. Heat shock proteins bound to the androgen receptor dissociate and the androgen receptor dimerizes. The dimer is translocated to the nucleus where it binds to the promoter region and results in gene transcription. Androgen receptor blockers block androgen binding to androgen receptor. PI3K: phosphoinositide 3-kinse, AKT: protein kinase B, mTOR: mechanistic target of rapamycin, PTEN: phosphatase and tensin homolog. AR: Androgen receptor, HSP: heat shock protein

Figure 3.

Mechanism of action of antibody-drug conjugates and HDAC inhibitors. (A) Antibody drug conjugates are humanized monoclonal antibodies bound to a cytotoxic drug by a linker. It binds to a tumor cell specific marker and is engulfed via endocytosis. The linker is degraded and the cytotoxic agent is cleaved from the antibody delivering the cytotoxic agent into the tumor cell which results in cell death. (B) Histone acetylation by HATs relaxes chromatin allowing for gene transcription. HDACs remove acetyl groups which results in condensed chromatin and suppression of gene transcription. In tumor cells, suppression of gene transcription of tumor suppressor and DNA repair genes can allow for tumor growth. HDAC inhibitors prevent removal of acetyl groups by HDACs leaving chromatin in its relaxed state allowing for gene transcription. A: acetyl group, HAT: Histone acetyltransferase, HDAC: histone deacetylase.