Recent Advances in the Treatment of Breast Cancer

Abstract

Breast cancer (BC) is the most common malignancy in women. It is classified into a few major molecular subtypes according to hormone and growth factor receptor expression. Over the past few years, substantial advances have been made in the discovery of new drugs for treating BC. Improved understanding of the biologic heterogeneity of BC has allowed the development of more effective and individualized approach to treatment. In this review, we provide an update about the current treatment strategy and discuss the various emerging novel therapies for the major molecular subtypes of BC. A brief account of the clinical development of inhibitors of poly(ADP-ribose) polymerase, cyclin-dependent kinases 4 and 6, phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, histone deacetylation, multi-targeting tyrosine kinases, and immune checkpoints for personalized treatment of BC is included. However, no targeted drug has been approved for the most aggressive subtype-triple negative breast cancer (TNBC). Thus, we discuss the heterogeneity of TNBC and how molecular subtyping of TNBC may help drug discovery for this deadly disease. The emergence of drug resistance also poses threat to the successful development of targeted therapy in various molecular subtypes of BC. New clinical trials should incorporate advanced methods to identify changes induced by drug treatment, which may be associated with the upregulation of compensatory signaling pathways in drug resistant cancer cells.

Keywords: breast cancer; cyclin-dependent kinases 4 and 6 inhibitors; hormone receptor; human epidermal growth factor receptor 2; poly(ADP-ribose) polymerase inhibitor; programmed cell death protein 1; trastuzumab; triple negative breast cancer.

Figure 1

Novel drugs under investigation for triple negative breast cancer (TNBC). PARP inhibitors are effective in BRCA-mutated breast cancer (BC). When BRCA function is absent and PARP is inhibited, cancer cells are unable to repair DNA damage by homologous recombination or base-excision repair and cell death results. The antibody-drug conjugate, glembatumumab vedotin, may be effective in gpNMB-overexpressing BC by releasing the cytotoxic drug into gpNMB-expressing tumor cells, resulting in a targeted-cell killing effect. Tyrosine kinase inhibitors against EGFR, VEGFR, and SRC have been investigated for the treatment of TNBC because these signaling receptors mediating cancer cell growth are overexpressed or dysregulated in TNBC. The monoclonal antibody, pembrolizumab, may be effective regardless of PD-L1 expression by inducing an immune response to kill cancer cells. Abbreviations: PARP, poly(ADP-ribose) polymerase; gpNMB, glycoprotein NMB; AR, androgen receptor; DHT, dihydrotestosterone; PD-1, programmed cell death 1 receptor; PD-L1, ligand of programmed cell death 1 receptor; EGFR, epidermal growth factor receptor.