Triple‑negative breast cancer therapy: Current and future perspectives (Review)

Abstract

Triple‑negative breast cancer (TNBC) accounts for 10‑15% of all breast cancer cases. TNBCs lack estrogen and progesterone receptors and express low levels of HER2, and therefore do not respond to hormonal or anti‑HER2 therapies. TNBC is a particularly aggressive form of breast cancer that generally displays poorer prognosis compared to other breast cancer subtypes. TNBC is chemotherapy sensitive, and this treatment remains the standard of care despite its limited benefit. Recent advances with novel agents have been made for specific subgroups with PD‑L1+ tumors or germline Brca‑mutated tumors. However, only a fraction of these patients responds to immune checkpoint or PARP inhibitors and even those who do respond often develop resistance and relapse. Various new agents and combination strategies have been explored to further understand molecular and immunological aspects of TNBC. In this review, we discuss clinical trials in the management of TNBC as well as perspectives for potential future treatments.

Keywords: triple-negative breast cancer; clinical studies; immunotherapy; DNA-damage response; targeted therapy; therapeutic strategy.

Figure 1

Immuno- and targeted-therapies in key TNBC clinical studies. Various agents in the networks of TNBCs and immune cells have been explored, as well as tumor-stroma interactions in the tumor microenvironment (TME). Targets and agents relevant to immune checkpoint, cell surface or intracel-lular receptors, signaling pathways, DNA damage response, and cell cycle checkpoint are shown. Various chemotherapy agents are listed in the box. AS, Adagloxad simolenin); LV, Ladiratuzumab vedotin; SG, Sacituzumab govitecan-hziy; T-DXd, tastuzumab deruxtecan; TNBC, triple-negative breast cancer; A_2aR, adenosine 2A receptor; A_2bR, 2B receptor; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; VEGF-A, vascular endothelial growth factor A; RTKs, receptor tyrosine kinases; PARP, poly(ADP-ribose) polymerase; CDK, cyclin-dependent kinase; CD, cluster of differentiation; ATR, ataxia telangiectasia and Rad3-related kinase; CHK1, checkpoint kinase 1; DNA-PK, DNA-dependent protein kinase; AR, androgen receptor; PI3K, phosphatidylinositol 3-kinase.

Figure 2

ATP-adenosine pathway. Adenosine is generated from ATP by CD39 and CD73. It binds to A2 receptors on immune cells and blocks T cell priming, expansion, and activation, natural killer (NK) cell degranulation, dendritic cell (DC) maturation and activation, and tumor-associated macro-phage (TAM) M1 polarization, thus leading to immunosuppression. ATP, adenosine triphosphate; AMP, adenosine monophosphate; CD, cluster of differentiation.

Figure 3

DNA damage response pathways. Double-strand breaks (DSB) or single-strand breaks (SSB) activate DNA damage response (DDR) pathways, leading to cell cycle arrest and DNA repair or cell death depending on cell context. PARP1 senses DNA breaks and is involved in SSB repair. Oncogenic pathways including RAS, PI3K, AR, and MYC signaling can affect HR repair activity and contribute to resistance to PARP inhibitor treatment. MRN, MRE11-RAD50-NBS1 complex; ATRIP, ATP interacting protein; HR, homologous recombination; NHEJ, non homologous end joining; H2AX, histone H2AX; XRCC4, X-ray repair cross-complementing protein 4; ATR, ataxia telangiectasia and Rad3-related protein; CHK1/2, checkpoint kinase 1/2; CDK1/2, cyclin-dependent kinase 1/2; DNA-PK, DNA-dependent protein kinase; AR, androgen receptor; PI3K, phosphatidylinositol 3-kinase.