Triple-negative breast cancer: A run-through of features, classification and current therapies

Abstract

Breast cancer is the most prevalent cancer in women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It is the most aggressive subtype of breast cancer and accounts for 12-20% of all breast cancer cases. TNBC is associated with younger age of onset, greater metastatic potential, higher incidence of relapse, and lower overall survival rates. Based on molecular phenotype, TNBC has been classified into six subtypes (BL1, BL2, M, MES, LAR, and IM). TNBC treatment is challenging due to its heterogeneity, highly invasive nature, and relatively poor therapeutics response. Chemotherapy and radiotherapy are conventional strategies for the treatment of TNBC. Recent research in TNBC and mechanistic understanding of disease pathogenesis using cutting-edge technologies has led to the unfolding of new lines of therapies that have been incorporated into clinical practice. Poly (ADP-ribose) polymerase and immune checkpoint inhibitors have made their way to the current TNBC treatment paradigm. This review focuses on the classification, features, and treatment progress in TNBC. Histological subtypes connected to recurrence, molecular classification of TNBC, targeted therapy for early and advanced TNBC, and advances in non-coding RNA in therapy are the key highlights in this review.

Keywords: clinical trials; metastatic; overall response rate; targeted therapy; triple-negative breast cancer.

Figure 1.

Histological classification of TNBC. Among the histological subtypes, invasive ductal carcinoma is the most common. Metaplastic, adenoid cystic, invasive lobular, mucinous and glycogen-rich clear cell carcinoma are rare subtypes of carcinoma. Metaplastic carcinoma can be further divided into matrix-producing, squamous, mixed and spindle-cell type, depending on the cell type (15). The permission to use this figure is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License with Elsevier. TNBC, triple-negative breast cancer.

Figure 2.

Mutation status of the top 20 genes in triple-negative breast cancer identified in the Catalogue Of Somatic Mutations In Cancer. (A) Bar graph showing the number of samples harbouring mutations in the top 20 genes with most mutations. The blue bar indicates samples with mutations, whereas the red bar indicates the total number of samples. The percentage of occurrence of mutation is also shown. TP53, PI3K, BRCA1 are among the top genes in the panel with a high number of mutations. (B) Pie chart classifying the type of mutations observed in all genes. Most of the mutations fall under nonsense and synonymous type. Other mutation types, such as frameshift and in-frame mutations, were also observed.

Figure 3.

Different modes of treatment employed in TNBC therapy. The traditional method of treating cancer (surgery and radiotherapy) is still the primary mode of initial treatment followed by chemotherapy. Taxanes and anthracyclines are common chemotherapeutic agents used for the treatment of TNBC along with platinum salts. Recently, due to the development of omics technology, targeted therapy has become a novel way of treating cancer. AR, androgen receptor; PARP, poly (ADP-ribose) polymerase; PD-L1, programmed death ligand 1; TNBC, triple-negative breast cancer.

Figure 4.

Targeted therapies currently explored for TNBC. (A) PARP inhibitors, such as olaparib and veliparib are currently under clinical trials to bring about synthetic lethality in homologous recombination-deficient TNBC harbouring BRCA1 mutations. (B) PI3K-activated TNBC with loss of PTEN can be treated with buparlisib or ipatasertib, which inhibit the PI3K enzyme. (C) In the LAR subtype of cancers, where the expression of AR is very high, AR blockers like bicalutamide and enzalutamide have made their way. (D) Antibody-drug conjugates are specific to cell-surface molecules and linked to a potent cytotoxic agent that kills the cancer cell. (E) PD-L1 blockade using atezolizumab has shown positive results in a clinical trial on patients with TNBC. AR, androgen receptor; DSBR, double-strand break; MHC, major histocompatibility complex; PARP, poly (ADP-ribose) polymerase; PD-1, programmed death-1; PD-L1, PD ligand 1; SSBR, single-strand break; TCR, T cell receptor; TNBC, triple-negative breast cancer; LAR, luminal androgen receptor; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and rad3-related protein; HR, homologous recombination; ADC, antibody-drug conjugates; TROP-2, tumour associated calcium signal transducer 2.