Triple negative breast cancer: approved treatment options and their mechanisms of action

Abstract

Purpose: Breast cancer, the most prevalent cancer worldwide, consists of 4 main subtypes, namely, Luminal A, Luminal B, HER2-positive, and Triple-negative breast cancer (TNBC). Triple-negative breast tumors, which do not express estrogen, progesterone, and HER2 receptors, account for approximately 15-20% of breast cancer cases. The lack of traditional receptor targets contributes to the heterogenous, aggressive, and refractory nature of these tumors, resulting in limited therapeutic strategies.

Methods: Chemotherapeutics such as taxanes and anthracyclines have been the traditional go to treatment regimens for TNBC patients. Paclitaxel, docetaxel, doxorubicin, and epirubicin have been longstanding, Food and Drug Administration (FDA)-approved therapies against TNBC. Additionally, the FDA approved PARP inhibitors such as olaparib and atezolizumab to be used in combination with chemotherapies, primarily to improve their efficiency and reduce adverse patient outcomes. The immunotherapeutic Keytruda was the latest addition to the FDA-approved list of drugs used to treat TNBC.

Results: The following review aims to elucidate current FDA-approved therapeutics and their mechanisms of action, shedding a light on the various strategies currently used to circumvent the treatment-resistant nature of TNBC cases.

Conclusion: The recent approval and use of therapies such as Trodelvy, olaparib and Keytruda has its roots in the development of an understanding of signaling pathways that drive tumour growth. In the future, the emergence of novel drug delivery methods may help increase the efficiency of these therapies whiel also reducing adverse side effects.

Keywords: Atezolizumab; BRCA1 and BRCA2; Breast cancer; Doxorubicin; ER; Epirubicin chemotherapy; HER2; Immunotherapy; Keytruda; Olabarib; PARP inhibitors; TNBC; Taxol.

Fig. 1

Mechanism of action of PARP inhibitors. PARP recognizes and binds to single-stranded breaks in DNA and initiates the recruitment of base excision repair (BER) machinery to repair the break. When inhibited, PARP becomes trapped at the site of the SSB, causing a double stranded break. In the absence of BRCA1/2 and homologous repair mechanisms, this break remains resulting in apoptosis downstream

Fig. 2

The mechanism of action of anthracyclines. Transcription and replication, the vital relieving of stress due to DNA super coiling, is conducted through the introduction of double stranded breaks by topoisomerase 1/2. These breaks are then sealed by DNA repair machinery. Doxorubicin inserts itself between DNA base pairs, thereby trapping topoisomerase 1/2 in place after it has catalyzed the double stranded break. This halts replication, leading to cell death

Fig. 3

Mechanism of action of the anti-cancer activity of immunotherapeutics. The interaction of the receptor PD-1 with its ligand PD-L1 normally reduces inflammatory response. Tumour cells use this interaction to suppress anti-cancer T-cell response. Inhibition of either the receptor PD-1 (using pembrolizumab) or the ligand PD-L1 (using atezolizumab) results in the activation of the immune response against the tumour cells

Fig. 4

Schematic of the mechanism of action of Taxanes. By binding to microtubules, taxanes prevent their disassembly, thereby disrupting the dynamic instability of microtubules, leading to centrosomal impairment and suppression of spindle dynamics during mitosis

Fig. 5

Schematic of sacituzumab govitecan and its mechanism of action. a Representation of the 3 main components of sacituzumab govitecan, the antibody, the cytotoxic payload and the linker between them. b The mechanism of action of Trodelvy in a triple negative breast cancer cell. The antibody recognizes and binds to Trop2, is then internalized into the cell. This process induces the cleavage of the linker, releasing SN-38 into the cytoplasm after which it binds to and inhibits TOP1B, causing double stranded DNA breaks and cell death thereafter. Created with Biorender.com