How shall we treat early triple-negative breast cancer (TNBC): from the current standard to upcoming immuno-molecular strategies

Abstract

Triple-negative breast cancer (TNBC) is a long-lasting orphan disease in terms of little therapeutic progress during the past several decades and still the standard of care remains chemotherapy. Experimental discovery of molecular signatures including the 'BRCAness' highlighted the innate heterogeneity of TNBC, generating the diversity of TNBC phenotypes. As it contributes to enhancing genomic instability, it has widened the therapeutic spectrum of TNBC. In particular, unusual sensitivity to DNA damaging agents was denoted in patients with BRCA deficiency, suggesting therapeutic benefit from platinum and poly(ADP-ribose) polymerase inhibitors. However, regardless of enriched chemosensitivity and immunogenicity, majority of patients with TNBC still suffer from dismal clinical outcomes including early relapse and metastatic spread. Therefore, efforts into more precise and personalised treatment are critical at this point. Accordingly, the advance of multiomics has revealed novel actionable targets including PI3K-Akt-mTOR and epidermal growth factor receptor signalling pathways, which might actively participate in modulating the chemosensitivity and immune system. Also, TNBC has long been considered a potential protagonist of immunotherapy in breast cancer, supported by abundant tumour-infiltrating lymphocytes and heterogeneous tumour microenvironment. Despite that, earlier studies showed somewhat unsatisfactory results of monotherapy with immune-checkpoint inhibitors, consistently durable responses in responders were noteworthy. Based on these results, further combinatorial trials either with other chemotherapy or targeted agents are underway. Incorporating immune-molecular targets into combination as well as refining the standard chemotherapy might be the key to unlock the future of TNBC. In this review, we share the current and upcoming treatment options of TNBC in the framework of scientific and clinical data, especially focusing on early stage of TNBC.

Keywords: triple-negative breast cancer.

Figure 1

Signalling pathways and involved entities that are unravelling experimental therapeutic targets for TNBC. Depicted molecular landscape of TNBC confers an insight of novel and investigational targeted therapeutic strategy which are directly unlocking its heterogeneous biology. In the context of its intrinsic genetic instability which derives an immunogenic microenvironment, blockade of the immune-checkpoint targeting PD-1 and PD-L1 as well as CTLA-4 can boost the adaptive immune reaction. PAM signalling pathways are actively participating in cell cycle regulation, which are in the tight network with various growth factors including EGF and MAPK signalling. Platinum-based agents and PARPi is a master regulator of DNA damage repair and can induce synergistic inhibitory effect in TNBC harbouring BRCAness. Other multikinase inhibitors involving angiogenesis or developmental process are also a potential therapeutic entity of current interest. All these investigational but key targets are consistently interacting with cytotoxic effect of conventional chemotherapy. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular signal-related kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; PAM, PI3K-Akt-mTOR; PARP, poly(ADP-ribose) polymerase; PARPi, PARP inhibitors; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; TNBC, triple-negative breast cancer.

Figure 2

Future aspects of therapeutic strategies in patients with TNBC based on its chemosensitivity and immune-molecular heterogeneity. Future challenge in TNBC is fundamentally to enrich the therapeutic efficacy to the optimal level both for chemosensitive and chemoresistant population. In this context, conventional chemotherapy and these four key entities constitute the main domain of upcoming treatment strategies. Targeting the BRCAness, revisiting our old but competent targets including PAM pathway and emerging immunotherapy can be the master molecular regulators of TNBC tumour microenvironment. Smart refining of conventional chemotherapy should be accompanied with these molecular targeting. Finally, combinatorial chains between these four independent domains would be the key of future therapeutics for TNBC. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; MAPK, mitogen-activated protein kinase; PAM, PI3K-Akt-mTOR; PARPi, poly(ADP-ribose) polymerase inhibitors; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; TNBC, triple-negative breast cancer.