Precision Breast Cancer Medicine: Early Stage Triple Negative Breast Cancer—A Review of Molecular Characterisation, Therapeutic Targets and Future Trends

Abstract

Personalised approaches to the management of all solid tumours are increasing rapidly, along with wider accessibility for clinicians. Advances in tumour characterisation and targeted therapies have placed triple-negative breast cancers (TNBC) at the forefront of this approach. TNBC is a highly heterogeneous disease with various histopathological features and is driven by distinct molecular alterations. The ability to tailor individualised and effective treatments for each patient is of particular importance in this group due to the high risk of distant recurrence and death. The mainstay of treatment across all subtypes of TNBC has historically been cytotoxic chemotherapy, which is often associated with off-target tissue toxicity and drug resistance. Neoadjuvant chemotherapy is commonly used as it allows close monitoring of early treatment response and provides valuable prognostic information. Patients who achieve a complete pathological response after neoadjuvant chemotherapy are known to have significantly improved long-term outcomes. Conversely, poor responders face a higher risk of relapse and death. The identification of those subgroups that are more likely to benefit from breakthroughs in the personalised approach is a challenge of the current era where several targeted therapies are available. This review presents an overview of contemporary practice, and promising future trends in the management of early TNBC. Platinum chemotherapy, DNA damage response (DDR) inhibitors, immune checkpoint inhibitors, inhibitors of the PI3K-AKT-mTOR, and androgen receptor (AR) pathways are some of the increasingly studied therapies which will be reviewed. We will also discuss the growing evidence for less-developed agents and predictive biomarkers that are likely to contribute to the forthcoming advances in this field. Finally, we will propose a framework for the personalised management of TNBC based upon the integration of clinico-pathological and molecular features to ensure that long-term outcomes are optimised.

RUNX1 is regulated by androgen receptor to promote cancer stem markers and chemotherapy resistance in triple negative breast cancer

“…One of the current principal clinical challenges in TNBC is the presence of inter- and intratumoral heterogeneity that hinders decision making and drives the lack of therapeutic efficacy [44,45]. Therefore, identification of better markers could reveal more accurate therapeutic strategies.…”

Recent advances in targeted strategies for triple-negative breast cancer

“…TGF-β inhibited the initiation and proliferation of chemotherapy-resistant tumor-initiating cells. This lays the groundwork for the adoption of combination chemotherapy in TNBC patients [ 151 ]. TGF-β overexpressed in TNBC cells, which leads to tumor metastasis.…”

Targeting Breast Cancer: The Familiar, the Emerging, and the Uncharted Territories

“…It has also been shown that everolimus is equally active in PIK3CA wild-type and mutant types of breast cancer, which suggests that other pathways (e.g., MAPK signaling) could activate mTOR complexes even in the absence of PI3K overactivation [ 114 ]. Many recent reviews have been published about the development of new pan-PI3K inhibitors, PI3K isoform-specific inhibitors, AKT inhibitors, mTOR inhibitors, and dual inhibitors (e.g., mTORC1/C2 inhibitors or PI3K/mTOR inhibitors) for treatment of TNBC [ 98 , 112 , 114 , 115 , 116 , 117 ]. Table 3 summarizes some of the most recent clinical trials for drugs targeting this pathway (specifically in HER2-positive breast cancer, or TNBC).…”