Triple-negative breast cancer is the most aggressive form of breast cancer that lacks expression of estrogen, progesterone, and human epidermal growth factor receptor 2. TNBC is characterized by poor clinic-pathological attributes, prognostic markers, unavailability of efficient therapeutic approaches, and higher chances of disease relapse along with metastasis to distant sites. Dysregulated epigenetic and transcriptional profiling was involved in cancer progression including histone modification, altered miRNA, DNA methylation, and long non-coding RNA signatures. This chapter will provide an insight into the molecular biology of TNBC including gene expression patterns and their subtypes. TNBC molecular spectrum was extensively studied to depict the distant metastasis-free survival and overall survival rate in affected individuals. Prevalence and epidemiology trends of TNBC patients across the globe were also studied to determine the impact of genetic predisposition and socioeconomic factors behind its aggressive behavior. 

Genetic, transcriptional, and clinical heterogeneity of disease has remained to be a prominent obstacle to the development of a targeted therapeutic approach against TNBC. So far, based on tumor size, lymph node status, and histologic features TNBC subtypes were stratified. Insights into inter and intratumoral heterogeneity of TNBC were gained by next-generation sequencing, genomic, transcriptomic, proteomic, and clinicopathological characterization. To depict tumor response to neoadjuvant chemotherapy, radiological characterization may also a play significant role. Biomarkers for subtyping TNBC were highly needed to depict the survival outcome. This chapter discussed the available and possible molecular and pathological diagnostic approaches to TNBC. Furthermore, the integration of morphological and genomic data may emerge as a promising approach for the identification of new therapeutic and prognostic markers to predict the likely outcome of the disease. This chapter aims to highlight the molecular and pathological diagnostic approaches to depict both metastatic and non-metastatic TNBC. 

Triple-negative breast cancer is characterized by distinct molecular profiles, unique metastatic patterns, aggressive behavior, lacks the targeted therapeutic approach, and caused significant mortality worldwide. The molecular complexity of angiogenesis, autophagy, apoptosis, and metastasis process in TNBC has fostered research efforts to unleash the molecular, pathological, and genetic drivers of their lethal cascade. This complex disease entity involves PI3k/Akt/mTOR, NF-kB, ERRs, and miRNA trafficking which has further worsened the clinical outcome. Due to their heterogeneous nature, none of the drugs were able to completely target the TNBC tumor spectrum. This chapter highlights the classification of TNBC on the basis of aberrated copy number, histology, proteomic, and mutational profiles to understand the aetiology of the disease. The identification of therapeutic vulnerabilities was also carried out by gaining insights into the above-mentioned signalling pathways and their role in further complicating the disease. 

Substantial cohort studies, pre-clinical, clinical trials, and in-depth genomic and proteomic analysis underlie that several molecular alterations exist in TNBC that may be favorable or detrimental to cancer progression. Molecular heterogeneity in TNBC has shortened the disease-free survival rate in response to adjuvant and neoadjuvant therapies. To determine possible vulnerabilities in TNBC, several drugs were under investigation. This chapter highlighted the current paradigm of the therapeutic approach including surgery, radiotherapy, and chemotherapy. In this review, we also highlighted the clinical trials involved in the management of TNBC by targeting angiogenesis, apoptosis, androgen receptors, cell cycle, and pro-survival signalling pathways. To overcome the constraints associated with the mono-therapeutic approach, pre-clinical and clinical studies of combinational therapy have also been discussed to improve OS, DFS, and DMFS in TNBC patients. 

The tumor microenvironment of TNBC cells was associated with the induction of angiogenesis, proliferation, apoptosis inhibition, immune suppression, and drug resistance. TME creates a niche for the survival and interaction of cancer cells with surrounding cells. TME promoted epithelial to mesenchymal transition, stemness, and chemoresistance and ensured the escape of TNBC cells from the chemotherapeutic and immunological responses. This chapter highlighted the role of cancer stem cells, hypoxia, lysosomal biomass, tumor-associated macrophages, PTEN, PI3K/Akt/mTOR pathway, and ABC transporters in inducing resistance against standard therapeutic regimens. The possible role of miRNA, transcriptional signatures, and tumorinfiltrating lymphocytes as a predictor of chemoresistance was also depicted. The impact of drug repurposing and combinational therapeutic approach to overcome the obstacle of chemoresistance have been underlined in this chapter for the treatment of TNBC.

In triple-negative breast cancers, there exist tumor-specific vulnerabilities that can be targeted to avoid compensatory adaptation of cancer cells in response to standard pharmaceutical therapies. Natural moieties are well-known to possess a multitude of medicinal properties and deserve attention for TNBC prevention and therapy. To overcome drug resistance and efficacy issues, the exploration of natural moieties as targeting agents may emerge as dynamic, promising, and new therapeutic strategies to benefit TNBC patients. This chapter summarizes the role of polysaccharides, flavonoids, phenols, saponins, and taxanes in targeting TNBC. The potent role of herbal medicine in targeting molecular signalling pathways with special emphasis on their ability to target uncontrolled proliferation, metastasis, angiogenesis, and autophagy has also been discussed. Furthermore, the ability of herbal medicine in inhibiting PI3K/Akt/mTOR, STAT3, and Wnt/β-Catenin has also been explored. Combinational therapy comprising chemotherapeutic drugs and active plant constituents was also explored to overcome the complications of TNBC. 

The development of an effective therapeutic approach against TNBC is a formidable challenge at present. Efficacy and drug resistance issues in response to adjuvant and neoadjuvant chemotherapy have prompted the development of new therapeutic regimens. In this concern, the scientific community has started exploring natural sources including medicinal plants exhibiting anti-cancer activity for their potent inhibitory potential against TNBC. The comprehensive analysis underlying the molecular mechanism of action of these natural bio-compounds provided substantial evidence to subject a few of these for clinical application. This chapter highlighted the momentous phytoconstituents as a genetic or epigenetic modulator by inducing demethylation and histone deacetylation in TNBC. Bioactive phytoconstituents including berberine, luteolin, cantharidin, saikosaponin D, wogonoside, and others targeted cell proliferation, metastasis, angiogenesis, autophagy, and induced apoptosis in TNBC. Furthermore, combinational therapy comprising phytoconstituents and chemotherapeutic drugs was explored to improve the clinical outcome of the disease. Additionally, drug ability parameters including bioavailability and bio-absorption of these phytoconstituents were also discussed. 

95% of anti-cancer agents were associated with the worst pharmaceutical and pharmacokinetic properties including poor targeted cellular uptake, shorter halflife, toxicity, and many more. In this regard, nanotechnology including nanomedicines, nano-carriers, and nanomaterials may emerge as a beneficial tool to facilitate an efficient delivery of therapeutic regimens by adapting active or passive targeting mechanisms. The nanotechnology-based delivery system of phytoconstituents can efficiently battle against recalcitrant TNBC. This chapter highlighted the nanotechnology-based therapeutic approach including smart nanoparticles, cell membrane-coated nanoparticles, and immunological cell-based nano-systems for the treatment of TNBC. Furthermore, the role of nano-soldiers in improving bioavailability and targeted drug delivery was highlighted. Nano conjugates of curcumin, anacardic acid, EGCG, betulinic acid, gambogic acid, and resveratrol were also evaluated to enhance the pharmacokinetic profile, distribution, and the release rate of respective compounds and ultimately their ability to target TNBC.

Apart from the absence of targeted therapies, poor prognosis in TNBC has affected the clinical outcome of the disease and has led to cause high mortality rate amongst diseased individuals. The discovery of potential biomarkers to determine the prognostic and predictive value may play a vital role in the development of an effective therapeutic approach and may improve the OS, DFS, and DMFS. This chapter highlighted the role of histological subtyping, lymph node status, lymphovascular invasion, miRNA, Ki-67, TILs, and BRCAness as prognostic markers of diseases. Nevertheless, patient selection and choice of treatment strategy will greatly impact the clinical efficacy of these prognostic markers but will remain to be a matter of further exploration.

Natural products exhibited a profound effect as a template or direct treatment strategy against TNBC. Implementation of natural products as a chemotherapeutic or chemo-preventive strategy faces diverse problems and challenges. Several constraints including selection, identification, and screening of bioactive components furthermore, preclinical and clinical evaluation, and approval from regulatory bodies are other hurdles to the application of phytochemicals in targeting TNBC. Although the natural metabolites possessed the substantial potential to target the disease along with reinvigorating the health of affected individuals. This chapter has highlighted the perspectives and controversies associated with herbal medicines such as consumer preferences, bio-pharmaceutics consideration, HM-HM & HM-CM interactions, and drug regulations, and discussed the need to introduce natural moieties as an alternative therapeutic approach against TNBC.