Abstract: The incidence and mortality of breast cancer (BC) have increased in recent years, and BC is the main cause of cancer-related death in women worldwide. One of the most significant clinical problems in the treatment of patients with BC is the development of therapeutic resistance. Therefore, elucidating the molecular mechanisms involved in drug resistance is critical. The therapeutic decision for the management of patients with BC is based not only on the assessment of prognostic factors but also on the evaluation of clinical and pathological parameters. Although this has been a successful approach, some patients relapse and/or eventually develop resistance to treatment. This review is focused on recent studies on the possible biological and molecular mechanisms involved in both response and resistance to treatment in BC. Additionally, emerging treatments that seek to overcome resistance and reduce side effects are also described. A greater understanding of the mechanisms of action of treatments used in BC might contribute not only to the enhancement of our understanding of the mechanisms involved in the development of resistance but also to the optimization of the existing treatment regimens.


Keywords: breast cancer, endocrine therapy, chemotherapy, resistance, emerging treatments


INTRODUCTION

Cancer is a common disease and represents one of the biggest health problems in the world and a significant global concern. The incidence and mortality rates of breast cancer (BC) have increased in recent years, and BC is currently the leading cause of cancer death in women worldwide.1 Decision making for the treatment of patients with BC is primarily based on the assessment of clinical and pathological parameters. In particular, the immunohistochemical evaluation of prognostic factors, such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) are critical for tumor subtype classification and histological grade, which play an important role in determining therapeutic strategies. For example, patients with ER-positive (ER+) tumors receive endocrine therapy, and a small fraction of these patients also receive chemotherapy. Patients with HER2-positive tumors (HER2 enriched or HER2+) are treated with antibodies directed against HER2 or small-molecule inhibitors in combination with chemotherapy. Patients with triple-negative tumors receive mainly chemotherapy.2–4


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BC is a heterogeneous and complex disease in which each patient has unique morphological and molecular features, rather than a disease in which only a few genes, proteins, and/or signaling pathways contribute to disease progression in a simple, independent, and autonomous manner. Studies have shown that patients with the same type of BC can show differential responses to treatment, which further indicates the high heterogeneity in this disease. Despite the great technological advances that have enhanced our understanding of human cancers as heterogeneous diseases, current clinicopathological and molecular parameters leave a significant number of patients at risk of over-treatment and side effects.

Currently, drug-resistant BC is treated by selecting other drugs, without understanding the molecular mechanisms involved in the resistance of a given case. Better understanding of the mechanisms involved in the development of resistance might not only reduce the adverse effects of treatment but also lead to the development of new strategies for improving diagnosis and prognosis and achieving a better response to therapy. This review focuses on recent studies on the biological and molecular mechanisms of response and resistance to treatment in BC.

BC

According to the International Agency for Research on Cancer, particularly the GLOBOCAN program, 2.1 million cases of BC were estimated in 2018 compared with 12.7 million in 2008,1,3 accounting for nearly one in four cancer cases in women.4 This increase in incidence may be explained by the growth and aging of the world population and the adoption of cancer-promoting lifestyles.

The development of molecular techniques, such as RNA sequencing, has allowed the determination of gene expression profiles, identification of tumor heterogeneity, and molecular classification of BC. Thus, six subtypes have been proposed based on the expression of ER, PR, estrogen-associated genes (ESR1, GATA3, FOXA1), and genes associated with the induction of proliferation, such as HER2 and other genes located in the region of the HER2 amplicon on chromosome 17.5 These six subtypes include the following: luminal A and luminal B, which are ER+ tumors, with expression of epithelial markers; HER2+ or HER2 enriched tumors, which show overexpression of the HER2 gene; normal-like, with an expression profile that is similar to non-cancerous breast tissue; basal-like/triple negative BC (TNBC), which are characterized by lack of expression of ER, PR and HER2; and claudin-low, which is enriched in epithelial-to-mesenchymal transition (EMT) features.6 Some authors only consider five of the six breast cancer subtypes mentioned above and exclude the low claudin subtype.

Treatment of BC

BC is a heterogeneous disease in which each patient has individual characteristics, which has led to the search for new markers to improve not only the diagnosis but also the prognosis and to achieve a better treatment response. Currently, strategies for the treatment of BC depend on the tumor subtype, and the selected treatments are directed to specific targets that are functionally altered in each subtype. For example, endocrine therapy is used for tumors with positive hormone receptors (ER and PR) (luminal A and luminal B),7,8 however, some patients also require chemotherapy. For HER2+ tumors (luminal B and HER2+), treatment involves the use of monoclonal antibodies that recognize the extracellular domain of HER2 (trastuzumab) and inhibitors of the tyrosine kinase domain of HER2 (such as lapatinib), or even RNAi-mediated silencing,9 as well as endocrine therapy in cases with positive hormone receptors. Although chemotherapy is usually only given for TNBC, several molecular targets are being explored for this BC subtype, including epidermal growth factor receptor (EGFR), androgen receptor (AR), poly (ADP-ribose) polymerase (PARP), and vascular endothelial growth factor (VEGF).

Generally, conventional therapeutic treatments for the management of BC patients have included endocrine therapy, targeted therapy and chemotherapy (Figure 1). However, in recent years, other treatments have been explored, including cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, microRNAs (miRNAs), immunotherapy, clustered regularly interspaced short palindromic repeats (CRISPR), tyrosine kinase inhibitors (TKIs), nanotechnological approaches, drug repurposing, and electrochemotherapy (ECT) (Figure 1). These new strategies may offer additional benefits to conventional treatments in terms of overcoming resistance and decreasing side effects.

Figure 1

Resistance and Overcoming Resistance in ER+ BC

Standard therapy for the treatment of ER+ BC is typically based on the use of endocrine therapy. This therapy includes the use of selective ER modulators, such as tamoxifen (TAM),10 selective ER downregulators (fulvestrant, FUL), and aromatase inhibitors (AIs)11 (Figure 1). Additional treatments include CDK4/6 inhibitors,12 PI3K inhibitors, and drug repurposing.

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