In terms of the predictive factors, ER and PR expression are also considered predictive, particularly in relation to the results that could be obtained with a pharmacological treatment such as tamoxifen 16 , and independent of the treatment, ER expression in tumor cells is associated with a better prognosis Finally, the gene CCNA2, which belongs to a highly conservative family of cyclins and is overexpressed in several types of cancer, has been associated with resistance to tamoxifen and endocrine therapies. Understanding the biology of cancer is a fundamental prerequisite for an appropriate treatment 23 since the response to cancer treatment is influenced by many factors, including the pharmacokinetics and pharmacodynamics of the drugs to be used, the tumor microenvironment, the characteristic angiogenesis and the genetic aberrations According to the American Cancer Society 25 , the main forms of breast cancer treatment are: surgery, radiation therapy, chemotherapy, hormone therapy, targeted therapy and bone-directed therapy.
These treatments can also be classified into local or systemic and adjuvant or neoadjuvant groups. The local therapy treats the tumor from within, without affecting the rest of the body as surgery or radiation does. Systemic therapy refers specifically to the drugs that can reach the cancer cells in any part of the body.
These include chemotherapy, hormone therapy and targeted therapy, among others. Adjuvant therapy is defined as the administration of chemotherapy to kill or inhibit clinically non-detectable micrometastases after the first surgery.
Neoadjuvant therapy is used in the initial stages of breast cancer before surgery where some cells can produce metastasis. The purpose of both is to destroy hidden cancer cells 26 by eradicating distant micrometastatic deposits The problem with this treatment is that it carries significant health risks, and therefore the selection of patients who need it must be based on predictive factors. There are significant differences in the treatment of invasive breast cancer according to its stage.
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By way of example and very generally, the treatment for invasive breast cancer can be divided into early and advanced stages If the patients have minimum risk and are node-negative: endocrine therapy with tamoxifen is added. If these patients do not respond to the treatment chemotherapy is initiated. The treatment is determined according to the molecular classification, age, predictive and prognostic factors and can be first-line hormone therapy or chemotherapy according to the case, and chemotherapy as a last resort in both situations Despite the advances, most clinical treatments for breast cancer including chemotherapy or hormone therapy are not very successful in eliminating meta-static cells; invasive cancer is highly lethal, in fact, patients in stage IV have a survival of 15—27 months despite the most aggressive treatment and the most effective drug use 27 , This occurs because the heterogeneous population of metastatic cells generally follows a different clinical course 27 due to changes in some factors of the tumor environment as energy metabolism 30 or genetic or epigenetic alterations of the cancer cells The purpose of adjuvant and systemic therapies is to improve the disease-free survival and survival rate associated with breast cancer through local-only treatments surgery and radiation.
For many years the treatment recommendations for adjuvant therapies were based on the anatomical classification and pathological factors such as tumor size, tumor grade and lymph node status. With the development of immunohistochemistry and genomic profiling techniques, different subtypes have been classified based on various markers and more specific therapies have been developed with a greater number of clinical benefits The list contains generic or brand names, and also includes the combinations in which they are used such as lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2 Chemotherapeutic agents can be classified according to many factors, including the specific phase of toxicity or the mechanism of action Phase-specific chemotherapy.
Methotrexate inhibits DNA synthesis; alkaloids inhibit the M phase of the cycle. Cell cycle-specific chemotherapy.
Molecular aspects of breast cancer resistance to drugs (Review)
In cells that divide actively there is a dose-related plateau due to loss of sensitivity, which is offset with increased exposure time. Non-specific chemotherapy. Alkylating agents with the same independent effect on the cell cycle. Alkylating agents. They add an alkyl group, interfering mainly in DNA replication cyclophosphamide among others.
Heavy metals. Platinum-based agents: carboplatin, cisplatin and oxaplatin bond mainly to DNA. They simulate the structure of natural substances like vitamins, nucleosides or amino acids. They act during the S phase. Folic acid antagonists: methotrexate. Pyrimidine analogs inhibit synthesis of nucleic acids. Purine analogs inhibit synthesis of nucleic acids.
Cytotoxic antibiotics. They alter synthesis and function of nucleic acids. Actinomycin D intercalates between G and C. Bleomycin: mixture of oligo-peptides that fragment the DNA. Mitomycin C inhibits DNA synthesis. Spindle toxins. Vinca alkaloids prevent formation of the spindle binding to the tubulin.
Taxoids activate apoptotic pathways, inhibiting disassembly of microtubules, such as paclitaxel or Taxol. T opoisomerase inhibitors. They alter the 3D structure of the DNA.
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Topoisomerase inhibitors prevent replication. Since alteration of the cell cycle plays a pivotal role in the pathogenesis of cancer, having cyclins, CDKs and CDKIs the former are positive regulators and the latter negative regulators of the cell cycle as targets is a recurring theme in oncology Multidrug resistance MDR is the greatest obstacle in the systemic treatment of breast cancer; it renders the disease uncontrollable and causes high mortality 35 — It is therefore of the utmost importance to find drugs that can control breast cancer and offer better results.
MDR can be intrinsic, where a fault is generated in the first-line therapy, which indicates there are pre-existing factors that mediate resistance in the tumor cells, or acquired, where initially the cells were sensitive to the treatment but resistance developed later on 30 , 39 , The latter is characterized as being a resistance parallel to several drugs with a diverse structure and function and which are made up of different cell factors and transduction signals In addition, as tumors are heterogeneous, it is believed that drug resistance may originate as a positive selection of a sub-population of drug-resistant cells Mechanisms of multidrug resistance.
There are several mechanisms involved in drug resistance, as anti-apoptotic resistance, epithelial-mesenchymal transition, ABC transporters, epigenetic changes, alterations in the drug target and miRNA micro-ribonucleic acid. EMT, epithelial-mesenchymal transition. CSC, cancer stem cells.
TRTP53, telomerase reverse transcriptase p PKD1, polycystic kidney disease 1 gene. MDR1, multidrug resistance protein 1. MRP1, multidrug resistance-associated protein 1. BCRP, breast cancer resistance protein. Epithelial-mesenchymal transition EMT. The epithelial cancer cells lose their polarity and their tight junctions, developing a fibroblast morphology associated with an increased mobility and invasiveness. Epigenetic changes. Epigenetic silencing of tumor suppressor genes such as TP53 or PKD1 that can influence the tumor microenvironment and promote the progression of a breast tumor to an aggressive metastatic phenotype 2 , 28 , Various studies show that miRNAs are key regulators in drug resistance in breast cancer through the positive regulation of drug efflux transporters, anti-apoptotic proteins, acquisition of the EMT and the formation of CSC 36 , Many tumors have an overall downregulation of miRNA expression ABC transporters.
The ATP-dependent drug efflux pumps reduce the intracellular accumulation of the drug 30 , 36 , Alterations in the drug target. Due to mutations or changes in the expression levels Anti-apoptotic resistance. The cells become addicted to a moderate number of anti-apoptotic proteins for their survival. Tamoxifen has been reported as being of significant benefit to hormone-sensitive patients. ER belongs to the superfamily of nuclear receptors According to authors 29 various resistance mechanisms can be found in endocrine therapy.
At both the epigenetic and transcriptional levels. They appear mainly in endocrine therapy with SERM. This occurs mainly in endocrine therapy with SERM. Alteration in the metabolism of the drug. Increase in growth factor signaling. Increase in ER sensitivity. Targeted therapy represents the greatest hope in the war against cancer and is a very important step in personalized medicine. To avoid the various toxic effects of some drugs, antibody-drug conjugates have been developed that can aim the treatment specifically at tumor cells.
One of these antibodies is trastuzumab emtansine T-DM1 , which can block the extracellular part of the bond to the HER-2 receptor ligand, inhibiting the pathological signal of HER-2 overexpression inside the cell. Because the benefit in the clinical response rate and absolute survival is small, more effective drugs are needed that can be conjugated with T-DM1 Despite an optimal local treatment, virtually all patients with invasive breast cancer have some risk of relapse. This risk varies according to several factors related to the disease, which is why all women with this type of cancer could obtain benefits from adjuvant therapy.
However, all these treatments have indirect side effects and potential risks that must be considered when evaluating the need for systemic therapy Some of the acute and chronic side effects associated with breast cancer treatment are cardiotoxicity, one of the most important for treatment with anthracyclins, radiation therapy, etc.
Some effects of endocrine therapy are documented mainly with the use of tamoxifen and include pulmonary embolism, deep vein thrombosis and endometrial cancer. The aromatase inhibitors have been associated with an increased risk of cardiovascular disease, high cholesterol and acceleration of bone tissue loss in post-menopausal women It is known now that cancer cell populations contain a subpopulation of self-renewing stem cells known as cancer stem cells CSC.
Unlike normal adult stem cells that remain constant in number, such cells can increase in number as tumors grow, and give rise to progeny that can be both locally invasive and colonize to distant sites known as one of the hallmarks of malignancy.
Overcoming endocrine resistance in hormone receptor–positive breast cancer
Cancer begins in normal somatic cells with a mutation that is called initiation. If the mutated cell has a selective growth advantage over its normal neighbor cells due to enhanced proliferation or resistance to apoptosis, then a clone of cells carrying the same mutation will emerge. The microenvironment surrounding blood vessels is conducive to the highest rates of tumor-cell proliferation, but it can also serve as the local stem cell niche, a microenvironment formed by nerves, mesenchymal cells and molecules of extracellular matrix that regulate aspects of stem cell behavior.
The insensitivity of cancer stem cells to chemotherapy and radiation treatment has suggested that anticancer drugs may not effectively inhibit such cells, thus targeting them will be important to eradicate tumors in an efficient way. The clinical relevance of targeting genes of such cells is supported by experimental and clinical studies. It is necessary to take into account that the mesenchymal phenotype is associated with characteristics of CSC for the development of anti-CSC therapies in the future.
Incorporating the concepts of CSCs and the EMT into the biology of cancer may dramatically change the paradigm of anticancer therapy. The overall goal of cancer therapy is to target only the cancer cells leaving the viable normal cells behind. Therefore CSC eradication seems possible.