Tarasenko T. Optimization of hormone therapy with aromatase inhibitors in patients with metastatic luminal (HER2-negative) breast cancer and its correlation with polymorphisms of estrogen receptor gene

The dissertation presents a scientific theoretical validation and a practical solution to the topical scientific issue in modern Oncology, namely enhancing the efficacy of treatment designed for patients with metastatic luminal (HER2-negative) breast cancer in relation to polymorphisms (variants) of estrogen receptor gene. The incidence of breast cancer (BC) dominates other oncological nosologies all over the world. The World Cancer Research Fund (WCRF) reported 2,26 million new BC cases in 2020. Despite successful screening programmes for early diagnosis and permanent improvement in treatment approaches, BC metastasis is the main cause of lethal outcomes in female cancer patients. In addition, after radical treatment of BC, progression of the disease is marked with more aggressive features of tumour cells and less optimistic prognosis [175]. Molecular heterogeneity of BC results in its sensitivity to therapy and in the potential development of the disease. BC is divided into the following types: luminal (hormone-positive), HER2-positive and three times negative. The largest number of cases (60 – 70%) is luminal BC that, in its turn, falls immunohistochemically into the following subtypes: luminal A, luminal B HER2- negative and luminal В HER2-positive [176]. Hormone therapy (HT) is a conventional standard treatment of patients with the expression of estrogen receptors (ER) in tumor tissue. Hormone receptors are a positive prognostic and predictive factor for HT. On the ground of their effect, the basic medications are selective modulators ER (SERM), aromatase inhibitors (AIs) and competitive antagonists ER (SERD). In Ukraine, treatment usually begins with HT of the AI group: nonsteroid (letrozole, anastrozole) or steroid (exemestane) in the mono-mode. Modern combinations with CDK 4/6 and mTOR inhibitors have demonstrated the positive effect both with the AI group and with others (e.g., Fulvestrant and Tamoxifen) in cases of hormone resistance to AI. These combinations produced the same or higher efficacy than cytotoxic medications with a better tolerability profile. However, there is no certainty if it is feasible to add, in particular, CDK 4/6 inhibitors already in the first line of treatment due to their toxicity and cost [177]. Besides, there is no definite algorithm to verify the procedure of monitoring HT medications or to establish the order in which they should be prescribed. Pathogenic variants of ESRI gene arguably correlate with insensitivity to HT with AI through the ligand-independent transcription ERɑ for cases of metastatic luminal (HER2-negative) BC. Mutations of ESR1 gene occur rarely (up to 1%) in BC cases detected for the first time, yet they are relatively widespread during the metastatic process (10 – 15%) and connected with the resistance to HT with AI and the decrease in the survival rate without the disease progression [178]. Patients with pathogenic variants of ESR1 gene have a clinical benefit from Fulverstrant or Tamoxifen compared to AI. In case of mutations in ESR1 gene, combining HT with CDK 4/6 inhibitors helps to achieve a higher survival rate among patients with metastatic luminal (HER2-negative) BC [179]. Besides, there is an ongoing active study of medications that have specific effects in patients with pathogenic variants of ESR1 gene. In particular, the results of the research into the third phase EMERALD prove that oral SERD Elacestrant increases the survival rate median without progressing in patients with ESR1 mutations that experienced a progression after at least one line of HT. Thus, identification of the factors that lead to HT insensitivity regardless of the luminal status of the tumor is a topical issue in modern Oncology. The thesis explores the effect of A-351G Т-397С genotypes of ESR1 gene and the expression level of ITSN2-S in patients with metastatic luminal HER2-negative BC who received non-steroid AI (letrozole/anastrozole) as the first line of palliative HT The objective of the paper is to enhance the efficacy of hormone therapy with aromatase inhibitors in patients with metastatic luminal (HER2-negative) breast cancer through studying variants of ESR1 gene (A-351G, T-397C).