Molecular-genetic prognostic factors endometrial cancer in stages I-II: Summary of the thesis of doctor habilitate in medical sciences: 321.20 – Oncology and radiotherapy

Abstract

SUMMARY. The dissertation for doctor in philosophy in medicine on topic: “Molecular-genetic factors for the prognosis of endometrial cancer in stages I-II” was elaborated by Tripac Irina in the Public Medico-Sanitary Institution Institute of Oncology, Chisinau, 2023. This work includes an introduction, 6 chapters, conclusions and practical recommendations. The paper contains 161 typed pages, 62 tables, 32 schemes. The bibliography list includes 206 sources. The results obtained have been published in 55 scientific papers. Key-words: Prognostic factors, clinical-morphological factors, molecular-genetic factors, prognostic model, endometrial cancer Study domain: Oncology and radiotherapy. The aim of the study: determination of clinical, morphological and molecular genetic factors of endometrial cancer (EC) stages I-II to develop a mathematical model for predicting relapses and patient survival for up to 3 years. Objectives of the study: To establish the clinical, morphological, immunohistochemical criteria as prognostic factors of the endometrial cancer (EC); estimating the correlation of immunohistochemical and molecular-genetic data according to the clinical and morphological characteristics of endometrial cancer; estimating the molecular profile of the tumour in the patients of the study group; multifactorial analysis of the complex of prognostic criteria established with the determination of the prognostic value for each separate factor in patients with EC in stage I-II; creation of the mathematical model of the complex prognostic evaluation of the EC in stages I-II according to the risk groups and the prognostic factors. Scientific novelty and originality: The mathematical model allows complex analysis of the prognostic factors of the evolution of endometrial cancer, based on the molecular profile of the tumour and the characteristics that make it possible to predict the response of the tumour to treatment. Determining the expression of Ki-67, PDL1, MLH1 proteins presents useful information about the biological behaviour of the tumour already in the early stages of EC. The solved scientific problem: The scientific problem solved in the thesis is that research based on clinical-morphological and molecular-genetic studies has found novel pathogenic mechanisms and predictors of EC exacerbation, such as the presence of c.389G>A epimutation (p.R130Q) of the PTEN gene, methylation of the MLH1 gene promoter, the Ki-67 proliferation marker, the increase of the neutrophil-lymphocyte index, which allowed the development of a mathematical model to predict the evolution of the disease in patients with EC from different risk groups. 12 Theoretical significance: The conclusive evidence obtained completes the concept and theoretical support of endometrial cancer. At this point, it is important to decant the contribution of the c.389G>A mutation of the PTEN gene, the increase of the proliferative activity of the mitotic cycle evaluated by the increase of the Ki-67 antigen, the mutation of the p53 gene resulting in the depreciation of the Bax/Bcl2 ratio. At the same time, the role of inflammation in promoting the EC is highlighted, and the increase in the neutrophil/lymphocyte index is not only a pathogenic mechanism, but also a feasible predictor of tumour prognosis. It is conceptually important that the EC has a significant link with the increase in body mass, as well as the absence of a link between the EC with regard to the risk of recurrence on the one hand and the characteristics of menstruation, births and miscarriages on the other. Predictive value on the increased risk of recurrence in patients with EC is attributed to factors inherent in the pathology of reproductive organs, such as ovarian cyst, uterine fibroids and fibrocystic mastopathy. The rate of serous papillary adenocarcinoma in the group of patients with stage II EC is on average 44-48% higher compared to the index of stage IA and IB. The degree of tumour differentiation has a conclusive impact on the risk of recurrence, so that the low degree of differentiation is estimated at 95% in high-risk patients, and the high degree of differentiation is characteristic of low risk (80%). Remarkably, the depth of the tumour invasion does not really correlate with the increase in risk. The presence of necrotic foci is a true predictor of increased risk. The impact of inflammation is imposed by maximum values of the ratio neutrophils/lymphocytes and platelets/lymphocytes in patients with high-risk EC. The marker of Ki-67 proliferation is directly related to the degree of risk as well as to the stage of the disease (the level of Ki-67 expression> 49% is detected only in the high risk group). The presence of the c.389G>A mutation (p.R130Q) of the PTEN gene is in the 4-8 times higher risk group compared to the intermediate and intermediate-increased risk. Important is the presence of this mutation only in patients with a hormone-dependent pattern of tumour in 36%, but stage II disease is required by reducing the rate of PTEN gene mutation vs. stage I. MLH1 epimutation does not show such a conclusive link with EC c.389G>A (p.R130Q) of the PTEN gene. Practical value of the study. The clinical significance of the expression of molecular biological markers that characterize apoptosis, cell proliferation and angiogenesis in tumour tissue in patients with stage I and II EC has been assessed on a wide range of clinical evidence. Precise clinical, morphological, immunohistochemical, and genetic criteria for EC diagnosis and prognosis in patients with stage I-II endometrial cancer have been determined. The immunohistochemical characteristics of EC (Ki-67 expression), the presence of the c.389G>A mutation of the PTEN gene, the identification of the methylation of the MLH1 gene promoter and the correlation according to the clinical-morphological characteristics of endometrial cancer in 13 patients of the study group with molecular profile were highlighted of the tumour for each patient. This approach allows to perform a detailed analysis of the prognostic value for each particular factor, which will allow the identification of the main prognostic factors. Its own prognostic model has been developed, which includes clinical, morphological, immunological, immunohistochemical and genetic characteristics of endometrial cancer. The survival of patients with EC over a 3-year surveillance period is minimal (72.2%) among those older than 60 years and belonging to the high risk group of recurrence. The relapse-free survival rate is also minimal in these patients (44%). At the same time, the rate of metastases in patients with EC is not intelligibly correlated with the stage of the disease. The mean time to progression of the EC is indirectly related to the value of the neutrophil/ lymphocyte ratio, which is minimal (6 months: 5 to 9 months) in patients at high risk of recurrence with an INL index>5.0. The Ki-67 marker has a definite predictive value on the survival and recurrence rate in patients with EC, so that increased proliferative activity (>49%) has a negative impact at a distance of 3 years. The presence of MLH1 epimutation also influences the recurrence of the disease in patients with EC at a distance of 3 years, given the minimum value of the mean time to progression of 10.5 years attested to the carriers of this mutation in the high risk group. Implementation of scientific results: The results of the study were reported to 8 national and 18 international forums. On the research side, 3 invention patents were validated. The results of the study will be presented in the form of practical recommendations for family doctors, gynecologists, but also for oncology specialists. In the clinical activity of the Cancer Biology Laboratory of the IMSP Oncological Institute, EC molecular-genetic research programs will be developed and implemented with the establishment of the molecular subtype of the tumor. Thus, the estimation of the evolution of endometrial cancer in stages I-II will be streamlined, which will allow its application in accordance with the elaborated criteria.