Molecular-biological factors of risk of recurrence and metastases development in patients with ovarian cancer of the III-IV stages

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Molecular-biological factors of risk of recurrence and metastases development in patients with ovarian cancer of the III-IV stages

Mikhanovskii A.A., Kochina M.L., Kharchenko Yu.V, Shchyt N.M., Fedorenko N.V., Mikhanovskii A.A.

Mikhanovskii A.A. Doctor of Medical Sciences, professor State Organization «Grigoriev Institute for Medical Radiology NAMS National Academy of Sciences of Ukraine», Kochina M.L., Doctor of Biological Sciences, professor Petro Mohyla Black Sea National University, Kharchenko Yu.V. State Organization «Grigoriev Institute for Medical Radiology NAMS National Academy of Sciences of Ukraine», Shchyt N.M. State Organization «Grigoriev Institute for Medical Radiology NAMS National Academy of Sciences of Ukraine», Fedorenko N.V. State Organization «Grigoriev Institute for Medical Radiology NAMS National Academy of Sciences of Ukraine »

Abstract. The study presents the results of studying the molecular-biological markers of ovarian tumors in patients with the III-IV stages of (T3a-cNxM0-1) disease. It is shown that a high level of mt p53 after conducting non-adjuvant polychemotherapy indicates the presence of chemo-resistant tumor cells. Lack of expression of VEGF, Bcl-2 and mt p53 at a moderate level (4-40%) of Ki-67 indicates a risk of generalization of the process. High expression of the proliferative activity (Ki67), in combination with the lack of expression of VEGF and Bcl- 2, may indicate a high risk of locomotor retinitis, but no expression of VEGF, Bcl-2 and mt p53, or weak positive expression of mt p53 in combination with weak positive Ki67 expression may indicate a risk of marker recurrence.

Keywords: ovarian cancer, molecular-biological tumor markers, recurrence, metastases.

Introduction

According to epidemiological studies in recent decades, there is a marked tendency to increase the incidence of ovaries malignant tumors in women. The risk of contracting ovarian cancer (OC) during life is 1.5%, and one in 100 women may die of this disease [1]. Ovarian tumor is the cause of disability, which determines the social and economic aspects of this pathology.

According to the combined data of population cancer registries in Europe, one-year survival rate of OC patients is 63%, those who live three years comprise 41%, those who live five years make up 35%. At the same time, if the disease is detected on the early stages, the five-year survival rate is 60-100%, and then at stages III and I its value do not exceed 10%. Moreover, the proportion of the I-II stages of OC accounts for 31.9% of the first identified patients, while the common forms make up 68.1% of observations. Among patients who were first diagnosed at the III and IV stages, 37.2% and 27.0% respectively [2].

Analysis of recent publications

Despite numerous epidemiological studies, the etiology of OC remains not clearly stated. Hormonal, genetic factors, as well as the state of the environment play an important role in the development of the OC [3, 4].

It is now known that malignant neoplasms are causing damage to the genetic apparatus in the terminal and somatic cells, which makes these cells sensitive to external carcinogenic factors capable of triggering malignancy. Depending on which cell the primary mutation occurred to the sex or somatic, the cancer may be hereditary or sporadic [5].

There are more than 100 proteins and / or genes which alternations can be found in malignant cells.

Each tumor is unique in a set of disorders involved in carcinogenesis. Such disorders, found in tumor tissue, are called molecular-biological markers (MBM) of tumors.

By definition, MBM of tumors are certain chromosomal and gene mutations, as well as expressions of various molecules that are qualitative or quantitative specific changes in the tumor and are involved in the development and progression of malignant diseases.

Significant theoretical and practical interest is the study of markers that characterize apoptosis, cell proliferation and angiogenesis, which include p53, Bcl-2, Ki67 and VEGF proteins [6]. MBMs characterize different properties of malignant tumors and can be used to predict the risk of OC recurrence and metastases.

The purpose of the study is to assess the relationship between the level of expression of the tumor MBM and the occurrence of OC recurrence.

Material and methods

polychemotherapy tumor chromosomal malignant

We studied MBM of ovarian tumors in 75 patients with the III-IV stages of OC (T3a-cNxM0-1). The age of the surveyed OC patients was from 23 to 77 years. There were 4 (5.3%) patients younger than 30 years old and 3 (4%) patients older 70 years.

Depending on the type of combination treatment, the patients were divided into groups. The first group consisted of 46 (61.3%) patients whose treatment was started with non-adjuvant polychemotherapy (NPCT) with subsequent surgical treatment. The second group comprised 29 (38.7%) patients who were first surgically treated and then received adjuvant polychemotherapy (APCT).

Among all the surveyed patients there were 54 (72%) persons with the Ill stage of OC and 21 (28%) people with the IV stage. The majority of patients with the III (T3a-cNxM0) and the IV (T3a-cNxM1) stages of OC were at the age of 50-60 years old.

Depending on the histological structure of the tumor, 43 (57.3%) patients had serous cystadenocarcinoma. 3 (4%) of these patients had endometrioid carcinoma and 6 (8%) of them had mucinous carcinoma; 14 (18.7%) patients had undifferentiated tumor, and 4 (5.3%) patients had poorly differentiated carcinoma; germinogenic tumors occurred in 2 (2.7%) patients, light cell illness was in 1 (1.3%) patient; in two cases (2.7%) the morphological structure of the tumor was not identified because of pronounced therapeutic pathomorphosis.

The criteria for predicting biological aggressiveness of tumors were studied using a marker of proliferative activity Ki67 (Mib-1) and markers of apoptosis Bcl-2 (124) and mt p53 with the use of primary monoclonal antibodies (MCAT), Rady-to-Use. The evaluation of tumor neoangiogenesis was performed by determining the vascular endothelial growth factor (VEGF).

As a result of the research, it was found out that in the first group patients treated with NPHT there was no expression of VEGF in the tumor in 46.4% of cases and Ki67 in 41.3% of cases, high level of mt p53expression (50-100% ) was observed in 41.3% of patients, Bcl-2 was detected in 52.2% of patients (Fig. 1).

In tumors of the majority of second group patients, there was no expression of Bcl-2 (in 60.7% of patients) and mt p53 (in 44.8% of patients) with proliferative activity level (Ki67) (4- 40)%, which was observed in 58.6% of patients. A high level of VEGF expression was observed in 53.8% of cases (Fig. 2).

Figure 1 - Distribution of the first group patients with OC of the III-IV stages depending on the MBM level of expression in the tumor

Figure 2 - Distribution of the second group patients with OC of the III-IV stages depending on the MBM level of expression in the tumor

During the observation period, recurrence of the disease was detected in 32 (42.7%) patients from 75. Distribution of patients with recurrence depending on the stage of the disease is shown in Table 1.

Table 1. Distribution of OC patients with recurrence of the disease depending on the stage

Distribution of patients depending on the type of recurrence is shown in Table 2.

Table 2. Distribution of OC patients depending on the type of recurrence, (%)

Note: * - Differences in incidence of generalization of abdominal cavity or distant metastases and marker recurrence are reliable according to criterion x2 (p <0,05).

The data presented in Table 2 indicate that the most common cases of recurrences in OC patients with the III stage were generalization of the abdominal cavity with / or distant metastases (in the lungs, liver, inguinal lymph nodes). In the group with the IV stage of the disease, all types of recurrences occurred in the same percentage of cases. The presence of marker recurrence was established on the basis of increasing the value of the serum marker CA-125 from the achieved as a result of treatment of normal levels, after the end of treatment.

In the study of the level of MBM expression in OC patients of the first group, in which the recurrence of the disease was detected, negative VEGF values were observed in 70% of cases, and its positive values were observed in 30% of patients. Expression of Bcl-2 was absent in 60% of patients, and proliferative activity (Ki67) - in 55% of patients. Expression of mt p53 and its absence was detected in the same frequency.

The study of MBM expression in OC patients of the second recurrence group showed that the negative VEGF was observed in 55.6% of patients, and the lack of expression of Bcl-2 was observed in 72.7% of patients. Expression of mt p53 was observed and absent in the same percentage of cases (50%). In 66.6% of patients, proliferative activity (Ki67) was moderate (in the range of 4-40%).

When comparing two groups of OC patients with the III-IV stages of recurrence, in both groups there were patients with no expression of vascular endothelial growth factor (VEGF) (70% and 55.6% respectively), as well as expression of Bcl-2 (60 % and 72.7% respectively). The level of expression of the indicator of proliferative activity (Ki67) was different. In patients of the first group, its expression was absent in 55% of cases, and in patients of the second group 66.6% of patients had moderate expression (in the range of 4-40%). The mt p53 level of expression in the first group patients was not significantly different; in patients of the second group 50% of the apoptosis marker expression was absent.

Table 3-6 shows the distribution of patients depending on the level of MBM expression and the presence of recurrence of the disease.

Table 3. Distribution of OC patients with the III-IV stages in terms of mt p53 expression depending on the presence of recurrence

Table 4. Distribution of OC patients with the III-IV stages in terms of Ki67 expression depending on the presence of recurrence

In the group of OC patients without recurrence, the indicator mt p53 exceeds zero (41 patients) more often than equals zero (no expression) (22 patients). Differences in the incidence of these values are statistically significant (x2 = 11.5; p <0.05). In the group of OC patients with relapsing, such differences were not detected. There is no significant difference between groups in the frequency of indicator occurrence.

In the group of OC patients without recurrence, currence of the indicated values are statistically signif- Ki67 exceeds zero (44 patients) more often than equalszero (19 patients). Differences in the frequency of oc icant (x2 = 33,6; p <0,05). In the group of OC patients with recurrence, no significant differences were detected.

Table 5. Distribution of OC patients with the III-IV stages in terms of Bcl-2 expression depending on the presence of recurrence

Groups of patients do not differ. The frequency of occurrence of a positive and negative indicator is similar in these groups.

Table 6. Distribution of OC patients with the III-IV stages in terms of VEGF expression depending on the presence of recurrence

No statistically significant differences were found. Distribution of OC patients with the III-IV stages depending on the level of MBM expression and type of recurrence is shown in Fig. 3-4.

Figure 3 - Distribution of OC patients with generalization of the process depending on the level of MBM Expression

Figure 4 - Distribution of OC patients with loco-regional and marker recurrences depending on the level of MBM expression

As shown in Figs. 3 and 4, in patients with generalization of the process, marker and loco-regional recurrence of the III-IV stages in most cases, expression of the growth factor of vascular endothelium was absent (in 69.2%, 55.6% and 71.4% of cases respectively). In all types of recurrences, the absence of expression of Bcl-2 was observed in 66.7%, 66.7% and 57.1% of cases, respectively. In generalizing the process, mt p53 was absent in 46.7% of patients, and in other recurrences in 33.3% and 37.5% of cases, respectively. Moderate Ki67 expression was observed in 46.7% of patients with generalization, and 37.5% with marker recurrence. In the local recurrence, in contrast to the generalization of the process and marker recurrence, in the majority of cases, high expression (40100%) of Ki67 was observed in 55.6% of patients. With the generalization of the process and biochemical recurrences, high expression (40-100%) of Ki67 was observed only in 13.3% and 25% of cases, respectively.

Conclusions

The high level of mt p53 in OC patients with the III-IV stages after NPCT suggests the presence of chemo-resistant tumor cells, which is why it is not recommended to use drugs of the second line of chemotherapy for NPCT as it reduces the effectiveness of APCT with second line drugs and survival of the sick.

In most patients with recurrence, there is no expression of the apoptosis marker Bcl-2 and VEGF. Indicators of proliferative activity (Ki67) and mt p53 depended on the type of treatment.

Absence of VEGF and Bcl-2 expression can serve as a predictor of the risk of disease recurrence in OC patients with the III-IV stages.

Absence of VEGF, Bcl-2 and mt p53 expression at a moderate level (4-40%) of Ki67 is a negative factor and indicates the risk of generalization of the process in OC patients with the III-IV stages.

High expression of the proliferative activity indicator (Ki67) together with the lack of VEGF and Bcl-2 expression may indicate a high risk of development of loco-regional recurrence of OC.

Absence of VEGF, Bcl-2 and mt p53 expression together with poor positive mt p53 expression and in combination with poor Ki67 expression may indicate a risk of marker recurrence.

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