#Shtabinskaya T.T. The prognostic significance of the expression of angiogenic markers in colon cancer depends on the stage of disease

Shtabinskaya T.T.

Grodno State Medical University, Belarus

The prognostic significance of the expression of angiogenic markers in colon cancer depends on the stage of disease

Colorectal cancer (CRC) is the second leading cause of death of cancer patients in developed countries [1]. Are well-known factors of prognosis of colorectal cancer. However, despite similar clinical and morphological signs of the disease, the survival rate of patients with the same stage of cancer and the amount of surgery is different, some patients live 5 years, while others die of disease progression.

Purpose: to determine the value of angiogenic markers expression in various stages of CRC for the prognosis of the disease.

Materials and methods: 72 cases of CRC were investigated. The cases were divided into 3 groups. The I group included 25 patients (14 men and 11 women) with I and IIA stage disease (T_1-3N₀M₀), the II - 35 patients (11 men and 24 women) with IIIA-C stage of the disease (T_2-4N_1-2M₀) in the III - 12 patients (4 men and 8 women) with IVA, in the stage of the disease (T_2-4N_0-2M₁). The study was performed on paraffin sections using antibodies to VEGF, CD 105, MMP-2, Erk2, iNOS, TGF-β, NRP1, MMP-9 according to standard procedure. Quantitation of the level of expression was described in the previous article [2]. Statistical analysis was performed using STATISTICA 10.0 (SNAXAR207F394425FA-Q).

Results: Adjusted free survival (AFS) patients in group I for 3-year time interval was 80%, 5-year - 60% and 10-year - 52%, respectively. Statistically significant differences between the Grade of adenocarcinoma and AFS patients from the I group haven’t been identified. A negative correlation between the depth of tumor invasion and 5-year AFS was founded (r=-0.4, p=0.04). 5-year term was adopted to predict the outcome of the disease.The level of general expression (GE) NRP1 higher survival at 5 years and more. The intensity of parenchymal expression (PE) TGF-β and the level of GE iNOS significantly higher survival at less than 5 years. No statistically significant differences were found in the expression of the other antigens. Using ROC-analysis for defined separation point prediction AFS 5 depending on the expression level of NRP1, TGF-β, iNOS. The area under the ROC-curve constructed during NRP1 expression analysis, equal to 0.86±0.10 (the accuracy of the differences with the area under the diagonal = 0.0004). The most distant point from the diagonal to the ROC-curve corresponds to the level of expression of NRP1 equal to 0.655 (sensitivity - 85.7%, specificity - 87.5%). The area under the ROC-curve constructed through the analysis of TGF-β expression is equal to 0.75±0.10 (the accuracy of the differences with the area under the diagonal = 0.016). The most distant point from the diagonal to the ROC-curve corresponds to the level of expression of TGF-β equal to 0.726 (sensitivity - 60%, specificity - 87.5%). The area under the ROC-curve constructed in the iNOS expression analysis, equal to 0.74±0.10 (the accuracy of the differences with the area under the diagonal = 0.02). The most distant point from the diagonal to the ROC-curve corresponds to the level of expression of iNOS equal to 0.79 (sensitivity - 78.6%, specificity - 60%). The AFS of patients of group II for a 3-year time period was 68.6%, 5-year - 48.6% and 10-year - 42.9%, respectively. There was a negative correlation between the 3-year AFS and tumor grade (r=-0.51, p= 0.002). Statistically significant differences between the depth of invasion and the AFS hasn’t been detected. The degree of injury of regional lymph nodes (pN) correlated with the 3- and 5-year AFS negatively (r=-0.44, p=0.007; r = -0.31, p = 0.069, respectively). Taking into account that had died or had a recurrence of the disease, more than half of patients in the first 5 years of follow up, and 61% of them in the first 3 years, and taking into account the correlation between the Grades, index pN and 3-, 5-year AFS, these terms (3 and 5 years) have been accepted for predicting disease. Were statistically significant differences in the expression of VEGF and TGF-β, depending on the AFS 3 years. The level of GE VEGF was significantly higher survival rates when 3 or more years. The tendency to a high level of positivity TGF-β in tumors of patients with survival less than 3 years. The level of PE MMP-9 in the tumor was significantly higher survival rates at least 5 years. The tendency to reliable connection a high level of MMP-9 stromal positivity in patients with tumor survival of less than 5 years. No statistically significant differences were found in the expression of the other antigens. Using ROC-analysis identified the dividing point for predicting the 3-year AFS depending on the level of GE VEGF and the overall 5-year, depending on the level of PE MMP-9. The area under the ROC-curve constructed in the VEGF expression analysis, equal to 0.76 ± 0.11 (the accuracy of the differences with the area under the diagonal = 0.017). The most distant point from the diagonal to the ROC-curve corresponds to the total expression of VEGF equal to 0.949 (sensitivity - 86.4%, specificity - 62.5%). The area under the ROC-curve constructed in the analysis of PE MMP-9 equals 0,71±0.09 (the accuracy of the differences with the area under the diagonal = 0.03). The most distant point from the diagonal to the ROC-curve corresponds to PE MMP-9 equal to 0.713 (sensitivity - 85.7%, specificity - 55.6%).

The survival rate of patients of group III for a 3-year time period was 33.3%, 5-year - 25%. Taking into account that in the first 3 years of follow died or had relapsed more than half of the patients, it is this term was adopted to calculate the outcome of the disease prognosis. Statistically significant differences between the expression of antigens and AFS weren’t found in this group.

Conclusion: The best 5-year AFS of patients with colorectal cancer stages I-IIA is possible with high reliability expected at the level of the GE NRP1>0.655, or intensity of PE TGF-β≤0.726 or GE iNOS≤0.79. The best indicators of a 3-year AFS of the patient's stage IIIA-C can be expected at the level of the GE VEGF>0.949, and 5 years - at a rate of PE MMP-9≤0,713. Patients with hematogenous metastases (IVA, B stage) the expression of angiogenesis markers hasn’t prognostic value and survival of patients in this group is less than 3 years.

Literature:

1. Брусина, Е. Б. Эпидемиология рака : учеб. пособие для последипломной подготовки специалистов / Е. Б. Брусина, Ю. А. Магарилл,
А. Г. Кутихин. – Кемерово : КемГМА, 2011. – 176 c.

2. Штабинская, Т.Т. Прогностическое значение уровня экспрессии фактора роста эндотелия сосудов в колоректальном раке / Т.Т. Штабинская, М. Боднар, С.А. Ляликов [и др.] // Научно-практический журнал УО «Гродненский государственный медицинский университет». – 2015. - № 3(51). - С. 64-69.