The Expression And Progrosis Analysis Of Cell Proliferation Marker Ki-67 In Breast Cancer

Objective:Breast cancer is one of the most common malignancy of women, the incidence and mortality of which ranks first in western countries in malignancy tumors, and second, only inferior to cervical cancer in China. It haven't seen significant decline in mortality, although it have made some progress in early diagnosis and treatment in recent years. With the continuous development of molecular biology techniques and application in breast cancer research, it have identified more and more markers which can reflect the prognosis of breast cancer. Ki-67 is a nuclear antigen which is related with cell division express in proliferating cells. Ki-67, with high expression, short half-life, rapid degradation from the cell cycle in tumor cells, has become the most reliable indicators to detect the tumor cell proliferation activity. The level of expression of Ki-67 has great significance in evaluating the cell proliferation, researching the biological behavior of tumor and determing the tumor harmfulness. This paper reviewed of 730 cases of breast cancer after surgery, used Non-parametric test and COX proportional hazards model and other statistical methods, analyzed the relationship between Ki-67 expressions and clinicopathological features and the significance in the prognosis of the breast cancer of which.Methods:This research collectedⅠ～Ⅱcases of operable breast cancer which has clear results of molecular markers(ER, PR, HER-2, Ki-67, AR) and clear pathological diagnosis in Fourth Hospital of Hebei Medical University first surgery (Breast surgery)between January 1,2008 to December 31,2008, excluded the cases of distant metastasis in newly diagnosed, and got 730 cases of surgical patients'data. Carrying on at least 1 follow-up (telephone follow-up and hospital review) to all cases, which ended by June 30,2010 or lost, the date of death. Setting the operation time as starting point, and patients' death, lost or the last follow-up time as terminal point as the research time. The Ki-67 positive cells defined as when the brown-yellow granules have appeared in the nuclei, randomly selected 10 fields, with 100 tumor cells per which under the high magnification (X 400), and calculated the percentage of positive cells to the total number of tumor cells as the Ki-67 proliferation index. The Ki-67 positive rates less than 10% is defined as "-", between 10%-30% is "+", between 30%-50% is "++", higher than 50% is "+++". Disease Free Survival (DFS), means from the radical surgery treatment to the tumor recurrence or death due to disease progression of the time. Overall Survival (OS), means the time between disease (tumor) diagnosis until died of various causes, is the most reliable endpoint of the tumor. There were 585 disease-free survival patients,102 patients with disease progression and 43 cases of death by the end point. Upload the follow-up data accurately to the SPSS 13.0 statistical package to do the statistical analysis.This research conducted on a more comprehensive analysis of ki-67 from four aspect. Which included the correlation between ki-67 and other molecular markers, the difference of ki-67 before and after menopause, the relationship between ki-67 and clinicopathological features and the relationship between ki-67 and prognosis. The enumeration data was analyzed by X2 test, the ranked data was by Non-parametric test, and the relationship between which was by Spearman rank correlation. The survival rate is calculated by using Kaplan-Meier method (Kaplan-Meier), applied Log-rank test for the comparison among the two groups. Quantifying the clinicopathological factors and the adjuvant treatment methods and making use of Cox proportional hazard model to analyze DFS and OS in univariate and multivariate ways to obtain the independent progrostic factors of DFS and OS. All tests were performed at the 0.05 level of significances.Results:1 The positive expression rate of Ki-67:in the whole group of 730 cases, Ki-67 positive rates was 95.5%, among which, Ki-67(+) accounts for 40.4%, Ki-67(++) 42.7%, and Ki-67(+++) 12.4%. 2 The survival situation:the 1,2,3-year overall survival rates in the whole group were separately 98.5%,95.3% and 94.1%, the 1,2,3-year disease-free survival rates were 92.5%,90.0% and 80.1%.3 The relationship between molecular markers:Ki-67 expression was negatively correlated with both ER and PR, positively with both HER-2 and AR(P<0.05)4 The differential expressions of molecular markers before and after menopause:there were no differences for ER and HER-2 expression; but different for Ki-67 and PR expression (P<0.05), and Ki-67 positive rates after menopause was higher than pre-menopausal, while PR positive rate after menopause was lower than pre-menopausal.5 The relationship between Ki-67 expression and clinicopathological features:Ki-67 expression was related to tumor size, histological grades, vascular tumor thrombus and clinical stages (P<0.05). Among which, it was more common that the emergence of vascular tumor thrombus exists in the Ki-67 positive group. With the higher of Ki-67 positive rates, the larger of the tumor, the worse of the histological grades and the later of the clinical stage.6 The expression of Ki-67 and prognosis:Ki-67 expression were divided into 3 groups:made Ki-67 positive rates lower than 10% as the low expression group (Ki-67-), which between 10%～50% as the intermediate expression group(Ki-67+～Ki-67++), and higher than 50% as the high expression group(Ki-67+++). Making use of DFS, OS for the horizontal axis respectively, the survival rate as the vertical axis to draw the Kaplan-Meier survival curves, and results showed that:The DFS survival curves were different between different Ki-67 expression groups. With the higher positive rates of Ki-67, the shorter the disease-free survival (P<0.05). However, the Ki-67 expression had no effects on the OS.7 Univariate analysis of DFS:Ki-67 expressions, the number of axillary lymph node metastasis, clinical stages, ER and PR expressions, adjuvant radiotherapy and adjuvant endocrine treatment were the significant factors to DFS of operable breast cancer patients (P<0.05). Multivariate analysis showed that, Ki-67 expressions, the number of axillary lymph node metastasis, clinical stage and adjuvant endocrine treatment were the independent prognostic factors to DFS (P<0.05)8 Univariate analysis of OS:the number of axillary lymph node metastasis, clinical stages, adjuvant radiotherapy and adjuvant endocrine treatment were the significant factors to OS of operable breast cancer patients (P< 0.05).Multivariate analysis showed that, the number of axillary lymph node metastasis and adjuvant endocrine treatment were the independent prognostic factors to OS (P<0.05)Conclusion:1 Ki-67 expressions were negatively correlated with ER and PR, but positively with HER-2 and AR.2 Both Ki-67 and PR expressions were different before and after menopause: Ki-67 positive rates after menopause were higher than pre-menopausal, PR positive rates were lower.3 The emergence of vascular tumor thrombus in the Ki-67 positive group was more common. With the higher of Ki-67 positive rates, the larger of the tumor, the higher of the histological grade and the later of the clinical stage.4 The DFS survival curves in different Ki-67 expressions groups were different. With the higher positive rates of Ki-67, the shorter the disease-free survival. However, the Ki-67 expressions had no effects on the OS.5 The independent prognostic factors of disease-free survival (DFS) were: Ki-67 expressions, the number of axillary lymph node positive, clinical stages and adjuvant endocrine therapy.6 The independent prognostic factors of overall survival (OS) were:the number of axillary lymph node positive and adjuvant endocrine therapy.7 Combine Ki-67, clinicopathological features and prognosis, it can be clearly defined Ki-67 as an adverse prognostic factor in breast cancer.