Association Between Ki67 After Neoadjuvant Chemotherapy and Disease-Free Survival in Breast Cancer

Background: Post Chemotherapy Ki67 in recent year has been investigated as a predictive and prognostic factor in locally advanced breast cancer patient undergoing neoadjuvant chemotherapy. Objectives: To describe the relationship between post-chemotherapy Ki67 and disease-free survival after neoadjuvant chemotherapy in patients with locally advanced breast cancer at Dr. Hospital. Mohammad


Introduction
Cancer is one of the leading causes of death worldwide. In 2012, approximately 8.2 million deaths in Indonesia were caused by cancer. Breast cancer is one of the most common types of cancer in Indonesia.
Based on Pathological Based Registration in Indonesia, breast cancer ranks first with a relative frequency of 18.6%. It is estimated that the incidence rate in Indonesia is 12 / 100.000 women 1,2 . According to the Indonesian Cancer Foundation, currently breast cancer is the leading cause of death with a mortality rate of 198.000 people per year. Among them there are 882.9 cases (per 100.000) originating from developing countries. In Indonesia, more than 80% of breast cancer cases are found to be at an advanced stage. Currently, locally advanced breast cancer is still the largest proportion (50-60%) of cancer patients who come to polyclinics or hospitals in Indonesia. In RSUP Mohammad Hoesin Palembang in 2014, the highest distribution of clinical stages was stage III, namely stage III A 26.53% and stage III B 48.98% [3][4][5][6] .
Breast cancer management includes surgery, radiotherapy, chemotherapy and hormonal therapy.
Chemotherapy is a treatment using a combination of drugs that aims to destroy or slow down the growth of cancer cells. Currently chemotherapy is a very important component in the treatment of breast cancer 7 .
Neoadjuvant chemotherapy has become the standard in the management of locally advanced breast cancer and is the therapy of choice in operable early-stage breast cancer. Neoadjuvant chemotherapy has many advantages in the management of breast cancer, including providing a better surgical option and being able to assess chemotherapy response [7][8] .
Neoadjuvant therapy in stage III B breast carcinoma patients aims to increase disease free survival, reduce the risk of relapse and reduce mortality. The advancement of neoadjuvant therapy causes the mortality rate to decrease sharply, but the incidence of relapse is still quite common 9 . Research conducted by Gunter et al in Germany stated that the recurrence rate was 39.5% and the mortality rate was 23.6% of the 667 patients observed for 5 years10. Relapse incidence is often associated with an increased risk of death regardless of type of treatment 11 .
The 2009 St Gallen Consensus stated that Ki67 could be a potential biomarker for prognosis and chemotherapy indicators in advanced breast cancer. 12 The St Gallen Consensus in 2011 and 2013 concluded that research in the last 32 years of Ki67 has been widely evaluated as a prognostic and / or predictive marker. breast cancer and other types of tumors. Ki67 has been suggested to be a biomarker for the definition of luminal A and luminal B in tumors. [13][14][15] However, cancer biomarkers are still not completely integrated in clinical decision making and the International Ki67 in Breast Cancer Working Group in 2011 reported that no cut of point was found ideal in clinical practice for the Ki67 value as a breast cancer Biomarker 2 .
Ki67 is an antigen that is closely related to the cell cycle and mitosis, so the percentage of Ki67 represents the proliferative fraction of cancer. 11 Where Ki67 is expressed in all phases of the cell cycle except G0 and at the peak of phase M, so it is very appropriate to be used as a tumor proliferation biomarker. 11 In breast cancer those with high risk have higher Ki67 expression, so they will have a worse prognosis when compared to tumors that give a lower image of Ki67 expression. 16 18 . In the second setting, the study was about predictive evaluation of survival in response to neoadjuvant therapy. In this case, the role of Ki67 as a chemotherapy response versus no chemotherapy has been observed and there is a significant relationship with a strong correlation between the role of Ki67 as a biomarker and survival evaluation in response to neoadjuvant and adjuvant therapy [18][19] . Therefore, in contrast to the neoadjuvant situation, the predictive role for Ki67 may not necessarily be established in adjuvant chemotherapy trials. 20 Fasching et al in their study showed that it is impossible to determine the best cut off point for Ki67, because the cut off point for each breast cancer subtype is different. In his research, Fasching used a cut off point of Ki67 > 13%, obtained Ki67 as an independent predictor for pathological complete response (pCR) (OR 3.5; 95% CI, 1,4, 10.1) and for overall survival (HR 8.1; 95%). CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9) 21 .

Methods
This study is an observational analysis study with a prognostic test design. The prognostic test is a study that aims to make the best model that can estimate the output value or the likelihood of output or the possibility of a subject with certain characteristics in the future. In this study a prognostic test was carried out to determine the relationship between Ki67 levels and the prognosis of stage III B breast cancer patients underwent neoadjuvant chemotherapy at Dr. Hospital. Mohammad Hoesin Palembang The subjects of this study were patients with locally advanced breast cancer who received neo-adjuvant chemotherapy at Dr. Muhammad Hoesin Palembang General Hospital who met the inclusion criteria.
The inclusion criteria were patients with stage III B breast cancer who have undergone surgery following neoadjuvant chemotherapy. The exclusion criteria were patients without available ki67 staining in the surgical specimen after neoadjuvant chemotherapy.
There were 30 subjects in this study. The independent variables were age and Ki-67 levels post neoadjuvant chemotherapy. The dependent variable was disease free survival. The confounding variables were ER, PR, Her2 receptors, lymph nodes status, histo-pathological grading, adjuvant therapy and obesity The data were analyzed using the Kendall Tau, Wilcoxon, Spearman rho's, Kaplan Meier and Cox Regression methods as well as the ROC analysis to obtain the area under curve (AUC), sensitivity and specificity. The data were presented in tables and flowcharts which will be analyzed univariate, bivariate and multivariate using SPSS 23.

Characteristics distribution
There were 30 patients with stage III B breast cancer and met the inclusion criteria. Examination of Ki67 patients was performed before and after neoadjuvant chemotherapy. Ki67 is divided into low (<14%), medium (14-30%) and high (> 30%). In this study, 10 samples were obtained with Ki67 post chemotherapy neoadjuvant low, medium and high respectively 10 samples (33.3%).
In this study, with the Kendall tau-c and Kendall tau-b tests it was found that there was no

Discussion
In this study, it was found that the majority of breast cancer patients who had Ki67 low levels were > 50 years old, patients with medium Ki67 levels were > 50 years old, while majority patients with Ki67 high levels were ≤ 50 years old, but statistically there was no relationship between age and the level of Ki67

Conclusions
There was a significant correlation between Ki67 post neoadjuvant chemotherapy and disease-free survival on stage III B breast cancer patients. The higher the Ki67 level, the shorter the Disease -Free