The Association of Sociodemographic and Clinicopathological with Survival of Breast Cancer Patients

BACKGROUND The research of breast cancer prognostic factors has been conducted for a long time, but the results are still controversial. The research on demography and clinicopathology factors that determine the survival of breast cancer (BC) patients, remains to be done. METHODS The observational analytic with a cross-sectional design would be conducted to describe the demographic, clinicopathology, therapy, and two years survival of breast cancer patients. The independent variables and the dependent variable were analyzed by univariate and bivariate statistics with a 95% confidence interval. RESULT Most age of breast cancer patients at diagnosis were ≥ 50 years (74.5%). The majority of sociodemographic profiles of BC patients were undergraduate education, have private jobs, and married. The main histological type was invasive ductal carcinoma. More than 50% of the patients were high stage (60.8%) and hormonal receptors molecular subtype (60.7%). Neoadjuvant chemotherapy was given to 40 patients (78.5%), only 9 patients (17.7%) were eligible for anti-HER-2/neu therapy. There were 42 patients (82.4%) have two years of survival. There wasn’t any association between age (p=0.586), Body Mass Index (p=0.617), stage of disease (p=0.587), molecular subtype (p=0.084), tumor size (0.158), lymph node status (p=0.446), metastatic status (p=0.327), grade (p=0.467), therapy (p=0.436) with two years survival of breast cancer patients. CONCLUSIONS The common risk factor of breast cancer is increasing age. Most breast cancer patients present high stage and hormone receptors positive for BC. Although there wasn’t a significant association, the prevalence of low stage BC patients had a higher two years survival. Population education and screening are important for early breast cancer detection to improve the final results of breast cancer patients.


INTRODUCTION
The known breast cancer risk factor studies have been conducted for decades, but still many unanswerable questions about the causal and basic biology of breast cancer. The studies about breast cancer environments as the breast cancer risk factors result in a consensus stamen of personalized early detection and prevention of breast cancer. (1) Risk factors associated with the incidence of breast cancer in women > 50 years are family history and genetic (gene mutation carrier BRCA1, BRCA2, ATM or p53), history of Ductal Carcinoma in Situ (DCIS), Lobular Carcinoma in Situ (LCIS), highdensity breast in mammography examination, early menarche (<12 years) or late menopause (>55 years), reproductive history (have no child and no breastfeeding), obesity, alcohol consumption, chest radiation. (2) The prognosis factors of breast cancer were determined by radiology imaging (size of tumor, multifocality or multicentricity, extensive intraductal components, skin and chest wall involvement, inflammatory breast cancer), pathology examination (histopathologic grade, histopathologic type, lymph node involvement, lymphovascular invasion), biomarkers (estrogen and progesterone receptors, human epidermal growth factor receptor 2, Ki 67), tumor biology (molecular subtype: luminal A, luminal B, HER2enriched and triple-negative), gene expression profile (Oncotype DX, MammaPrint, Endopredict and Prosigna PAM50 that help the prediction of adjuvant therapy responses). (3) Until now, the association of survival of breast cancer patients with predictive and prognostic factors still needs to be investigated in studies with different methods. Although the breast cancer early detection methods have advanced and the finding of breast cancer therapeutic modalities have been implemented and prolonged the survival of breast cancer patients, there are disparities between regions and racial on the patients' survival. (4) Because of the disparities, the studies should be continue to conduct to know the better management of breast cancer diseases from communities to clinical practice in our population. This study aims to analyzed the association between demography and clinicopathology factors that are associated with the two-year survival of breast cancer patients.

METHODS
This study was an analytical observational study with a retrospective cohort design. The data sources were the secondary data from Medical Records (MR) of breast cancer patients, who received treatment from January 2017 to December 2019 at Bethesda Hospital Yogyakarta. This study got ethical clearance from Bethesda Hospital Yogyakarta number 135/KEPK-RSB/ XII/20.
The research samples from consecutive sampling methods met the inclusion and exclusion criteria. The inclusion criteria were all female breast cancer patients recorded in Bethesda Hospital Yogyakarta MR from January 2017 to December 2019, diagnostic approved by cytopathologic or histopathologic results, molecular subtype approved by immunohistochemistry results. The exclusion criteria are patients who transferred to another hospital to get advanced therapy. The demographic data were age (< 50 years and ≥ 50 years), education, job, marriage status. The Clinicopathologic data were Body Mass Index (nonobese < 25 and obese ≥ 25), histopathologic type (ductal type and non-ductal type), stage of diseases (Early Breast Cancer (EBC) (I and II), Local Advance Breast Cancer (LABC) (III ) and Metastatic Breast Cancer (MBC) (IV)), histopathologic grade (I, II, III), breast side (Right, right-left and left), a molecular subtype of tumor (Hormonal receptor positive (luminal A and luminal B), hormonal receptor negative (HER2-neu enriched and triple negative breast cancer (TNBC)). The therapy data was neoadjuvant therapy (NAD) and adjuvant therapy (NAD + hormonal, NAD + trastuzumab, NAD + chemotherapy, hormonal only, trastuzumab only, NAD + radiotherapy). The > 2 years survival data was yes or no. The variables were analyzed by the univariate statistics. The association of predictor variable (age, BMI, stage, tumor size, lymph node status, metastatic status, histopathologic differentiation, molecular subtype, and therapy) and two years survival was analyzed by chi-square or Fisher exact test if independent variables had two categories and one-way Anova or Kruskal-Wallis test if independent variables had more than two categories. The mean of observed months recorded in MR with standard error (SE), confident interval 95% and significancy describe the association between two variables. The analyzing of missing data with expectation maximation. If the missing data is randomly distributed, the data would transform to replace missing value.

Observation of Medical Records from
January 2017 to December 2019 as many as 51 Medical Records were included in the study. We have recorded demographic data, clinicopathologic data, and treatment history. There were missing data because oaf the data not record well in MR. The analyzing of missing data with expectation maximation was Missing Completely at Random (p=0.582). The data frequency of variables is presented in table 1 The mean age of the patients was 54.27 ± 1,479 years, the median age was 53 years ± 10.564. The youngest age was 32 years and the oldest age was 80 years. The percentage of age ≥ 50 years is 74.5%. The majority of sociodemographic profiles of BC patients are undergraduate education, have private jobs, and married. There was the same percentage proportion of Body Mass Index data between non-obese and obese patients. The most common type of breast cancer was invasive ductal carcinoma (76.5%), other types found by the researcher were lobular carcinoma, mucoid carcinoma, ductal carcinoma with part of comedo carcinoma, ductal carcinoma with mucoid carcinoma (21.67%), and malignant phyllodes tumor. The most disease stage was LABC (49%), followed by EBC (39.2%), and MBC (11.8%). Tumors were generally larger than 5cm T3 (29.4%) and T4 (29.4%). Lymph node status was generally positive (58.4%). Metastatic status was generally negative (84.3%). The most histopathological differentiation was poor (51%) followed by moderate (33.3%) and good (2%). The side of the breast affected by cancer is relatively more on the right side (49%  The association between age, BMI, stage of disease, molecular subtype of breast cancer, tumor size, lymph node status, metastatic status, histopathologic grade, and therapy with two years survival was not observed.

DISCUSSION
We tried to describe the demographic, clinicopathological, and therapeutic factors of breast cancer patients through this study. The bivariate analysis the association between clinicopathologic and therapy with two years survival of breast cancer patients was not observed. The socio-demography of breast cancer- of patients' education the higher of disease stage on the first time of diagnosis. (8) Sociodemographic factors including age, educational history, and work history are factors that have been widely studied to affect breast cancer patient survival. Research at the Central General Hospital Dr. Sardjito used data from medical records of breast cancer patients in 2009 regarding age and education history, age <50 years and education history not reaching high school, high cancer stage, large tumor size, and tumor location in the center showed less fiveyear survival rate. (9) Sociodemographic factors associated with breast cancer specific survival and overall survival. The associated factors are age at diagnosis, race/ethnicity, histology, grade, tumor size, number of positive lymph nodes, metastasis, ER/ PR status, surgery, chemotherapy, radiation, marital status, insurance, median household income. The un-associated factors are residence rural or urban, poverty rate, unemployment rate, education level. (10) Research on cancer registration in 9 European countries on 7581 cases of stage I/IIA breast cancer showed that patients were 35% young (15-54 years old), 50% middle age (55-74 years) and 15% old age (> 75 years). In the older age, the Charlson comorbidity index (CCI) ≥2 (severe comorbidity) is increasing. The increase of CCI is related to comorbidities, time of diagnosis until the start of treatment, and the type of therapy given. (11) The increasing age is a common risk factor for breast cancer patients, so it is important and urgent to screening programs for cancer detection as early as possible for familial risk assessment tools using the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, 7-Question Family History Screening Tool, International Breast Cancer Intervention Study instrument (Tyrer-Cuzick), and brief versions of BRCAPRO. (12) The diagnosis of the earliest breast cancer disease through symptoms by breast selfexamination, clinical breast examination, and mammograms are also very important. (13) Younger women under 40 years had unfavorable prognostic parameters of disease than women over 60 years of age. (14) Research on the Surveillance, Epidemiology, and End Results (SEER) data from 1988-2003 showed that young patients < 40 years old compared to older patients > 40 years showed a higher degree of tumor differentiation, many of which were in advanced stages (stages II and III), larger tumor size, more positive lymph node status, more negative ER/PR expression and higher mortality at low disease stage (stage I). (15) The study conducted in Dr. Sardjito Hospital, younger age patients below 40 years are 11.4%, had high frequency of breast cancer with biologically more aggressive tumors, late diagnosis, frequent relapse, and poor prognosis. The finding, quarantine to improve clinical management and meet psychosocial needs in young breast cancer patients. (16) Women under 40 years with axillary lymph node invasion negative and over 80 years had high breast cancer specific mortality. The older women not suitable for surgery and axillary dissection, have not receive treatment according to the guidelines, especially radiotherapy. (17) The therapy given to the elderly early breast cancer patients (≥80 years) is less aggressive than in younger patients although have similar clinicopathology characteristic tumor grade, histology, hormone receptivity) to the younger patients. Radical mastectomy is the more common type of surgery for stage I at older ages without radiation therapy and chemotherapy is associated with poor survival. Breast conservation surgery (BCT), chemotherapy, and radiotherapy are a more common therapy for early-stage younger ages breast cancer patients (67-79 years). (18) The study conducted in RSUP Haji Adam Malik Medan, BMI overweight-obese were more likely to have invasive carcinoma NST subtype and higher grade of breast cancer. (19) Obesity affects the histopathologic profile and survival of BC patients. Obese women more late stage and high grade BC, and obese women with hormone receptors positive more likely to die from cancer compared to normal weight women. (20) The 5-year disease-free survival and overall survival was reduced in overweight and obese patients, and independent predictors for increased risk of breast cancer relapse and death. (21) The study at Hasan Sadikin General Hospital, concluded that molecular subtype of breast cancer important to address the targeted therapy, personalized therapy, and survival of the patients. Luminal A is the most molecular subtype, and followed by HER-2/neu, TNBC and Luminal B. Luminal A and luminal B had average survival longer than HER-2neu and TNBC. (22) Another study had the same results of the association between molecular subtype and five year survival. Patients with luminal A, luminal B, HER-2/neu and TNBC subtypes of breast cancer, the 5-year OS rate were 92.6%, 88.4%, 83.6%, 82.9%. (23) But patient in advanced stage with hormone receptor (HR) positive/ HER-2/neu positive subtype had better survival than HR + /HER-2/neu -. (24) The limitations of this study were the small sample size and incomplete demographic, clinicopathological, and therapeutic data. Characteristic of breast cancer patient study from this research could be used by clinicians and pathologists to analyze the management of breast cancer patients in Bethesda Hospital, and the better laboratory and medical services. Research with larger numbers of samples needs to be done to clarify the role of demography, clinicopathology, and therapy characteristics of the young and older breast cancer patients to survival.

CONCLUSIONS
The common risk factor of breast cancer is increasing age. Most breast cancer patients present high stage and hormone receptors positive of BC.
Although there wasn't a significant association, the prevalence of low stage BC patients and hormone receptor-negative tended to higher two years survival. Population education and BC screening for early detection are urgent for our population to improve the outcome of BC patients.