Overall Survival for Stage III Breast Cancer Patients at DR. Mohammad Hoesin General Hospital Palembang and the Influencing Factors
Raehan Satya Deanasa
1*, Mulawan Umar
2, Agita Diora Fitri
31 Medical Undergradute, Faculty of Medicine, Sriwijaya University, Palembang, Indonesia
2 Surgery Department, Faculty of Medicine, Sriwijaya University, Palembang, Indonesia
3 Public Health Department, Faculty of Medicine, Sriwijaya University, Palembang, Indonesia
*Corresponding author:
Raehan Satya Deanasa Medical Undergradute, Faculty of Medicine, Sriwijaya University, Palembang, Indonesia
raehansatyad@gmail.com
INTRODUCTION
Based on a recent report from GLOBOCAN, breast cancer still affected women more than any cancer in 2020 [1]. Breast cancer is a major problem for public health in Indonesia with an age-standardized incidence (ASR) of 44.0 and the highest mortality rate of 15.3 ASR [2]. Thus, breast cancer is considered a deadly cancer group in women due to the high incidence and death. Regardless of advances in medicine, frequent findings of an advanced stage of breast cancer diagnosis in resource-limited (developing) countries due to poor early detection, diagnosis, and treatment cannot be promoted efficiently [3]. The problem of cancer in Indonesia is, among others, almost 70% of patients with this disease are found in an advanced stage [4,5].
Previous studies have shown various patient survival across Indonesia as one of the indicators of breast cancer therapy outcomes [6–8]. Based on global surveillance, 5-year survival of breast cancer patients in Indonesia is still lower compared to high-income countries, ranging from 80% to 90% for all stages [9]. In limited-resource countries, with survival ranging from 50% to 60%, the patient usually comes to the hospital in advanced stages [6,10]. Several studies justify the prognostic and clinical factors associated with overall survival, but there was still limited study to observe the determinant from a sociodemographic perspective [11–13].
Overall survival of breast cancer has been linked to numerous factors. The patient’s survival is related to several clinicopathological factors, including tumor size, clinical stage, metastasis history, histological grade, and A R T I C L E I N F O
Received : 26 January 2022 Reviewed : 02 March 2022 Accepted : 12 April 2022 Keywords:
advanced breast cancer, chemotherapy, overall survival, stage
A B S T R A C T
Background: There is still a limited number of studies related to overall survival in breast cancer patients in Indonesia. This study determines the overall survival and the factor which can affect the survival of stage III breast cancer patients.
Methods: This study was a retrospective study. Patients first diagnosed with stage III breast cancer from January 1 to August 31, 2018, at DR. Mohammad Hoesin General Hospital Palembang had been studied. The primary outcome of this study was overall survival. The sociodemographic, clinicopathology, and treatment factors were analyzed to identify the independent variables associated with overall survival using Kaplan-Meier and Cox proportional hazard regression.
Results: In this study, 78 samples were included. The 3-year overall survival for stage III breast cancer was 71%. In the bivariate analysis, several factors including older age (> 40) (HR = 2.795, 95% CI 1.223–6.387), higher stages for IIIB (HR = 7.155, 95% CI 0.960–53.334), and IIIC (HR = (HR
= 33.450, 95% CI 3.013-371.354), history of not undergoing surgical intervention (HR = 3.999, 95% CI 1.684–9.495), and adjuvant chemotherapy (HR = 2.768, 95% CI 1.211–6.327) have been associated significantly to lower overall survival. Multivariate analysis showed IIIC breast cancer stage as an independent factor and had a significantly increased probability of mortality (HR = 14.677, 95% CI 1.268–169.948).
Conclusions: The stage at diagnosis was the only significant predictor for the survival outcome, indicating that early diagnosis may need more attention.
type [11–13]. The differences in treatment modality based on the clinical and tumor characteristics as well as the expression of hormone receptors may result in different survival [14–16]. Sociodemographic status, including age, education, marital status, and family history is known to be an influencing factor for breast cancer survival [7,17–20].
The high incidence of advanced stage and mortality in breast cancer in Indonesia is due to the lack of a screening program and poor access to or the availability of treatment [4,5]. The visit of patients with advanced- stage breast cancer, specifically stage III, in Palembang was relatively high at 64% [10]. Considering the stage III breast cancer patients’ visits and the unknown survival rate of breast cancer at a local hospital in Palembang, the study aims to know the overall survival rate of stage III breast cancer patients and the influencing factors of breast cancer at the local hospital in Palembang.
METHODS
Ethical ApprovalThis research was approved by the Ethics Commission of the DR. Mohammad Hoesin General Hospital Palembang (85/kepkrsmh/2021). The data were collected from the medical record installation. The respondents who had incomplete data in medical record installation were contacted and had informed consent. Hence, the respondents have the right to choose and need to know the goals and steps they follow during the study. The well-being, fairness, and life protection of research subjects were maintained by weighing the risks and steps of research implementation. The researcher must guarantee the confidentiality of subject data and privacy.
Participants and Settings
This retrospective study was conducted for people who were first diagnosed with stage III at DR.
Mohammad Hoesin General Hospital Palembang. The data of patients diagnosed with stage III breast cancer based on the American Joint Committee on Cancer (AJCC) 5th edition staging criteria breast cancer from January 1 to August 31, 2018, at DR. Mohammad Hoesin General Hospital Palembang were collected. The cases were excluded if the cases were considered recurrent or the patients had received treatment. The patients were treated according to the standard protocol and followed up by their medical records to assess their survival of three years. Several well-known influencing factors of the overall survival of breast cancer patients were examined, including sociodemographic, clinicopathologic, and medical treatments.
Data Collection
The data were collected from August 1 to November 31, 2021. Details of the patient’s information, specifically,
sociodemographic, clinicopathologic, and treatment characteristics, were extracted from the medical and pathological records from the medical record central unit. The following relevant data were collected, including age, marital status, clinical stage, histological type, and treatment (surgical and chemotherapy). The core family member of the patient was considered as a respondent if the patient had passed away. A semi- structured questionnaire was used to complete data from the medical record. The data were considered missing and dropped out if the authors could not collect the life status data from medical records or had no response from three attempts to contact the patient.
Statistical Analysis
Univariate analyses were performed to find out the patient characteristics which were described as percentages.
The survival time of the patient referred to the number of months from the date the first patient got treatment to the date he died, the date of loss to follow-up, or the date of the end of the study for patients who were still alive. All data were analyzed using SPSS software.
Before analysis, the data were edited, coded, entered, and cleaned. Survival analysis was conducted by checking the assumption of proportional hazards (PH), bi-variable, and multivariable analysis. Kaplan-Meier constructs were conducted to estimate Overall Survival (OS) rates and to determine the PH assumption. Multivariable analysis was performed to calculate the adjusted hazard ratios of the OS. All variables with p < 0.25 on bivariable analysis and fulfilling PH assumption were then entered into the multivariable analysis.
RESULTS
A total number of 83 eligible female patients with breast cancer were recruited (Figure 1). Eighty-three patients (24.2%) were known to be eligible for the inclusion and exclusion criteria. The remaining 260 patients (68.4%) were excluded due to the limitation of the data about the clinical stage, and some cases were considered recurrent cases which were referred to DR. Mohammad Hoesin General Hospital Palembang. Seventy-eight patients (31.6%) were known about their survival status after being followed up three years after their first treatment, and 5 patients dropped out due to unknown survival status. Death was reported for 23 patients (29.5%), and 55 patients (70.5%) were reported as still being alive.
Sociodemographic, clinicopathological, and treatment characteristics for stage III are shown in Table 1. As many as 59 (75.6%) patients were aged > 40 years and married (71, 91%). Most of the patients came to the oncology department with an advanced stage of disease at the time of diagnosis, with stage IIIB (58, 74.4%) and IIIC (2, 2.6%) breast cancer. Based on the histological type, invasive ductal carcinoma (60, 76.9%) is represented
Table 1. Sociodemographic, clinicopathologic, and treatment status of respondents
Characteristics Total study population
N %
Age ≤ 40 19 24.4
> 40 59 75.6
Marital Status
Married 71 91.0
Widow 7 9.0
Stage
IIIA 18 23.1
IIIB 58 74.4
IIIC 2 2.6
Histological Type
Invasive ductal carcinoma 60 76.9
Noninvasive ductal carcinoma 18 23.1 Surgical Intervention
Simple mastectomy 7 59.1
Modified radical mastectomy 58 40.9
No surgical intervention 13 15.4
Neoadjuvant Chemotherapy
Yes 26 33.3
No 52 66.7
Adjuvant Chemotherapy
Yes 29 37.2
No 49 62.8
Abbreviations: N, number of patients
Table 2. 3-year overall survival of the respondents based on their characteristics
Characteristics 3-years OS
% p
Age ≤ 40 47 0.010
> 40 78
Marital Status
Married 70 0.882
Widow 71
Stage
IIIA 94
0.002
IIIB 66
IIIC 0
Histological Type
Invasive ductal carcinoma 63 0.016
Noninvasive ductal carcinoma 94 Mastectomy
Yes 77 0.001
No 38
Neoadjuvant Chemotherapy1
Yes 100 0.535
No 92
Neoadjuvant Chemotherapy2
Yes 64 0.803
No 62
Adjuvant Chemotherapy
Yes 80 0.011
No 55
Abbreviations: N, number of patients; OS, overall survival
1 Neoadjuvant chemotherapy intervention for stage IIIA
2 Neoadjuvant chemotherapy intervention for stage IIIB and IIIC Figure 1. Consort diagram
in most cases. As many as 58 patients (75.6%) underwent a modified radical mastectomy. The regiment of chemotherapy was stratified by cancer stage into stage IIIA and stage IIIB-IIIC because most of the patients with stage IIIA breast cancer did not receive neoadjuvant chemotherapy (13, 72.2%) and underwent surgical intervention, respectively for stage IIIB-IIIC (13, 21.7%).
In stage IIIA, most of the patients received adjuvant chemotherapy (12, 66.7%). The overall survival rates of stage III breast cancer for one and three years, respectively, are 85% and 71%.
Patients aged ≤ 40 years, who were present with advanced cancer stage, had not undergone surgery and received adjuvant chemotherapy significantly associated with worse 3-year survival than their counterparts. Based on the demographic characteristic (Table 2), 3-year overall survival for patients who were aged ≤ 40 years was 47% vs 78% (p = 0.010). Cancer stages were inversely associated with the 3-year overall survival for
stage IIIA (94%), stage IIIB (66%), and stage IIIC (0%) (p = 0.002). Invasive ductal carcinoma represents worse overall survival compared to non-invasive ductal carcinoma (63% vs 94%, p = 0.016). The patient who underwent mastectomy had better overall survival than those who had not (77% vs 38%, p = 0.001). The 3-year overall survival among those who had adjuvant chemotherapy is 80% vs 55% (p = 0.011). Of note, in this study, neoadjuvant chemotherapy did not contribute significantly to the overall survival of the patient either in stage IIIA or stage IIIB-IIIC. Figure 2 shows Kaplan- Meier curves for overall survival, respectively, by demographic, clinical, and treatment characteristics. Stage, histological type, surgical intervention, and adjuvant chemotherapy were known to fulfill PH assumptions.
Table 2 provides crude and adjusted hazard ratios for all variables. The crude hazard ratio of patients who were aged ≤ 40 years was worse compared to > 40 years (HR = 2.795, 95% CI = 1.223–6.387). Cancer stages
I
p = 0.010
p = 0.002
II
p = 0.016
III
p = 0.001 p = 0.011
Figure 2.
Kaplan-Meier survival probability by demographic (I), clinicopathologic (II), and treatment (III) characteristic breast cancer patients.
were inversely associated with the overall survival hazard significantly for stage IIIB (HR = 7.155, 95% CI = 0.960–
53.334) and stage IIIC (HR = 33.450, 95% CI = 3.013–
371.354). The patient who did not undergo surgical treatment had poor survival probability (HR = 3.999, 95% CI = 1.684–9.495). Chemotherapy only had a significantly high survival outcome for the patient who had adjuvant chemotherapy compared to patients who had not (HR = 2.768, 95% CI = 1.211–6.327). In the multivariable analyses, the combination of several variables which fulfilled PH assumption and had p < 0.25 (cancer stage, histological type, surgical intervention, and adjuvant chemotherapy) was used. As shown in the Table 3, that the IIIC breast cancer stage was an independent factor and significantly increased the probability of mortality (HR = 14.677 95% CI = 1.268–
169.948). Nevertheless, the limited stage IIIC patient may impact the result of wide CI; thus, the conclusion cannot provide a precise representation of the population mean.
DISCUSSION
The data on the overall survival of breast cancer patients in Indonesia is still limited. In Southeast Asia, the 5-year OS rates in Malaysia and Singapore are 52%
and 66%, respectively, which is lower compared to the high-income country ranging between 70–83% [21,22].
This study found that the 3-year survival for stage III breast cancer is 71% which is like the other study conducted in Indonesia. Recently, the annual report of a cancer center hospital in Indonesia mentioned that the 1- and 3-year survival rates for stage III breast cancer in Dharmais Cancer Hospital were 84.8% and 65%,
respectively [6]. Conversely, this rate was lower compared to the Iraq Hospital which studied patients with breast cancer, 44.1% of whom were in advanced tumor stages (III and IV), and the overall observed three- year survival of 83.3% [23]. Variation in survival rates may be influenced by the inadequate quality of health facilities and the lack of implementation of the four key components (cancer prevention, early detection, diagnosis, and treatment with palliation) to control cancer in developing and developed countries [23,24].
Many factors could influence the survival of breast cancer patients, such as demographics, clinicopathologic, and the treatment obtained by the patients. In bi- variable analysis, this study suggests that age, cancer stage, histological type, surgical intervention, and Adjuvant Chemotherapy (ACT) were significantly associated with overall survival. Younger women (≤ 40 years) described in genomic analysis by Anders et al.
may have a larger tumor size of higher grades, have more positive lymph nodes, and tend to be more susceptible to being hormone receptor-negative [25].
Of note, several retrospective studies have reported that younger age is an independent predictor of lower survival in breast cancer patients [7,26].
Our study found that marital status had no association with survival although, theoretically, patients who were married would get mental and financial support; thus, diagnosis and appropriate treatment would be performed earlier [27,28]. This theory justified by Hinyard et al. [29] observed that unmarried women were 1.18 times (95% CI 1.15–1.20) more likely to be diagnosed at a later stage than married women across all AJCC stages.
Table 3. Bivariable and multivariable analysis
Demographic variables Crude Hazard Ratio Adjusted Hazard Ratio
CHR 95% CI
(min-max) p AHR 95% CI
(min-max) p
Age > 40 2.795 1.223-6.387 0.015
Marital Status
Widow 0.896 0.210-3.829 0.883
Stage IIIB
IIIC 7.155
33.450 0.960-53.334
3.013-371.354 0.004
0.055 5.802
14.677 0.775-43.564
1.268-169.948 0.087 0.032 Histological Type
Noninvasive ductal carcinoma 0.126 0.017-0.936 0.043 0.195 0.026-1.481 0.114
Surgical Intervention
No 3.999 1.684-9.495 0.002
Neoadjuvant Chemotherapy
No 0.680 0.268-1.726 0.417
Adjuvant Chemotherapy
No 2.768 1.211-6.327 0.016 2.133 0.899-5.058 0.086
Abbreviations: CHR, Crude Hazard Ratio; AHR, Adjusted Hazard Ratio; CI, confidence interval.
Based on the clinicopathologic characteristic, the cancer stage had a significant inversely associated with survival, but the limited stage IIIC patients may not provide a precise representation of the population mean.
The limited study is known to observe survival for each stage IIIA, IIIB, and IIIC. Mursyidah et al. [30] observed that the 5-year overall survival for stage IIIA, IIIB, and IIIC, respectively, were 71.4%, 53.8%, and 50%. The problem of inadequate local healthcare providers, therapeutic facilities, and accessibility to healthcare centers in Indonesia may explain the high number of advanced-stage (IIIB-IIIC) patients which may lower the overall survival in this study [6,10,24]. Some patients, especially stage IIIB-IIIC, did not regularly come to the hospital after receiving surgery to receive adjuvant chemotherapy. Accordingly, a previous study highlighted the importance of joining the complete procedural cancer medication and intervention; thus, longer life expectations can be achieved [31].
Similarly, invasive ductal carcinoma may indicate poor prognostic outcomes although this study compared noninvasive ductal carcinoma which had many varieties of histological types, specifically, invasive lobular carcinoma, invasive micropapillary carcinoma, medullary carcinoma, metaplastic carcinoma, ductal carcinoma in situ (DCIS), and pleomorphic sarcoma [32]. Invasive ductal carcinoma was noted to have higher mortality and survival rate compared to noninvasive ductal carcinoma [33,34].
Lobular tumors are likely to be hormone receptor-positive and are more likely candidates for hormonal treatment which reduces the mortality rate [33].
This study suggests that surgical intervention and ACT would improve overall survival. Neoadjuvant Chemotherapy (NACT) and ACT had been observed to improve survival among patients. It had been observed that recurrency frequently occurred in patients who undertook only NACT than ACT [31]. Supporting those findings, our study found that NACT is not significant to improve survival among stage III patients compared to ACT. Accordingly, patients with high-grade, hormone receptor-negative tumors were most likely to achieve a complete clinical response after having an ACT regimen;
thus, the complete procedure of cancer intervention would improve overall survival [16,35]. The limited number of subjects and characteristic differences of stage III breast cancer patients may explain some disagreement.
Still, we believe no study in local tertiary hospitals in Indonesia provides the data across various variables, specifically demographic, clinicopathologic, and treatment.
CONCLUSIONS
The 3-year OS of stage III breast cancer patients in the local hospital in Palembang was 71%, which is like the survival of patients in other hospitals in developing countries. Among many prognostic factors, the stage
at diagnosis was the only significant predictor for the survival outcome, indicating that early diagnosis by screening may need more attention and more aggressive treatment compared to the advanced stages. This also demands further studies to explore the risk factors in the local population, in particular all stages.
DECLARATIONS
Ethics ApprovalThis research was approved by the Ethics Commission of the RSUP DR. Mohammad Hoesin Palembang (85/
kepkrsmh/2021).
Competing of Interest
The authors declare no competing interest in this study Acknowledgment
None.
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