Epidemiology, Pattern of Recurrence and Survival in Triple-negative Breast Cancer: A Retrospective Analysis

Breast cancer is the most common cancer diagnosed annually, as per GLOBOCAN 2018 data the incidence and mortality of breast cancer is 11.6% and 6.6% respectively [1]. Breast cancer is the leading cause of cancer-related death among women around the world. Breast cancer is the most frequently observed cancer (14% of the total cases) and it is the leading cause of cancer death (11·1% of the total cases) in India [2]. In India among the females breast cancer is the most common cancer with an incidence of 27.7%. In developing countries, about half the breast cancer cases and 60% of the Abstract


Introduction
Breast cancer is the most common cancer diagnosed annually, as per GLOBOCAN 2018 data the incidence and mortality of breast cancer is 11.6% and 6.6% respectively [1]. Breast cancer is the leading cause of cancer-related death among women around the world. Breast cancer is the most frequently observed cancer (14% of the total cases) and it is the leading cause of cancer death (11·1% of the total cases) in India [2]. In India among the females breast cancer is the most common cancer with an incidence of 27.7%. In developing countries, about half the breast cancer cases and 60% of the (ER-negative; Her2neu-positive) and triple-negative or basal-like (ER-negative; Her2neu-negative) [6][7]. The triple-negative breast cancers (TNBC) are considered as most malignant subtypes as these subtypes are associated with increased tumor size, increased incidence of axillary lymph node involvement and poor prognosis as compared to other subtypes [8,[9][10]. TNBC accounts for approximately 12% to 17% of all invasive breast cancers in Western populations. This study was aimed to investigate the epidemiological characteristics and survival in non-metastatic TNBC presented at a tertiary care center at Kolkata.

Materials and Methods
Data from the medical records of patients attending the department of Radiotherapy at the Institute of Post Graduate Medical Education and Research (IPGME&R), Kolkata were retrieved between January 2014 to August 2018 of non-metastatic TNBC were identified and analyzed after approval from Institutional Ethics Committee. Tumors with IHC of ER, PR with expression ≤1% and a score of 0 or +1 for Her2neu considered as TNBC. IHC for Her2neu having a score of +2 were considered for fluorescence in situ hybridization (FISH) and those with FISH negative for Her2neu also considered as Her2neu negative. IHC done on formalin-fixed paraffin-embedded sections by polymer horseradish peroxidase technique. Patients with TNBCs classified histopathologically according to WHO classification [11]. Histological grade of tumors was determined using Nottingham histological score [12]. All the patients were staged according to the American Joint Committee on Cancer (AJCC TNM) 7th edition. Patients with stage I, IIA and a subset of IIB (T2N1M0) considered as early breast cancer (EBC) while a subset of stage IIB (T3N0M0), IIIA, IIIB and IIIC as locally advanced breast cancer (LABC). The morphological parameters analyzed were tumor size, histological type, histological grade, Lymphovascular invasion (LVI), perineural invasion (PNI), number of involved lymph nodes, total number of lymph nodes in the specimen and lymph node ratio (ratio of involved lymph nodes to the total number of lymph nodes in the post-operative specimen). The information was entered into pre-designed Performa followed by analysis of epidemiological characteristics, survival and their correlations. Disease-free survival (DFS) was defined from the start of primary therapy to the date of disease recurrence, or last follow-up. Overall survival (OS) was defined as the time from the date of the start of primary therapy to date of death or the last follow-up.

Statistical analysis
Statistical evaluation was done using SPSS version 25. Baseline demographic and tumor characteristics of TNBC were analyzed. Univariate analysis of prognostic factors was done using the Log Rank test. Co-relation between tumor size and lymph node involvement, upfront surgery and recurrence rates, lymph node status and type of recurrence, and relapses were analyzed. Chi-square test was done to assess the statistical significance of these correlations. Survival estimation was done using the Kaplan Meier method. Multivariate analyses were performed using the Cox regression model. A 'p' value of <0.05 was considered statistically significant.

Results
A total of 457 nonmetastatic breast cancer patients were registered at our institute from January 2014 to August 2018, of which 137 were triple-negative breast cancer (TNBC). This accounted for 29.9% of nonmetastatic breast cancer during this period. 137 patients were eligible for this study as non-metastatic TNBC. The median age at diagnosis was 45 years   27%, 30.7%, 21.2%, 6.6%, and 0.7% respectively. The age group distribution of the patient concern to the stage given in Figure 1 Figure 3A) and OS is represented in (Figure 3B). The 3-year DFS for patients with EBC and LABC was 92.5% and 55.8% respectively (p= < 0.001), the Kaplan-Meier survival curve is represented in Figure 4. In univariate analysis age ≤ 35, stage, nodal status, pathological T status, and pathological N status, have a significant impact on DFS and OS given in the Table 2.

Discussion
TNBC is known for its heterogeneity and early recurrence. One of the important things to consider in TNBC is that the ineffectiveness of the therapies targeted against ER, PR, and Her2neu receptors. Patients expressing these receptors having different therapeutic strategies due to the available number of anti-targeted agents. Therefore, the non-TNBCs have a good prognosis in comparison to TNBC. When TNBCs diagnosed earlier and treated adequately, the survival rates are comparable to non-TNBCs [13]. In this study TNBC accounted for 29.9% of non-metastatic breast cancer. Studies by Indian authors have reported a wide range of TNBCs from 11.8% to 31.9% [14][15]. Sarin et al. reported an incidence of 20%, similarly Chintalapani et al. reported an incidence of 19.3% of TNBC [16][17]. Murtaza et al. reported TNBC incidence in their study as 43.5% [18]. In our study the median age at presentation was 45 years which was similar to other studies as Lakshmaiah et al. and Suresh et al. the median age in their studies were 45 years and 49 years respectively [19][20]. Previous reports have also suggested a younger age at diagnosis in TNBCs (Hudis and Gianni, 2011; Sen et al., 2012). The median age at presentation in the Western population in a study was 53 years [21]. In this study the most commonly involved age group was 41-50 years with 30.7% followed by 31-40 years with 27%. A study by Chowdhary et al. of 185 TNBC patients, almost reported the similar findings [22]. In this study the tumor was right-sided in 49.6% and left-sided in 50.4% at presentation. Doval et al. in their study of 148 patients found 53.45% right-sided and left-sided in 46.6% [23]. In our study the majority of the patient were postmenopausal 53.3% which was similar to that of a study by Chintalapani et [19]. A study by Doval et al. shows postmenopausal patients with 69.9%, which is higher than our study [23]. These studies suggest that the hormonal status of the patient in the postmenopausal state may have a role in the tumor growth or angiogenesis (Demicheli et al., 2004). In this study most of the patients (75.2%) underwent upfront surgical intervention and the rest of 24.8% were considered for NACT followed by surgical intervention. In this study MRM was the main surgical intervention followed by BCS similar reports were also found in other Indian studies [17,. The type of surgical procedure depends on the extent of the presenting disease, patient's preference, and access to tertiary health care center. In this study majority of the patient were pathological stage III (56.2%) and grade III (66.4%). Indian literature regarding TNBC also reported similar findings as most of the TNBC presented with stage III [25,. In this study the pathological T2 (37.2%) was the most common finding followed by T3 (34.3%), similar findings were reported by Lakshmaiah [23]. In our study majority (61.3%) of patients presented with node-positive almost similar findings were reported by Lakshmaiah et al. in their study with 63% node-positive. Other Indian studies reported axillary node positivity in their studies from 50% to 74% [27,18,28] while Doval et al. reported 36.8% node-positive in their study [23], which was not consistent with our study. In our study 30.7% of patients were EBC and 69.3% were LABC. A study by Suhani et al. reported 56.1% of patients of TNBC presented as LABC [29]. Most of the Indian studies reported the presentation of LABC from 35% to 60% [18, 26-23-19]. The recurrence rate in this study was 29.2% at the median follow-up of 38 months. In this study the brain was the most common site of recurrence followed by liver and lung in TNBCs. Rathi et al. in their study reported lungs as the most common site of recurrence [28]. The mean DFS and OS were 43. 6 [30]. A study from the USA reported a 3-year RFS of 63% and an OS of 71% [31]. These data reveals wide variability of survival outcomes around the regions of the world. This may be due to stage at presentation and survival analysis without stage IV disease etc. In our study the lower DFS may be due to a higher percentage of patients with LABC compared to other Indian studies on TNBC. The survival was better in EBC compared to LABC. The survival analysis revealed that better DFS and OS are significantly associated with EBC. The patients with EBC were managed with surgical intervention followed by adjuvant systemic chemotherapy and radiotherapy (when indicated) to reduce the risk of recurrence. Those patients presented with LABC, the majority of them were managed with NACT followed by surgery and adjuvant chemotherapy and radiotherapy. Axillary lymph node involvement results in poor DFS and OS which is statistically significant. This node involvement is well known prognostic factor in breast cancer that can predict the recurrence. The result of this study is per other studies (Tian et al. 2008; Ovcaricek et al., 2011). The pathological feature LVI did not influence DFS or OS but PNI was associated with poor DFS and OS with statistical significance. TNBC responds well to anthracycline and taxane-based systemic chemotherapy, which provide good response to treatment, though it may result in early recurrence [32][33].
In conclusion, triple-negative breast cancers constitute a significant proportion of breast cancer which is ERnegative, PR-negative, and Her2neu negative. They are high-grade tumors mostly presented in locally advanced stages and most of the patients are young. Locally advanced TNBCs are clinically more aggressive than early breast cancers. TNBCs are clinically aggressive with high risk of metastasis to visceral organs compared to non-TNBCs. However TNBCs respond well to systemic chemotherapy, thus better and less toxic management options to be considered along with there is also a need for newer targeted therapy. The survival of TNBCs in the Indian scenario is less in comparison to the Western population, probably due to racial factors, socioeconomic factors and health care access facility. The present study has a limitation of selection bias which may be due to retrospective nature.

Financial support and sponsorship
Nil