Comparison of Survival Rate of Triple Negative versus Luminal B HER2 neu-positive Breast Cancer Patients in Oncology Medicine Center in Suez Canal University Hospital

Introduction

Breast cancer (BC), which is considered the most widespread malignancy present in women, exhibits significant heterogeneity. The molecular type of BC is important to guide different treatment modalities and to alter the survival of patients’ treatable stage, breast cancer has a 97% probability of surviving 5 years. However, women’s likelihood of surviving 5 years decreases to 20% once it spreads to other body parts⁽¹⁾. Regarding molecular classification, breast cancer is classified into 4 subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 neu (HER2 neu). Positive expression of ER/PR and/or HER2 neu determines the ER-positive and/or HER2-positive subtype, while the absence of ER, PR, and HER2 neu expression defines triple-negative breast cancer (TNBC), known also as a basal-like subtype⁽²⁾. Both ER-positive and HER2-positive subtypes are routinely and effectively treated with specific targeted therapy. In contrast, TNBCs lack targeted therapy and are still being treated with systemic chemotherapy drugs⁽³⁾. Triple-negative breast cancer (TNBC) accounts for 15%–20% of breast cancer patients⁽⁴⁾. Triple-positive breast cancer (TPBC) is thought that roughly 20% to 25% of breast cancers are HER2-positive⁽⁵⁾. TNBC patients are young-er in age, with increased tumor size, higher recurrence incidence, and metastasis⁽⁶⁾. It tends to be present with more aggressive clinical features and tends to recur earlier, which makes it one of the most aggressive subtypes of breast cancer⁽⁷⁾. TNBC has a higher response rate than luminal but with shorter disease-free survival (DFS) and overall survival (OS). While luminal B HER2 neu-positive breast cancer patient (TPBC) also has higher tumor grade, larger tumor size, and exhibits worse prognosis with a distinct profile of response to hormonal therapy and chemotherapy in view of Her2 neu overexpression⁽⁸⁾. So, this study aimed to identify clinicopathological features and patient survival in a cohort of Egyptian women diagnosed with breast cancer, comparing triple-negative breast cancer (TNBC) with luminal B HER2 neu-positive breast cancer tumors (triple-positive breast cancer -TPBC-), and assess possible associations of the parameters with recurrence and survival.

Patient and Methods

Research design and setting:An analytical, record-based retrospective cohort study was conducted at the Clinical Oncology and Nuclear Medicine Department of Suez Canal University Hospital (SCUH), Ismailia, Egypt. The patients were identified through the department Registry, and data was obtained through a standardized form from the medical records.

Study population:Breast cancer patients, attending the Clinical Oncology and Nuclear Medicine department in Suez Canal University Hospital in the period between January 2010 and December 2018 and fulfilling the Inclusion Criteria. They were stratified into two groups according to the pattern of hormonal receptors then selection of patients from each group as following:Group-A: Triple-negative Breast Cancer (TNBC): Patients with immunohistochemical staining negative for estrogen receptor (ER-), progesterone receptor (PgR-) and Her-2 neu negative and Group-B: Luminal B HER2 neu-positive breast cancer / Triple Positive Breast Cancer (TPBC): Patients with immunohistochemical staining positive for estrogen receptor (ER+), progesterone receptor (PgR+) and Her-2 neu positive.

Inclusion criteria:Age between 18-75 years.Patients who underwent surgical resection either by modified radical mastectomy (MRM) or breast conservative surgery (BCS) and histopathologically proven to have cancer breast. Exclusion criteria:Luminal A patients (ER+, PR+, Her-2 neu -ve).Double pathology patients.Comorbidities such as ischemic heart disease could affect choosing the appropriate protocol.

Sample size

The study sample was selected by simple random sampling from all cancer patients who were diagnosed with cancer breast by pathology and fulfilled the inclusion and exclusion criteria who attended to Clinical Oncology and Nuclear Medicine department of Suez Canal University Hospital from January 2010 to December 2018. A list of the two groups was done then simple random sampling was selected. The sample size was determined using the following equation:⁽⁹⁾

n = Sample size, r = Sample size ratio = 1, Alpha (α): Type 1 error rate = 0.05, Beta (β:) Type 2 error rate = 0.2, P1 = Prevalence of outcome (patient survival) in Non-exposure (Triple negative group) = 0.62 ⁽⁴⁾, RR: Expected Risk Ratio = 0.5 ⁽⁴⁾, Therefore, the calculated sample size was 50 participants per group.

Study variables, and data collection

A list of all eligible patients in the specified period from January 2010 to December 2018 was retrieved from the department Registry. The obtained data included: Background variables: patient age, and chronic illness (diabetes, hypertension, cardiac and renal disease). Independent variables: TNM staging, grade of the tumor, histopathological features, and molecular type. Dependent variables: Disease-free survival (DFS): was defined as the interval between the surgery and recurrence (locoregional recurrence) or metastasis, proven by imaging or pathology⁽⁴⁾.

Results

The present study was designed as a retrospective cohort study that included 100 breast cancer patients, attending the Oncology and Nuclear Medicine department, SCUH in the period from 2010 to 2018. The study included two groups TNBC and TPBC. This study aimed to compare disease-free survival (DFS), and clinicopathological data between the two study groups. Table 1shows that there was no statistically significant difference between patients in TNBC and TPBC regarding age group with about 68% of patients were ≤50 years. Meanwhile, about 34% of total population had different comorbidities, with no statistically significant difference between both groups. Diabetes and hypertension were the most reported comorbidities in both groups. Moreover, table 1 also shows that there is a statistically significant difference between the two groups regarding tumor stage (T) where 74% of TNBC had T2 stage compared to 44% of TPBC (p= 0.003). On the other hand, there was no statistically significant difference between both groups and other staging parameters. Meanwhile, there was no statistically significant difference between the two groups regarding the staging of the disease. The most reported stage in TNBC was IIA (24%) and the most reported stage in TPBC was IIIA (32%). Table 2. shows that there is a statistically significant difference between the two groups regarding histopathological type, ENE, LVI, and PVI. Where 88% of TNBC had invasive duct carcinoma (IDC) compared to 68% of TPBC (p= 0.02), Extra-nodal extension (ENE) where 28% of TNBC were positive compared to 52% of TPBC (p= 0.024), Lymphovascular invasion (LVI) where 12% of TNBC were positive compared to 44% of TPBC (p= 0.001) and Peri-neural invasion (PNI) where no patient (0%) with TNBC was positive compared to 20% of TPBC (p= 0.001). On the other hand, there was no statistically significant difference between both groups and other histopathological variables. Regarding the site of metastasis, 34% had metastasis to different sites, with no statistically significant difference between both groups (p=0.53). The liver was reported as the most common site for 1^st metastasis location (in both groups) followed by bone and lung. Table 4. shows 3-year and 7-year survival analysis for disease progression; (DFS) of TNBC and TPBC patients.

The 3-year cumulative survival rate was 73.5% and 77.5% of patients with TNBC and TPBC, respectively (Figure 1a). Moreover, there was no statistically significant difference (p =0.6) between both groups regarding their 3-year DFS with a mean survival time of 2.63 years for TNBC and 2.78 years for TPBC. Regarding 7-year survival analysis for disease-free survival (DFS) of TNBC and TPBC patients, the cumulative survival rates reach 60.5% in TNBC group and drop to 45% for TPBC group (Figure 1b).

However, there was no statistically significant difference between both groups regarding their mean survival time. Multivariable linear regression analysis was used to assess predictors of disease progression among triple-negative breast cancer patients (TNBC) and (TPBC) (Table 5). It was found that patients without Lympho-vascular invasion (LVI) had significantly 2.624 years higher disease-free survival time than patients with LVI (p=0.007) in TNBC while none of the tested predictors was found to have a significant impact on DFS in TPBC.

Discussion

Breast cancer is a heterogeneous disease, with substantial genotypic and phenotypic diversity. (TNBC) accounts for 15–20% of diagnosed breast tumors, with a higher incidence in young women.

Also, HER-2 protein overexpression is reported in about 15–20% of primary breast carcinomas and is associated with decreased disease-free survival (DFS) and overall survival (OS)^(5,10). In the past, different studies highlighted the difference in clinic-pathological features and prognosis of patients with TNBC and non-TNBC with diverse results⁽⁶⁾. Thus, this study aimed to identify clinical, and pathological features and compare disease-free survival (DFS) of patients with triple-negative breast cancer (TNBC) and triple-positive breast cancer (TPBC) patients attending Oncology and Nuclear Medicine Department, Suez Canal University Hospital which is a regional reference for cancer care. Regarding clinical characteristics, 68% of patients were ≤50 years among both groups. An observational study by Sajid et al. showed that TNBC was noted in 65.88% of patients with age<50 years ⁽¹¹⁾.

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That was similar to a Mouh et al., study that showed both TNBC and non-TNBC cases occur in younger women, with no statistical difference between the two groups. Some results showed that in all ethnic/racial groups, the incidence of TNBC increased among young patients ⁽¹²⁾. For comorbidity, diabetes (26% of the target population) and hypertension (22% of the target population) were the most reported comorbidities in both groups which is similar to the study by Sharma et al., where they reported the incidence of hypertension among BC patients to be 21.8%, and they stated that hypertension is the most prevalent comorbidity associated with BC and similar to a Alzahrani et al. study where half of the patients had co-morbidities and the commonest was hypertension (25.8%) ^(13,14).