Clinicopathological Characteristics and Survival of Triple-Negative Breast Cancer Patients : A Single Institution Study from Egypt

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is characterized by being more aggressive, presentation in younger age, and higher response rate to chemotherapy. It is more likely to recur and to metastasize early. Methods: Retrospective review of the medical records of TNBC patients treated in a single Egyptian cancer center during a 4-year period. Results: Sixty-five patients were included. Forty-six percent of patients were < 50 years old and 22% had a positive family history. Ten (15%) patients were metastatic at presentation. Modified radical mastectomy was performed in 42% of patients and adjuvant chemotherapy was administered in 55% of them. Relapse occurred in 12 (22%) out of 55 patients who had no distant metastasis at presentation (M0). The overall survival rate of M0 patients at 12, 24 and 36 months was 96%, 91% and 88%; respectively. The disease-free survival rate of M0 patients at 12, 24 and 36 months was 90%, 81% and 71%; respectively. Conclusion: TNBC is an aggressive subtype of breast cancer that occurs at younger age. Frequently, it is of high grade and presents in an advanced stage.


INTRODUCTION
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that tests negative for estrogen receptors (ER), progesterone receptors (PR) and Her2 protein which means that the proliferation of this type of cancer is not fueled by the estrogen and progesterone hormones or by the Her2 protein 1 .That is why TNBC does not respond to hormonal therapy or to drugs that target Her2 protein receptors 2 .
Triple-negative breast cancer constitutes about 10-20% of breast cancers 3,4 .It is more aggressive and has a poorer prognosis than other types of breast cancer as studies have shown that TNBC is likely to metastasize early at presentation and to recur after treatment 5 .It tends to present with a higher grade than other subtypes and usually has a basal-like cellular morphology 1 .
Patients with TNBC are more likely to be < 50 years of age and about 70% of them have an inherited BRCA mutation, particularly BRCA1 mutation 6 .
This study describes the clinicopathological characteristics, management, recurrence rate and survival of TNBC patients treated in a single cancer institution in Egypt.

METHODS
This retrospective study included TNBC patients treated at the Kasr Al-Ainy Center of Clinical Oncology and Nuclear Medicine -Cairo University Hospitals in the period from 2011 to 2014.
After obtaining the institutional ethical approval, the medical records of breast cancer patients were reviewed.
Adult (> 18 years of age) females with immunohistochemistry (IHC) negative expression of ER, PR and Her2Neu were included in the study.Those who had Her2Neu +1 or +2 expression by IHC were included after being proved to be negative by Fluorescence in-situ hybridization (FISH) result.
A total of 162 TNBC patients were identified.Only 65 (40.1%) of them were included in the study.The remaining patients were excluded because of loss of records, incomplete documentation or loss to follow up.
The data retrieved included: patients' characteristics (age at diagnosis, menopausal status and family history), tumor characteristics (grade, size, nodal involvement and metastases at presentation), treatment received (surgery, chemotherapy and radiotherapy) and recurrence data (type, site and date) if any.
Data were described in terms of mean ± standard deviation (SD) or frequencies and percentage when appropriate.The mean and median disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method.P value < 0.05 was considered statistically significant.The percentage of patients who underwent modified radical mastectomy (MRM) or breast conservative surgery (BCS) was 79%.Adjuvant chemotherapy was administered in 55.4% of the patients while neoadjuvant chemotherapy was administered in 44.6% of patients.An anthracycline-based chemotherapy regimen was the most commonly regimen used, being administered in 61.5% of patients.Adjuvant radiotherapy was given to 71% of patients.
Relapse occurred in 12 (21.8%)patients out of the 55 who were not metastatic at diagnosis.Bone was the most common site of distant metastasis followed by lung then liver.Only one patient developed brain deposits.
The 12-months OS rate of patients who received neoadjuvant chemotherapy was 84% while it was 97% for those who received adjuvant chemotherapy (p = 0.054) (figure 3).

DISCUSSION
Triple-negative breast cancer is known by its aggressive clinicopathological features.It presents at a younger age with larger tumor size and higher grade and tends to metastasize and recur after treatment 7 .
At our institution, representing a lower-income setting, TNBC represents 10% of all breast cancer cases, which is comparable to most of the studies which reported an incidence ranging from 10% to 20% 4 .
The mean age of TNBC in our study was 49 years, which is similar to many other studies including those from Egypt where a recent study conducted at the Egyptian National Cancer Institute found a similar mean age of 49 years 8 .However, some other studies reported different mean age ranging from 44 to 56 years 5, 7 .
Positive family history was documented in 22% of our patients similar to that reported by Fayaz et al from Kuwait 9 , while Ghosn et al reported a family history in 10% of patients with TNBC in Lebanon 10 .
Invasive duct carcinoma is the predominant histopathology type in our study being presented in 94% of our patients similar to studies done in Singapore [11]  and Japan 11,12 .
Most of the cases in our study were T2 stage (43%) followed by T3 (15%), and grade II (63%) followed by grade III (24%).This is compatible with the aggressive nature of TNBC which is usually of high grade and large tumor size as reported by other studies 13 .
Zhang et al 14 and Dent et al 15 reported a percentage of node positivity among TNBC cases higher than that among our patients.This may be attributed to the small number of patients included in our study.However, Lin et al and other related studies reported that TNBC was less likely to be lymph node positive 16 .
In our study the 1-year OS rate was 84% for patients who received neoadjuvant chemotherapy, which was lower than the 97% rate of those who received adjuvant chemotherapy.This could be attributed to the fact that neoadjuvant chemotherapy is administered to patients presenting with more advanced disease to downstage it.However, difference between the two groups was not statistically significant.It is difficult with the current study design and sample size to come out with a conclusion regarding that issue.
The 5-year OS rate in our study was 88% which is comparable to that reported by a study from China where the 5-year OS rate was 88.5% 17 , and another study from Iran where the 5-year survival was 86.1% 18 .On the other hand, the 5-year OS rates were much lower in other studies.A study from New Zealand reported a 5year OS rate of 72% 19 and another study from Brazil done by Gonçalves et al reported a rate of 62% 20 .This was similar to the 64% rate found by Liedtke et al 21 .The higher 5-year OS rate in our study could be attributed to the earlier stage (T2 and T3) at presentation among our patients.Studies that reported lower 5-year OS rates included patients with more advanced stage, mostly T3 and T4 at presentation.

Conclusion
Triple-negative breast cancer is an aggressive subtype of breast cancer that occurs among younger patients (< 50 years old) and usually presents with large tumor size and high grade.This confirms that the clinicopathogical characteristics of TNBC among Egyptian female patients are more or less similar to that in other regions of the World.To improve the treatment outcome of TNBC, novel therapies are needed, such as the PARP inhibitors and antiandrogens.Patients should be encouraged to be treated in large clinical studies that are well-designed using the newly developed molecularly targeted therapy.

Figure 1 :Figure 2 :Figure 3 :
Figure 1: Kaplan-Meier curves of estimated overall survival according to metastatic status at diagnosis

Table 1 : Patients' characteristics (n= 65)
Table 2 illustrates tumor characteristics and treatment lines received.The most common histopathological type was infiltrating duct carcinoma and approximately one third of patients had grade III tumor.At presentation, almost half the patients had positive lymph nodes and 15% had distant metastases.