Expression of Hormone Receptor and Human Epidermal Growth Factor Receptor (HER2/neu) Status of Breast Carcinoma and Their Correlation with Clinico-Pathological Parameters

To investigate, the expression profiling of ER, PgR and HER2/neu in breast cancer cases of tertiary care hospital and to correlate the hormone receptors and HER2/neu expression with clinico-pathological parameters...

In this context, it becomes highly relevant to investigate tumor biology in our population in order to devise appropriate diagnostic, therapeutic and prognostic approaches.

Strengths and limitations of Study
Our study suggests, that in Pakistan, there is increase frequency of triple negative breast cancer which demands correlation with more parameters for predicting early prognosis and decision the strategic plan for further treatment option. b) One of the limitations is we did not use Fluorescence hybridization in situ (FISH) assay in order to further re-evaluate HER 2/neu (+2 equivocal cases), due to budget/ resources and time constrain.

c)
All cases are of invasive ducal carcinoma, a subtype of breast cancer, other subtypes are excluded in the study.

Introduction
Breast cancer is the second most common cancer amongst all cancers and fifth major cause of cancer associated deaths globally [1].  [4,5]. For example, contrary to the Western countries where breast cancer is common in 60-70 years of age, in Pakistan it is more common in a younger age group (mean age of breast cancer diagnosis is 40-50 years) [5,6]. Moreover, expression patterns of estrogen receptor (ER), progesterone receptor (PgR) and HER2/ neu differs substantially in different ethnic groups across the world [7,8]. In this context, it becomes highly relevant to investigate tumor biology in various ethnic populations in order to devise appropriate diagnostic, therapeutic and prognostic approaches.
A major challenge while classifying breast tumors is to adapt such a classification system that accurately predicts/depicts patient's prognosis. In this attempt, various prognostic factors have been used that anticipate the outcome of patient in absence of systemic therapy, estimate the outcome of systemic therapy and also act as predictive factors [9]. This includes the more conventionally used tumor grading system [10,11] and a relatively neoteric algorithm, the Nottingham Prognostic Index (NPI), which is calculated using tumor grade, tumor size and lymph node metastasis [12][13][14]. More recently, expression patterns of ER, PgR and HER2/neu expression is also detrimental in starting the anti-Her2 therapy (Herceptin).
Expression of ER and PgR denotes a favorable prognosis while HER 2/neu expression is considered as a marker of tumor aggression [11,17]. The worst prognostic group however is triple negative/ basal like (ER-, PgR-, Her2/neu-) breast tumors, which accounts for 15% of breast tumors globally [18]. Data regarding expression patterns of ER, PgR and HER2/neu in breast cancer from Pakistani patients is scanty and therefore demands active investigation. In this study, breast cancer patients were investigated for various clinico-pathological parameters as well as ER, PgR and HER 2/neu expression status.

Patient and Public Involvement:
No Patients were involved in the study. The study was conducted on histopathology tissue blocks of the cases and the results for ER, PgR and HER2/neu was informed to the patients through histopathological reports.

ER, PgR and HER2/neu Expression in Breast Cancers
Of the 104 cancers that we investigated, a total of 27 (25%) were

Correlation of ER, PgR and Her2 expression with clinic-pathological parameters and NPI scores
Expression of ER and PgR correlated significantly with tumor grades (

Discussion
Breast tumor is the most common malignancy in females and its prognosis depends on many clinic pathologic parameters like age, histologic type, grade, lymph node status, tumor size and receptor status, the last being the most important prognostic marker as it effects the 5 year survival rate, mortality rate and disease free survival [19]. Breast cancer biology and the associated clinicopathological features show varied patterns in various parts of the world -probably due to varying genetic and environmental factors [4][5][6]. It is therefore extremely important to investigate breast cancer biology in geographically distinct populations in order to better understand the underlying carcinogenic mechanisms/events and to improvise the currently available diagnostic, therapeutic and prognostic approach. Alarmingly, our data show a total of 27 (25%) patients with triple negative cancers (ER,PgR-, HER2/neu-) and most of these patients were 40-50 years of age. These data are in agreement with the literature which reports increased number of triple negative breast cancers in African patients at younger age compared to the patients in western countries, where 15% of the cancers are triple negative [7,8,[16][17][18][19].
Moreover, data from other Asian countries including China, India, Malaysia and Indonesia, demonstrate that Asian females usually present to the clinics with higher tumor grade compared to the Western world [20,21]. Patients with triple negative and poor prognosis tumors are challenging to manage as there are illdefined therapeutic options available [22,23]. Increased number of triple negative tumors and tumors with poor prognosis (as per the NPI scoring), particularly at an early age, in Pakistani population is therefore an alarming finding that needs to be reported and addressed accordingly. In our study, majority of the low-grade tumors (IDC-I and IDC-II) expressed ER and PgR while majority of the high grade tumors (IDC-III) did not express these receptors.
These findings are in line with the available literature where ER and PgR expression has been linked to a better prognosis (and lower tumor grades). Intriguingly, we did not see any correlation between HER2/neu expression and tumor grades, tumor size and lymph node status. This finding is in stark contrast to several reports where HER2/neu expression has been significantly correlated with tumor size, higher grade and positive LN status [14,24,25].
However, use of IHC in order to assess HER2/neu expression itself is a debatable issue. Therefore, it would have been more confirmatory if these samples could also be investigated using Flourescent insitu hybridization (FISH). Taken together, we highlight alarming findings in breast cancer patients from Pakistan i.e, increased triple negative tumors, patients with poor prognosis at the time of clinical presentation and early onset of breast tumors that demand further investigation.

Key message
Breast cancer is the most common tumor in females globally and ranks as first in our country Pakistan. The diagnosis and prognosis of breast cancer depends on hormone receptor and HER2/neu status. The expression of these receptors and clinic pathologic parameters differ in various ethnic population of world.
In this context, it becomes highly relevant to investigate tumor biology in our population in order to devise appropriate diagnostic, therapeutic and prognostic approaches. Our study suggests that in Pakistan there is increased number of triple negative tumors and most patients present at the time of poor prognosis, so this demands further investigation.

Author contribution
Dr. Bushra Sikandar: Substantial contributions to conception and design, Acquisition of data, analysis and interpretation of data,

Conflicts of Interest
None.

Ethics Approval
Ethics approval was provided by Institutional Review Board.

Provenance and Peer review
Not commissioned.

Data Sharing Statement
There are no additional data available.