Correlation of ER, PR, Her2neu and Ki67 with other Prognostic factors in Breast Carcinoma

Background: In females, breast carcinoma is the most common malignancy accounting for 23% of all malignant tumours. Various predictive and prognostic factors affect tumour progression. In addition to estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor (Her2neu), recently Ki67, a proliferative marker has been recognized as an important predictive and prognostic marker in many studies. The aim of the study was to find the correlation of ER, PR, Her2neu and Ki67 tumour markers with menopausal status, tumour size, histopathological grade, mitotic index, lymphovascular invasion and lymph node metastasis. Methods: The present study was conducted on 50 cases of breast carcinomas. The histopathological grading of the breast carcinoma was done according to the Nottingham modification of the Bloom Richardson grading system. All the cases underwent immunohistochemistry for ER, PR, Her2neu and Ki67 expression. Correlation of ER, PR, Her2neu and Ki67 with various prognostic factors was done. Results: The expression of ER and PR decreased as the grade of the tumour increased. Ki67 proliferative index increased as the grade of the tumour increased. Ki67 proliferative index also increased as the mitotic count increased. None of these markers showed a correlation with other prognostic factors. Conclusion: The present study concludes that ER, PR reveals inverse relationship and Ki67 showed a direct relationship with the grade of the tumour.

Recently Ki67, a proliferative marker has been recognised as an important predictive and prognostic marker in many studies [3]. Independent prognostic factors include the type of tumour, number of involved lymph nodes, size of the tumour, tumour grade and the patient's age [4].

Materials and Methods
Setting-The present study was done in a tertiary     Lymph nodes were recovered in 43 cases out of which metastasis was seen in 27 cases ( Figure 2).
ER, positivity was observed in 46% of cases (23/50) and PR positivity was observed in 30% of cases (15/50). In all of these cases, Her2neu was negative. Amongst the 50 cases, only five cases came out to be positive for Her2neu, seven cases were equivocal with 2+ score and 38cases were negative. The equivocal cases were not subjected to Fluorescent in situ Hybridisation and hence it was taken as negative in the present study. (Table 4, Figure 4 to 6).  Her2neu positive in the present study (Table 6).
There was a significant inverse correlation between Her2neu positivity and ER and PR negativity.  (Table 8).   Tropical Journal of Pathology and Microbiology 2020;6(5) As IDC NOS constituted the bulk of cases (46 cases) with only one case of medullary carcinoma and three cases of colloid carcinomas there was no correlation of histological type of tumour with hormonal receptor status and Ki67 index (Table 9).
In the present study as the grade of the tumour increased the ER and PR negativity increased. This was statistically significant for ER having a 'p' value of 0.021. However, the PR results were statistically insignificant. There was no correlation between Her2neu with tumour grade as all five Her2neu positive cases belonged to grade II. High Ki67 proliferation index significantly correlated with a higher grade of the tumour with 'p' value being 0.000 (Table 10). In the present study, there was not much of a correlation between the nodal status and ER/PR/or Her2neu receptor status. Ki67 expression was high in lymph node metastasis positive cases but statistically insignificant ('p' value -0.984) (Table 11). While comparing lymphovascular invasion there was no significant correlation between the receptor status and Ki67 expression (Table 12). In the present study ER negativity and PR negativity significantly increased with increase in mitotic Index however 'p' value was statistically insignificant for ER status (0.243). But 'p' value was significant for PR status (0.036). There was no correlation with Her2neu and mitotic Index. High Ki67 index (≥ 15%) has significantly correlated with high mitotic index (Table 13). On comparison of Ki67 expression with ER/ PR/ Her2neu, there was no significant correlation seen as high Ki67 expression was seen in both ER/PR positive and negative cases and only five Her2neu positive cases were present in the study (Table 14).

Discussion
Breast cancer is most common among women worldwide, its incidence is expected to increase by 26% by 2020 in developing countries [9]. Similar to the Indian and Western population studies, the mean age of BC is 49.52 (±11.2SD) years and also the incidence of BC is high in postmenopausal patients (54.0%) [10].
Our present study showed estrogen receptor positivity in 23  However, the incidence was higher in western authors when compared to black and Asians, which might be due to inherent biology and low incidence in Indian population may be due to decreased Hormone Replacement Therapy [13].
In the present study, 30% was positive for PR which was closely similar to Kaur

Limitations of the present study
Equivocal cases of Her2neu were not confirmed by FISH due to financial constraints of the patient which has an effect of Her2neu true positivity.

Conclusion
What does the study add to the existing knowledge?
This study shows that the addition of Ki67, a proliferative marker is an important predictive and prognostic marker. Future work should focus on specifications of its role in treatment decisions.

Author's contributions
Dr.Purushotham Reddy: Conceptualized the study, senior author on the manuscript, helped with manuscript construction, data analysis and proofreading.
Dr.Mithraa Devi S: Helped with data collection, analysis, manuscript construction and involved in the submission of the final report.

Reddy P. et al: Correlation of ER, PR, Her2neu and Ki67
The present study concludes that ER, PR reveals inverse relationship and Ki67 showed a direct relationship with the grade of the tumour.

Increased
Ki67 proliferative index was associated with increased mitotic activity and less expression of ER, PR; thus carrying a poor prognosis and requires treatment accordingly.  [Crossref] Tropical Journal of Pathology and Microbiology 2020;6(5)