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A Prospective Observational Study of the Correlation between Hormone Receptor Status and Other Prognostic Factors in Carcinoma Breast in a Rural Set Up in Central India

Raju Gore, Tanweerul Huda, Bharati Pandya*

Department of General Surgery, All India Institute of Medical Sciences, Bhopal, India

Abstract: Breast cancer is a major concern in modern India. The growing population of the patients and the increased death toll require immediate attention from the scientific and medical community. Patients’ age, socio-economic condition, and disease awareness play vital roles in the disease onset and progression. In this study, we have conducted a rigorous survey between 2012 and 2014 and investigated all possible contexts in relevance to the disease. From socio-economic to clinical and histopathological relevance were explored. Detail analysis was done for 112 patients. Our data shows Indian scenario having differences not only in stage at presentation with poorer survival but also that the age at presentation is almost a decade earlier than western studies. Only 8% of the participant patients were found to be nulliparous. Very few patients (11.60%) were found to be linked with the disease hereditarily. Statistical co-relation was found between ER status, PR status, lymph nodes, and age of the patients. Our study has shown similarity with the earlier studies as well as dissimilarity in certain facts. We expect this study will increase the present understanding of breast cancer in India.

Keywords: breast cancer, hormone receptor, rural study, staging, and grading

Received June 05, 2020; Revised July 06, 2020; Accepted July 14, 2020

Citation: Raju Gore, Tanweerul Huda, Bharati Pandya, A Prospective Observational Study of the Correlation between Hormone Receptor Status and Other Prognostic Factors in Carcinoma Breast in a Rural Set Up in Central India. Journal of Cancer Research and Treatment, 8 (2). 15-20. January 2020. doi:10.12691/jcrt-8-2-2

1. Introduction

Cancer as a synonym to death is largely negated by the western data on breast cancer where the survival figures are steadily improving. However, the same is not true for most developing countries due to delayed presentations and inadequate access to cancer care. Globally, breast cancer is known as the most widespread invasive form of cancer in women. Epidemiology of breast cancer has been reported for years which aided in understanding the expansion of the disease worldwide [1,2,3,4]. The WHO based Globocan cancer monitoring and survey analysis suggested that in 2018 alone, 2,088,849 (11.6%) new cases have been reported in all age groups for men and women together [5]. In the same year, the number of the death toll due to breast cancer was reported as 6,26,679, i.e., 6.6% of the total death (9,555,027) caused by cancer. Even though women from developed countries are becoming a victim of this disease regularly but women population of lower and middle-income group countries are also on the rise where detection of the disease and pathological analysis has become a challenge [6]. Along with the loss of human life and suffering, it is becoming economically challenging for the Government to meet the required expenditure [7].

Among Indian women, breast cancer turned out to be the most lethal form of cancer with an average age-adjusted rate of 25.8/100,000 women and calculated mortality of 12.7/100,000 women [8]. The relation of the prognostic factors and impact of each associated factor with the disease is poorly understood so far. A large number of epidemiological, molecular, social, environmental factors are responsible for the disease onset and progress. Age, genetic makeup and genes, economic condition, lifestyle, food habits, cultural beliefs, awareness, frequency of medical checkups are vital to the disease onset and progression [9,10,11,12,13].

Several prognostic factors such as microRNA (mir-24-3p) in the metastasis process of breast cancer and the expression of androgen receptors in triple-negative breast cancer are being explored recently [14,15]. Griffith et al. recently reported the prognostic effect of somatic mutation in ER-positive breast cancers and emphasized on the TP53, NF1, PIK3CA, and PIK3R1 genes as the prognostic drivers irrespective of the clinical variables accounted for a particular case [16]. These sophisticated tests are unfortunately not feasible in rural settings. The degree of correlation with hormonal receptor status, which is rather freely feasible even in remote areas may suggest a critical amendment in the present treatment regime. With this objective, we have attempted to focus on the correlation of these factors in women less than 45 years of age with respect to hormone receptor status (ER/PR). In this study, the correlation of hormone receptor status (ER/PR) with lymph node status and histopathological grading and staging of breast cancer was investigated for the patients under 45 years of age.

2. Materials and Methods

The present study on the hormone receptor status and its correlation with age and important prognostic factors was carried out in the Department of Surgery, (MGIMS, Sevagram, India) from May 2012 to June 2014.

2.1. Inclusion and Exclusion Criteria

All women of all age groups with breast cancer and who have undergone a unilateral mastectomy were included in the study. Patients who received neoadjuvant chemotherapy were not considered in this study.

The patients who did not undergo mastectomy or had undergone a bilateral mastectomy and received neo-adjuvant as part of their chemotherapy were excluded from the study.

2.2. Diagnostic Investigations and Data Collection

All subjects who were part of the study underwent detailed physical and clinical examination and relevant information about them was collected and tabulated. Information on patient’s general health history, past disease history, family history, obstetric history, general and routine physical and clinical examination of lump, specific and local inspection, estimation of palpation, regional information on the lump was collected for each patient. Imaging techniques were made part of the investigation. FNAC report, histopathology report, tumor grade, axillary lymph node status was considered, and stage of the disease was determined using standard TNM staging process. In addition, ER/PR status, primary treatment condition, adjuvant therapy-related information, presence of any further complications due to surgery or chemotherapeutic treatment, and histopathological reports were also observed and documented for this analysis. Documentation of each parameter was done using a detailed proforma. The standard TNM classification system rendered by the International Union against Cancer (UICC), was adapted to determine the stages of cancer in considered patients.

Routine pre-operative investigations were performed. Metastatic work-up was done where necessary. All the patients were subjected to surgery and further chemotherapy, radiotherapy-based treatment, or hormonal therapy depending on the individually determined treatment regime. Detailed histopathological diagnosis along with receptor status was conducted based on the obtained biopsy report. Obtained records were tabulated and analyzed for statistical and clinical significance. Patients were followed up as per the protocol of three-monthly clinical examinations and radiological tests along with metastatic work up yearly.

2.3. Statistical Analysis

Statistical analysis was conducted using the SPSS 26 environment. Continuous variables were represented as mean±SD and the categorical variables were presented as n (%). Chi-square test and Pearson’s correlation analysis was used to find the association between different parameters. Pearson’s correlation analysis was conducted between the ER status, PR status, Lymph node isolated, Lymph node histological parameter, and the histopathological outcome. A p-value of less than 0.05 was considered to be significant.

3. Results

2.1. Patient Enrollment

1,118,615 patients visited the hospital for treatment during the study phase of May 2012 to June 2014 of which 103,916 attended the surgery OPD. Total in-patients were 73,811 of them, 13,812 received treatment from the Department of surgery. The number of all the different malignant patients was 4927 and 2139 patients had surgical malignancy. The total breast cancer patients were 193, the incidence of breast cancer was 9.02 % of the surgical malignancies at our institute.

Table 1. Distribution of the observed and categorized age of the patients and the patient’s age at menarche

2.2. Age of the Patients and Early Menarche

We have observed in this study that 48.21 % of patients were present in the age group 25-45 yrs. (Table 1). The youngest patient was 27 years and the eldest patient was of 72 years. Last decade onwards some studies have reported this trend in the patient age. Our study also supported these recent reports where the mean age observed in our study was 47.20 years. (S.D. ± 10.89 yrs.). Our study suggested that 38 (33.92%) patients achieved menarche at the age of 13 years and 30(26.78%) at the age of 14 years. Only 4 (3.57%) patients reported menarche at the age of 17 years. The mean age of the patients to have menarche was 14.03 years (SD ± 1.18 yrs) (Table 1). Thus, the obtained results are in coordination with global data.

2.3. Parity and Age of the Patients during First Childbirth

We found 9 (8.03%) patients were nulliparous and the majority of the patients (82%) patients had less than two children. Only, 5% of the total patients had more than 4 children, whereas 16% of patients were a mother to 3-4 children. In addition, 21 out of 112 patients had delivered more than 2 children.

Our data had 103 patients; 97 (94.17%) of which had breastfed and only 6 patients (5.82%) did not. Analysis of the menopausal status suggested that 54 patients (48.21%) were premenopausal and 58 (51.78%) patients postmenopausal. The ratio of pre and postmenopausal was 1:0.93. 13 patients (11.60%) in our study had a family history of the disease whereas 99 (88.39%) did not.

2.4. Statistics of Clinical Conditions

Detail clinical investigation of the disease status was done in the patients who were part of the study group. Information on complaint type, specific location, and side of the problem, duration of lump formation, tumor size, involvement of the specific quadrant, clinical condition (palpability), axillary lymph node number, lymph node status for metastasis, procedure followed for biopsy, hormone receptor status, histopathological grading, TNM staging analysis of the samples was intensely documented and investigated following the standard international guidelines. Most of our patients reported the presence of the painless lump (76.78%) whereas only 5.35% complained about a painful lump. In our study population, 11.60% of the patients reported having nipple discharge and 6.25% reported the presence of an ulcer. 42.85 % (48 out of 112) of the patients presented left-sided breast involvement, whereas 57.14 % (64 out of 112) patients had right breast involvement. Interestingly, our report suggested the presence of breast cancer in the right breast for the considered study population, although earlier reports found it to be on the left side. It was observed that the majority of the patients 52 (46.42%) complaint about the existence of the lump for 6 months or more, followed by 3-6 months 41 (36.60 %) and then 3 months 19 (16.96 %). Thus, negligence towards the initial reporting may cause progression and poor outcomes of treatment.

2.5. Analysis of the Tumor-related Information

Probably late reporting of the disease due to lack of awareness led to most of the patients presenting with a tumor size of >5.1 cm (56.25%). Next were the patients who had tumor size between 2.1cm-5cm (37.50%). Only 6.25 % of the total patients had a lump of less than 2 cm in size (also with lymph node involvement) as we did not include early breast cancer in our study. Grading, TNM staging, and diagnosis analysis: Histopathological grading analysis revealed that out of a total of 112 patients, 78(69.64%) were in Grade III and 34 (30.35%) were in Grade II.

Detailed Tumor, Node, Metastasis (TNM) staging was done for all the cases as mentioned in the methodology section. The obtained data suggested that the majority of the patients (65 in number, 58.03%) under consideration were in Stage III (a, b, c), followed by Stage II (42 in number, 37.50%). Patients found in Stage I and Stage IV were only 2 (01.78 %) and 3 (2.67%) respectively. The majority of patients were found in Stage IIIa (37, 33.03%) followed by Stage IIIb (16, 14.28%) and Stage IIIc (12, 10.71%) again suggestive of delayed presentation (Table 2). Confirmatory diagnostic investigation was done through FNAC (88 patients, 78.57%), Core-cut biopsy (12 patients, 10.71%), Frozen section (8 patients, 7.14%) and Excision biopsy (4 patients, 3.57%).

Table 2. Observation outcome of the TNM staging for the study population

2.6. Association of Lymph Node Status with the Disease Condition

On clinical inspection of the lymph nodes, 88 patients (78.57%) were found to have palpable lymph nodes. We found 48.21% (54 patients) of the total patients were having 6-9 axillary lymph nodes followed by more than 10 nodes were found in 40 patients (35.71%). The presence of positive and negative nodes was found to be 73.21% and 26.78% respectively.

2.7. Estimation and Analysis of the ER/PR Receptor Status

Hormonal prognostic factors are especially important in understanding the disease condition and progression. Up and down-regulation of Estrogen and Progesterone hormones and interactivity of their respective receptors, i.e., Estrogen receptor (ER) and Progesterone receptor (PR) are related and have a deep influence in deciding breast cancer treatment modality (Table 3). represents the outcome of the analysis pertaining to the status of ER and PR observed. The maximum number of patients (56 patients, 50%) were found in the ER+ group for the patient category of ≥ 46 years and a similar category of the PR counterpart was having 46 patients (41.07%). The estimated Chi-square values were found to be significant. Thus, most of the patients (72 patients, 64.28%) were found under the ER+/PR+ group in this study, followed by ER+/PR-(17.83%), ER-/PR-(12.5%) and ER-/PR+ (5.35%).

Table 3. Observed Estrogen receptor (ER) and Progesterone receptors (PR) status of the patients and statistical estimation

Table 4. Correlation of hormone receptor status with lymph node positivity for metastasis

Table 5. Relation of hormone receptor status and staging of breast cancer and histopathological grading

Additional analysis of the hormone receptor categories in the patients with relation to lymph node status is presented in Table 4. The outcome depicted that the presence of ER and PR simultaneously also coexisted with lymph nodes in 92.85% of the patients. The absence of ER and PR receptors corresponded with 100% positive lymph nodes. The stage and grade-wise correlation to ER/PR status are shown in Table 5 which confirms a higher stage and grade in patients with absent hormone receptors.

2.8. Correlation Analysis

The probable correlation was investigated for ER and PR with the age of the patient, lymph node status, and histopathological grading. Estimation of the correlation was done by Pearson Correlation and its significance was conducted through a two-tailed test. To improve and confirm the obtained outcome, bootstrap was set to 1000 along with a 95% confidence interval.

Following the study objective, correlation analysis was done between the ER status, PR status, and two important age-related variables, ie., the actual age of the patient and age of the patient at menarche. The patient's age was found to be negatively correlated with the ER and PR status. Age at menarche of the patients also displayed a similar trend for the PR status. However, the relation between ER status and PR status was found to be strongly correlated.

The other analysis was conducted between receptor status (ER and PR), age, and lymph node status which further confirmed the probable relationship between the ER and PR. Correlation analysis of the ER, PR status, and the staging did not show any statistically significant relational information, even though the outcome hinted towards probable positive correlation. The rest of the parameters did not show any correlation. A study with a larger patient population may provide a better outcome.

4. Discussion

Age is an established factor for breast cancer. In the Indian peninsular region, breast cancer was observed in patients over 40 years of age, especially between 45-65 years of age [17]. Socio-economic conditions also played a vital role in this context as younger patients have been reported earlier in the developing Asian countries in comparison to the developed countries [18]. Reports suggest that till menopause, the risk of having breast cancer doubles every 10 years for women [19].

Sandhu et al. surveyed breast cancer occurrence in the North Indian population between 1998 and 2010 and reported that 65.8% of patients were in the age group of 31-50 years [20]. A similar report of the reduced average age of the patient between 30-50 years in the South Indian region has been done by Parmeshwari et al [21]. The decline in the average patient age is a concern. Early menarche is associated with an increased risk of breast cancer in females [22].

Parity and age of the patient during the first childbirth were found to be associated with breast cancer for long. Nulliparity is associated with the breast cancer risk factor [23]. Our reports were found in accordance with the earlier reports by Lodha et.al [24]. They have documented that the lowest number of patients (2.4%) were found nulliparous in the entire study group. Parity and risk of breast cancer are inversely related as per the earlier observations [25].

Analysis of the literature suggests that those mothers who breastfeed the child have almost 33% of lower risk of breast cancer compared to those women who do not breastfeed at all [26]. Menopausal status is another associated issue. In recent studies conducted in the Indian context, Gajalakshmiet al. reported that breastfeeding was found inversely related to breast cancer risk in premenopausal women in India [27]. Recently, Zhou et al. stated that long term breastfeeding is associated with breast cancer risk inversely in their meta-analysis [28].

Therefore, even this small study group showed more than 10% of the patients having genetic linkage for the disease. Recently, Colonna et al. supported the association between family history and breast cancer [29].

Burgess et al. stated a similar reason for delaying initial reporting earlier [30]. Nipple discharge could be an important symptom in this relation as suggested by Richards and colleagues [31].

Busk and Clemmesen, described long back regarding the frequencies of the presence of breast cancer in the left or right side [32]. Another study by Garfinkel et al. proposed that breast cancer in women is predominant in the left breast compared to the right side [33].

Among the most prognostic indicators, tumor size and axillary lymph node involvement are most important [34]. Tumor size and positive lymph node involvement are directly related.

Veronesi et al. reported that out of 1446 cases of breast cancer 839 were having metastasis in the axilla with level one lymph node involvement in the majority [35]. Thus, it can be stated that the spread of breast cancer patterns often affects axillary lymph nodes, progressing to the first level initially and subsequently damaging the second and third levels. Axillary lymph nodes frequency and the patterns of lymph node involvement have been rigorously studied earlier [36,37].

From a prognostic point of view, a number of positive lymph nodes are of immense significance [38]. An excellent study has established that higher the number of negative lymph nodes, better the survival chance for the patient after invasive surgical treatment [39]. The lymph node ratio (LNR) also proved to be a better predictor of survival in breast cancer patients compared to the pN classification technique [40]. Therefore, an increased number of negative lymph nodes favorably affect the survival of these patients.

Research reports have outlined that ER influences the expression of PR genes [41]. ER and PR expression are higher in premalignant and lower in malignant lesions in comparison to the neighboring healthy tissues [42]. Therefore, ER and PR levels are used as a prognostic indicator for the clinical purpose to understand the course of the disease and assess the adjuvant hormonal therapy response.

Further, the clinical and molecular investigation revealed that ER+/PR+ patients respond well and survive longer than ER-/PR- patients. Individually, ER or PR is not sufficient to act as an excellent prognostic factor, thus, a combination of both are used to solve the purpose. In breast cancer, ER+/PR+ was found to be associated with parity, age at menarche, age at first childbirth, BMI, and waist-hip ratio. We have reported that the Estrogen receptor, tumor staging, axillary node metastasis, and histopathological grading are related to each other in many aspects. An earlier study also supported such an outcome [43].

5. Conclusion

The present study was focused on the understanding of the epidemiological, social, clinical, histopathological parameters, and their probable correlations. Detailed clinical investigation and histological analysis provide ample vital information. Several patients (48%) fall in the age group of 25-45 years which shows a trend towards affliction amongst the younger population. Sophisticated tests are unfortunately not feasible in rural settings. So, the degree of correlation with hormonal receptor status was utilized and found to be associated with lymph node status and histopathological grading and staging of breast cancer for patients under 45 years of age. This could suggest a critical amendment in the present treatment regime. We believe this study will help future breast cancer related epidemiological studies in India and will serve as a knowledge resource.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Funding Statement

The authors haven't received any funding from any external or internal source.

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