|Year : 2021 | Volume
| Issue : 1 | Page : 21-27
Association of body mass index with clinicopathological characteristics and hormone receptor status in breast cancer patients: An observational study
Divya Dahiya1, Maninder Deep Kaur2, Budhi Singh Yadav3, Ashok Kumar1
1 Department of General Surgery, PGIMER, Chandigarh, India
2 National Institute of Nursing Education, PGIMER, Chandigarh, India
3 Department of Radiotherapy & Oncology, PGIMER, Chandigarh, India
|Date of Submission||12-Jan-2021|
|Date of Decision||10-Feb-2021|
|Date of Acceptance||11-Feb-2021|
|Date of Web Publication||23-Jul-2021|
Dr. Budhi Singh Yadav
Department of Radiotherapy & Oncology, PGIMER, Chandigarh
Source of Support: None, Conflict of Interest: None
BACKGROUND: There have been inconsistent results on the association of body mass index (BMI) with tumor characteristics, hormone, and menopausal status in breast cancer (BC) patients.
OBJECTIVE: This study was intended to analyze the association of BMI with menopausal status, tumor characteristics, and hormone receptor status in BC patients. We also analyzed the significance of human epidermal growth factor type 2 receptor (HER-2)/neu status in association with menopausal status, tumor size, tumor grade, and nodal status in patients with BC.
MATERIALS AND METHODS: Histologically proven 188 patients of BC with IHC report were included in this study done over 1 year period. Demographic data, pathologic features, and biological receptor status of cases were collected from the patient's records. Chi-square/Fisher's exact test, independent t- and analysis of variance (ANOVA) test were adopted to explore whether BMI differed according to biological receptor status in pre- and post-menopausal women.
RESULTS: BMI was found to be significantly associated with the menopausal status of patients (P = 0.02). However, BMI lacks significant association with tumor size, stage, grade, and lymph node status in both pre- and post-menopausal patients. Estrogen receptor, progesterone receptor, and HER-2/neu expression were found to have a statistically significant correlation with tumor size (P < 0.001). Statistically significant correlation was also observed between age at the time of diagnosis and HER-2/neu expression (P = 0.02).
CONCLUSION: This study revealed that BMI has a significant association with menopausal status. The frequency of expression of ER/PR was the same as reported in the literature; however, expression of HER-2/neu was high in postmenopausal women. Findings from this study may help to develop patient awareness of potentially modifiable lifestyle risk factors such as overweight and obesity as HER-2/neu positivity is associated with poor prognosis.
Keywords: Body mass index, breast cancer, hormone receptors
|How to cite this article:|
Dahiya D, Kaur MD, Yadav BS, Kumar A. Association of body mass index with clinicopathological characteristics and hormone receptor status in breast cancer patients: An observational study. Ann Oncol Res Ther 2021;1:21-7
|How to cite this URL:|
Dahiya D, Kaur MD, Yadav BS, Kumar A. Association of body mass index with clinicopathological characteristics and hormone receptor status in breast cancer patients: An observational study. Ann Oncol Res Ther [serial online] 2021 [cited 2021 Oct 16];1:21-7. Available from: http://www.aort.com/text.asp?2021/1/1/21/322146
| Introduction|| |
Breast cancer (BC) is the most common cancer affecting women worldwide. The incidence of BC is on the rise in India (25.8%) and at present, it is the most frequently diagnosed cancer in women., Global burden of BC will increase to over 2 million new cases per year by 2030. Essentially, 1 in 10 women has the risk of developing BC during her lifetime.
Obesity is a modifiable risk factor for the development of BC. Obesity is the 5th leading risk of mortality, resulting in around 2.8 million deaths of adults worldwide yearly. In addition, 44% of the diabetes burden, 23% of the cardiovascular disease and between 7% and 41% of cancer burden is attributable to obesity. India has more than 30 million obese people, and the number is increasing rapidly., The problem is more severe among women than men. In urban India, more than 23% of women are either overweight or obese, which is higher than the prevalence among men (20%).
High body mass index (BMI) was found to be positively associated with the risk of developing BC in postmenopausal women, and it has also been found that obese women have a high incidence of metastasis and worse prognosis. Obesity is also associated with resistance to BC treatment. This aggressive nature of tumor may be attributed to higher levels of estrogen released from endogenous estrone from adipose tissue in obese women which in turn also contributes to an increase expression of both estrogen receptor (ER) and progesterone receptor (PR) in BC.,, The expression of ER, PR, and human epidermal growth factor type 2 receptor (HER2 neu) is essential in determining prognosis and treatment in patients with BC.
The aim of this study was to analyze the association of BMI with menopausal status, tumor characteristics, and hormone receptor status in BC patients. Also, to analyze the significance of ER/PR and HER-2/neu status in association with menopausal status, tumor size, tumor grade, and nodal status in patients with BC.
| Materials and Methods|| |
This was a retrospective analysis of BC patients at a tertiary cancer center in North India over 1 year. It included 188 BC patients having histopathology and immunohistochemistry reports. Patient records were analyzed for age, BMI, menopausal status, tumor size, lymph node involvement, tumor grade, and hormone receptor status.
Only women with natural menopause were considered postmenopausal. BMI was calculated by the investigator by using the standard method as weight in kilograms divided by the square of height in meters (Quetelet index). Patients were divided into four groups based on WHO classification for the Asian population. The WHO defines BMI classes as underweight (<18.5 kg/m2), normal (18.5–22.9 kg/m2), overweight (23–24.9 kg/m2), and obese (≥25 kg/m2). A small number of patients (n = 7) were classified as underweight; therefore, the “underweight” and “normal” BMI classes were categorized together as one unit for the purposes of the current analysis.
Tumor characteristics were taken from the pathology report that included tumor size, grade, stage, and lymph node status. Expression status of ER, PR, and HER-2/neu receptor was determined using immunohistochemical methods. The stage of the disease was classified according to the pathological tumor-node-metastasis cancer staging systems of the American Joint Committee on Cancer. The staging was done at the time of treatment after all mandatory staging investigations. The grade of carcinoma was determined based on the Nottingham Combined Histologic Grade system. Accordingly, tumors were classified into Grade I (well-differentiated/low grade), Grade II (moderately differentiated/intermediate grade), and Grade III (poorly differentiated/high grade) carcinomas.
The collected data were analyzed with IBM SPSS (Armonk, NY: IBM Corp) statistical package 22.0 version. Frequency and percentage analysis were used for categorical variables. Mean and standard deviation were used for continuous variables. Pearson Chi-square or Fisher's exact test was used to find out the association of clinicopathological factors with BMI of BC patients. Independent sample t-test was applied to compare mean BMI with hormone receptor subgroups. One-way ANOVA test was used for multiple comparisons of clinico-pathological characteristics of BC patients among BMI groups. In the above statistical methods, a two-tailed P ≤ 0.05 was considered significant with 95% confidence interval.
| Results|| |
Demographic and clinical characteristics of BC patients are shown in [Table 1]. The mean age at diagnosis was 46 ± 9.39 years (range 26–72 years). More than half of the patients (61.2%) were diagnosed between the ages of 41 and 60 years. Majority of patients had attained menopause (either natural or surgical) (80.9%), 63.3% were obese, 25% had advanced disease (stage III/IV), and 53.7% had intermediate grade tumor.
|Table 1: Demographic and clinical characteristics of breast cancer patients (n=188)|
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Association between body mass index and clinicopathological characteristics
Tumor characteristics of the study population classified using BMI are shown in [Table 2]. There was a significant difference in mean age at diagnosis between the different BMI groups (P = 0.04) on one-way ANOVA analysis. Mean age at diagnosis was significantly higher for obese patients as compared to normal and overweight groups (P < 0.001). There was a significant association between BMI and menopausal status (P = 0.028). No statistically significant association was found between BMI and others tumor characteristics.
|Table 2: Body mass index association with clinicopathologic characteristics of breast cancer patients|
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Association of clinicopathological characteristics with body mass index according to menopausal status
The association of clinicopathological characteristics with BMI in premenopausal and postmenopausal groups is shown in [Table 3. There was no significant association of BMI with all clinicopathological characteristics.
|Table 3: Association of clinicopathologic factors with body mass index of breast cancer|
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Co-relation of clinicopathological factors with estrogen receptor/progesterone receptor and human epidermal growth factor type 2 receptor/neu expression
The association between clinic-pathological factors with the immunohistochemical profile is shown in [Table 4]. HER-2/neu expression of tumor between women < 50 years and those > 50 years, age was found to be statistically significant (P = 0.02). Moreover, ER/PR/HER-2 expression of tumor decreased with increase in the tumor size, which was statistically significant (P < 0.001). On comparing tumor grade or nodal status with the receptor status, no statistical significance could be found.
|Table 4: Co-relation of clinicopathological factors with estrogen receptor/progesterone receptor and human epidermal growth factor receptor 2/neu expression|
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Relationship of human epidermal growth factor type 2 receptor/neu expression with estrogen receptor/progesterone receptor status
The relationship between HER-2/neu expression with ER and PR status is shown in [Table 5]. There was a direct relation between HER-2/neu positivity with ER and PR positivity which was significant statistically (P < 0.001).
|Table 5: Relationship of human epidermal growth factor receptor 2 Neu expression with estrogen receptor and progesterone receptor status|
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| Discussion|| |
Obesity in postmenopausal women has been reported to be associated with the development of BC. A clinical trial by women's health initiative on 67,142 postmenopausal women in the age group of 50–79 years at a median follow-up of 13 years showed that obese postmenopausal women were at a greater risk of developing BC as compared with their normal-weight women. In a meta-analysis, Liu et al. found that the risk of BC increases by 2% for each 5 kg/m2 increase in BMI. They also found that higher BMI in premenopausal women decreases the risk of BC in contrast to higher BMI in postmenopausal women. Our study showed that BMI was significantly correlated with BC at the mean age of 46 years at the time of diagnosis (P = 0.04); and also there were more postmenopausal women who were obese (P < 0.001).
In this study, BMI lacked significant association with all clinicopathological characteristics in both pre and postmenopausal patients. We also analyzed the incidence of ER, PR, and HER-2/Neu positivity and correlation of expression of ER, PR, and HER-2/neu with menopausal status. We found high expression of ER, PR, and HER-2/neu in postmenopausal women (80.5%, 82%, and 81%, respectively). There are many studies in the literature where significant expression of ER/PR and HER-2/neu with the menopausal state was shown. Faheem et al., found that postmenopausal women had higher expression of ER (62.2%) and PR (60.1%) than Her2neu (38.9%). Hussein et al., also observed significantly high ER and PR positively stained cells in postmenopausal women. However, Jing et al., reported high PR positivity among postmenopausal Chinese women with elevated BMI (BMI >24 kg/m2). Shieh et al. found that postmenopausal overweight/obese patients who were not taking hormone therapy had a high incidence of ER-positive cancer as compared to premenopausal overweight/obesity women. However, ER PR and HER-2/neu positivity were not significantly associated with the menopausal state (P = 0.71, 0.85, and 0.52, respectively) in this study. There is a growing concept that BMI has an effect on ER-negative and triple-negative BC risk. However, the findings in this study did not support this concept. Furthermore, we found an inverse relationship between HER-2/neu positivity with ER and PR positivity, which was significant statistically (P < 0.001). The results obtained in this study are comparable to those reported worldwide with some exceptions like there was higher expression of HER-2/neu (81%) in postmenopausal women. HER-2/neu is an oncogene that encodes a transmembrane glycoprotein with tyrosine kinase activity and belongs to the epidermal growth factor receptor family. HER-2/neu overexpression serves as a useful predictor of response to trastuzumab therapy. There are reports showing an inverse correlation of ER, PR with HER-2/neu. However, the present study does not show this inverse correlation, as the expression of ER, PR, and HER-2/neu in postmenopausal women was 80.5%, 82%, and 81%, respectively. In the subset of patients with Her-2/neu overexpression, the difference between women <50 years and those >50 years was found to be statistically significant (P = 0.02).
Tumor size is one of the important prognostic factors, which is directly correlated with survival. It has been reported by many that with the increase in tumor size there will be increased involvement of skin, chest wall, lymph nodes, and distant metastases. On the contrary, there are reports where no significant relationship between receptor status and tumor size was found.,,,, However, in the present study, we found a strong association of ER, PR, and HER-2/neu expression with tumor size (P < 0.001). Although a definitive association has been reported between Her-2/neuexpression with grade of the tumor, we could not uncover any correlation between tumor grade and ER, PR, and Her-2/neu expression (P > 0.05). However, some findings in this study have the reflection of some previously reported literature; the strength of this study is we have included patients who were treated by the same team of surgeons and radiation oncologists.
There are few limitations in this study. One, it was a retrospective study and there was a lack of information about waist circumference and hip circumference in the study population, which is considered a superior index for evaluating central obesity. Second, our sample size was small. Third, response to treatment and survival analysis was not performed in receptor positive or negative patients based on menopausal state or obesity. Lastly, there were only 36 cases among pre-menopausal BC cases. If these 36 cases have been further stratified into 3 BMI strata, there would be <10 cases in each stratum and it would be difficult to draw any concrete conclusion from such small strata.
| Conclusion|| |
This study revealed that BMI has significant association with the menopausal state but lack significant association with tumor size, stage, grade, and lymph node status in both pre and postmenopausal patients. The frequency of expression of ER/PR was the same as reported in the literature although expression of HER-2/neu was higher in postmenopausal women, Her-2/neu expression, in addition, showed statistically significant association with age at diagnosis. Furthermore, there was a significant correlation of ER/PR and HER-2/neu receptor with tumor size. Findings from this study may help to improve patient awareness of potentially modifiable lifestyle risk factors such as overweight and obesity as HER-2/neu positivity is associated with poor prognosis.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Ferlay J, Soerjomataram, I, Dikshit R, Eser S, Mathers C, Rebelo M, et al
. Parkin. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:359-86.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569-78.
International Institute for Population Sciences. National Family Health Survey (NFHS-2), 1998-99: India. Mumbai: International Institute for Population Sciences; 2000. Available from: https://www.dhsprogram.com/pubs/pdf/FRIND2/FRIND2.pdf
. [Last accessed on 2021 Jan 12].
Brandt PA, Spiegelman D, Yaun SS, Adami HO, Beeson L, Folsom AR, et al
. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol 2000;152:514-27.
Neuhouser ML, Aragaki AK, Prentice RL, Manson JE, Chlebowski R, Carty CL, et al.
Overweight, obesity, and postmenopausal invasive breast cancer risk: A secondary analysis of the women's health initiative randomized clinical trials. JAMA Oncol 2015;1:611-21.
Davis LV, Rose DP, Hazard H, McNatt MH, Adkins F, Partin J, et al
. Triple-negative breast cancer and obesity in a rural appalachian population. Cancer Epidemiol Biomarkers 2008;17:3319-24.
Althuis MD, Fergenbaum JH, Garcia-Closas M, Brinton LA, Madigan MP, Sherman ME. Etiology of hormone receptor-defined breast cancer: A systematic review of the literature. Cancer Epidemiol Biomarkers Prev 2004;13:1558–68.
Ewertz M, Jensen MB, Gunnarsdottir KA, Hojris I, Jakobsen EH, Nielsen D, et al
. Effect of obesity on prognosis after early-stage breast cancer. Clin Oncol 2011;29:25-31.
Kawai M, Minami Y, Nishino Y, Fukamachi K, Ohuchi N, Kakugawa Y. Body mass index and survival after breast cancer diagnosis in Japanese women. BMC Cancer 2012:12:149.
Garcia FA, Gimenez N, Fraile M, Gonzalez S, Chabrera C, Torras M, et al.
Survival and clinicpathological characteristics of breast cancer patient according to different tumour subtypes as determined by hormone receptor and Her2 immunohistochemistry. A single institution survey spanning 1998 to 2010. Breast 2012;21:366-73.
Liu K, Zhang W, Dai Z, Wang M, Tian T, Liu X, et al
. Association between body mass index and breast cancer risk: Evidence based on a dose-response meta-analysis. Cancer Manag Res 2018;10:143-51.
Faheem M, Mahmood H, Khurram M, Qasim U, Irfan J. Estrogen receptor, progesterone receptor, and Her 2 Neu positivity and its association with tumour characteristics and menopausal status in a breast cancer cohort from northern Pakistan. Ecancermedicalscience 2012;6:283.
Hussein MR, Abd-Elwahed SR, Abdulwahed AR. Alterations of estrogen receptors, progesterone receptors and c-erbB2 oncogene protein expression in ductal carcinomas of the breast. Cell Biol Int 2008;32:698-707.
Li J, Huang Y, Zhang BN, Fan JH, Huang R, Zhang P, et al
. Body mass index and breast cancer defined by biological receptor status in pre-menopausal and post-menopausal women: A multicenter study in China. PLoS One 2014;9:e87224.
Shieh Y, Scott CG, Jensen MR, Norman AD, Bertrand KA, Pankratz VS, et al
. Body mass index, mammographic density, and breast cancer risk by estrogen receptor subtype. Breast Cancer Res 2019;21:48.
Iqbal N, Iqbal N. Human Epidermal growth factor receptor 2 (HER2) in cancers: Overexpression and therapeutic implications. Mol Biol Int 2014;2014:852748.
Thiygarajan M, Navrathan N, Mohanapriya T, Kumar A, Singh B. Correlation between estrogen receptor, progesterone receptor, HER2/neu status and other prognostic factors in carcinoma breast in Indian population. Int Surg J 2015;2:515-22.
Ayadi L, Khabir A, Amouri H, Karray S, Dammak A, Guermazi M, et al
. Correlation of HER-2 over-expression with clinico-pathological parameters in tunisian breast carcinoma. World J Surg Oncol 2008;6:112.
Prati R, Apple SK, He J, Gornbein JA, Chang HR. Histopathologic characteristics predicting HER-2/neu amplification in breast cancer. Breast J 2005;11:433-9.
Huang HJ, Neven P, Drijkoningen M, Paridaens R, Wildiers H, Van Limbergen E, et al
. Association between tumour characteristics and HER-2/neu by immunohistochemistry in 1362 women with primary operable breast cancer. Clin Pathol 2005;58:611-6.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]