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Abstract

BACKGROUND:

Breast cancer, a global health problem with a high mortality rate, has several risk factors, including obesity and increased lipid profile. Postmenopausal obesity is associated with estrogen production from adipose tissue, while abnormal cell growth is triggered by insulin-like growth factor 1 (IGF-1) and insulin. Obesity could be assessed by measuring body mass index (BMI). An increase in lipid profile signifies an increased risk for breast cancer. Histopathological findings in the form of grading and differentiation can indicate how serious the condition is. Breast cancer with good differentiation is always associated with a positive prognosis.

OBJECTIVE:

This observational analytic study aims to determine the relationship between BMI and cholesterol levels based on the menopausal status and the histopathological grading findings of breast cancer patients.

METHODS:

The observational cross-sectional study analyzed histopathological grading, total cholesterol level, and body mass index. Data were analyzed with Spearman rank correlation statistical test, and the results are significant when the p-value is <0.05.

RESULTS:

Analyzing the relationship between cholesterol levels and histopathological gradings indicated a moderate correlation. The results of another correlation test based on menopausal status showed a weak correlation value, while menopause was said to be significant, indicating a moderate correlation. However, results from the analysis of BMI data in the menopausal subject group were associated with histopathological assessment.

CONCLUSIONS:

There is a relationship between cholesterol levels and histopathological degrees in the two menopausal status groups. However, no relationship was found between BMI and the histopathological grades of breast cancer.

Keywords

Breast cancer BMI cholesterol levels menopause histopathology obesity

1. Introduction

Breast cancer, a global health problem, was ranked as the fourth leading cause of cancer deaths, with 458,000, according to data from the World Health Organization (WHO) in 2008 [1]. Furthermore, the American Cancer Society (ACS) 2012 reported that breast cancer was the second leading cause of death in females (14%), after lung cancer (26%), in the United States. This disease also affects men but with a frequency of only about 1% [2–4].

Various studies indicate that obesity is associated with an increased risk of breast cancer in postmenopausal females but not in premenopausal females [5]. The adipose tissue of obese postmenopausal patients produces estrogen-containing growth factors such as IGF-1 and insulin. The combined effect of these substances can reduce normal apoptosis, stimulate cell division, and induce the aromatization of androstenedione to estradiol in peripheral adipose tissue and the low-binding sex hormone globulin [6].

An abnormal increase in the lipid profile components can also increase the risk of breast cancer associated with obesity. In another study, total cholesterol and triglycerides did not significantly influence the risk of breast cancer, although high-density lipoproteins seemed to have an effect [7].

Through anatomical pathology, the activity and aggressiveness of breast cancer cells can be assessed. From these histopathological findings, grading can be used to determine the level of differentiation. Research shows that histopathological grading is closely related to the prognosis. Therefore, breast cancer with good differentiation is always associated with a positive prognosis [8].

Given how these risk factors influence breast cancer and other clinical conditions, parameters such as body composition, metabolic, and physiological factors must be monitored. It is important to identify how they can be assessed clinically, whether they can affect the prognosis, and how these factors can reduce risk and improve outcomes [9]. Therefore, this study will observe the relationships between body mass index and cholesterol level with histopathological grading of breast cancer in premenopause and postmenopause patients.

2. Methods

This analytic observational study with a cross-sectional design was conducted starting in May 2020 with a sample of 60 patients. The Institutional Ethics Committee has received ethical permission with the approval number: 473/UN4.6.4.5.31/pp36/2020. Sampling was done using the consecutive sampling method, which is a technique based on the order of arrival of the participants and those that met the inclusion and exclusion criteria. The inclusion criteria were female patients with breast cancer at all stages who were willing to participate in the study. On the other hand, the exclusion criteria were female patients using hormonal-based treatments (contraception, replacement therapy, basic therapy), those undergoing chemotherapy or radiotherapy, and patients suffering from metabolic disorders such as diabetes mellitus liver disease. The body mass index value was obtained according to the WHO (2011). It is calculated by taking a person’s weight, in kilograms, divided by their height, in meters squared, or BMI = weight (in kg)/height² (in m). BMI was categorized into four groups according to the conventional WHO classification: underweight (<18.5 kg/m²), normal weight (18.5–24.9 kg/m²), overweight (25–29.9 kg/m²), and obese (≥30 kg/m²) [10,11]. Histopathological grading is based on the Nottingham Combined Histologic Grade and Elston-Ellis’ modification of Scarff–Bloom–Richardson. The grading is divided into three grade levels: grade I is low, grade II is moderate, and grade III is high. In addition, the total cholesterol level was measured from the patient’s blood serum (normal value is less than 200 mg/dl).

2.1. Data analysis

Correlation data analysis of body mass index and breast cancer cell grading was performed using a Spearman’s rank correlation statistical test, and the results are considered to be significant when the p-value is <0.05.

Table 1
Patient characteristics

Characteristics Frequency

n (%)

Age (years) <40 10 16.7

40–49 27 45

50–59 16 26.7

≥60 7 11.7

Menopause status Premenopause 32 53.3

Menopause 28 46.7

BMI (kg/m²) Low 5 8.3

Normal 23 38.3

Obese 32 53.3

Cholesterol levels Normal (<200 mg/dl) 18 30

Increased (≥200 mg/dl) 42 70

Histopathological Good 7 11.7

grading Moderate 30 50

Poor 23 38.3

	Characteristics	Frequency
Age (years)	<40	10	16.7
	40–49	27	45
	50–59	16	26.7
	≥60	7	11.7
Menopause status	Premenopause	32	53.3
	Menopause	28	46.7
BMI (kg/m²)	Low	5	8.3
	Normal	23	38.3
	Obese	32	53.3
Cholesterol levels	Normal (<200 mg/dl)	18	30
	Increased (≥200 mg/dl)	42	70
Histopathological	Good	7	11.7
grading	Moderate	30	50
	Poor	23	38.3

3. Result

This study was conducted on 60 breast cancer patients that met the criteria for body mass index (BMI) and cholesterol levels. Afterward, a histopathological examination was performed to assess the breast cancer grading.

Based on the results of the univariate analysis, Table 1 shows the age groups of the research subjects, which are 40–49 years (45%), 50–59 years (26.7%), less than 40 years (16.7%), and more than 60 years (11.7%). In this study, an assessment of menopausal status was also carried out. It was found that 32 patients (53.3%) were premenopausal, and 28 (46.7%) were menopausal.

The group with the highest body mass index were the ones with obesity status (53.3%), followed by the normal BMI group (38.3%), while the lowest size group was the low BMI group (8.3%). Meanwhile, patients with high mean cholesterol levels (70%) were more than those with normal values (30%). Most histopathological gradings were moderate (50%), followed by poor (38.2%), while the lowest grade was good (11.7%).

Table 2 shows the distribution value of each research variable, which consists of the mean, median, mode, and standard deviation. The table also shows the highest and lowest average value of each tested variable.

Table 2
The descriptive statistics of patient’s characteristics

Characteristics Age (years) Body mass index (kg/m²) Cholesterol levels (mg/dl) Grading

Mean 49.17 24.822 234.32 2.27

Median 48.00 25.100 244.50 2.00

Mode 55 25.7^a 198^a 2

Std. deviation 8.494 3.2777 40.047 0.660

Range 37 16.2 159 2

Minimum 32 15.8 161 1

Maximum 69 32.0 320 3

Characteristics	Age (years)	Body mass index (kg/m²)	Cholesterol levels (mg/dl)	Grading
Mean	49.17	24.822	234.32	2.27
Median	48.00	25.100	244.50	2.00
Mode	55	25.7^a	198^a	2
Std. deviation	8.494	3.2777	40.047	0.660
Range	37	16.2	159	2
Minimum	32	15.8	161	1
Maximum	69	32.0	320	3

Meanwhile, the BMI variable had values of mean 24.822 kg/m², median 25.1 kg/m², mode 25.7^a kg/m², standard deviation 3.2777 kg/m², range 16.2 kg/m², minimum 15.8 kg/m², and maximum 32.0 kg/m². For the cholesterol variable, the mean value was 234.32 mg/dl, median 244.50 mg/dl, mode 198^a mg/dl, standard deviation 40.047 mg/dl, range 159 mg/dl, minimum 161 mg/dl, and maximum 320 mg/dl. For the histopathological grading, the mean was 2.27, median 2, mode 2, standard deviation 2, minimum 1, and maximum value 3.

Table 3

Characteristic frequency distribution based on menopausal status

	Characteristics	Premenopause n (%)	Menopause n (%)
BMI	Low	4 (12.5)	1 (3.6)
	Normal	9 (28.1)	14 (50)
	Obese	19 (59.4)	13 (46.4)
Cholesterol	Normal	11 (34.4)	7 (25)
levels	Increased	21 (65.7)	21 (75)
Grading	Good	4 (12.5)	3 (10.7)
histopathology	Moderate	15 (46.9)	15 (53.6)
	Poor	13 (40.1)	10 (35.7)

Table 3 indicates that the frequency distribution of each variable is based on menopausal status. Furthermore, the distribution of cases in premenopause and menopause are the same. The highest and lowest BMI variables were obesity and poor BMI status, respectively, and these results are the same for both premenopause and menopause. Groups with increased cholesterol at the premenopausal and menopausal stages had similar variables. Similar findings were also seen in groups with moderate and low gradings.

In Table 4, the p-value obtained after analyzing BMI with histopathological grading was >0.05 (0.091). Therefore, it can be concluded that there is no significant relationship between BMI and cancer histopathology grading.

Table 4

Correlation between body mass index and histopathological grading

	Characteristics		Body mass index			r-value*	p-value*
			Low	Normal	Obese
	Good	N (%)	1 (1.6)	2 (3.3)	4 (6.7)
Grading	Moderate	N (%)	1 (1.6)	16 (26.7)	13 (21.7)	0.220	0.091
	Poor	N (%)	3 (5%)	5 (8.3)	15 (25)

*Rank Spearman test.

A correlation test was performed based on menopausal status. In Table 5, the premenopausal status is tested with a p-value > 0.05 (0.757). Meanwhile, after testing the menopause status, a p-value < 0.05 (0.018) and an r-value of 0.444 were obtained. Therefore, it can be concluded that the premenopausal status does not have a significant value, while the menopausal status has a significant value and a moderate correlation.

Table 5

Correlation between body mass index and histopathological grading based on menopausal status

	Characteristics		Grading			r-value*	p-value*
			Good	Moderate	Poor
	Low	N (%)	0 (0)	0 (0)	4 (12.5)
BMI premenopause	Normal	N (%)	1 (3.1)	8 (25)	6 (18.8)	0.057	0.757
	Obese	N (%)	3 (9.4)	1 (3.1)	9 (28.1)
	Low	N (%)	1 (3.6)	2 (7.1)	0 (0)
BMI enopause	Normal	N (%)	0 (0)	8 (28.6)	7 (25)	0.444	0.018
	Obese	N (%)	0 (0)	4 (14.3)	6 (21.4)

*Rank Spearman test.

Table 6

Correlation between cholesterol levels and histopathological grading

	Characteristics		Cholesterol levels		r-value*	p-value*
			Increased	Normal
	Low	N (%)	4 (7.7)	3 (5.8)
Grading	Moderate	N (%)	16 (26.9)	14 (25)	0.440	0.000
	High	N (%)	22 (32.7)	1 (1.9)

*Rank Spearman test.

As shown in Table 6, the p-value was <0.05 (0.000), and the r-value was 0.440. Therefore, it can be concluded that there is a significant relationship between cholesterol levels and histopathological tumor grading, with a moderate correlation value.

Table 7

Correlation between cholesterol levels and histopathological grading based on menopausal status

			Premenopause
	Characteristics		Cholesterol levels		r-value*	p-value*
			Increased	Normal
	Low	N (%)	3 (9.4)	1 (3.1)
Grading	Moderate	N (%)	6 (18.8)	9 (28)	0.352	0.048
	High	N (%)	12 (37.5)	1 (3.1)
			Menopause
	Low	N (%)	1 (3.6)	2 (7.1)
Grading	Moderate	N (%)	10 (35.7)	5 (17.9)	0.485	0.009
	High	N (%)	10 (25.7)	0 (0)

Table 7 shows that the p-value of the premenopausal status is <0.05 (0.048), which means that it is significant and has a weak correlation (r = 0.352). These results are the same for menopausal status, where the p-value is <0.05 (0.009), which means that the value is significant, with a moderate correlation. (r = 0.485).

4. Discussion

Based on the protocols for the study, 60 breast cancer patients met the inclusion criteria. These subjects had their BMI, cholesterol levels, and histopathological grading measured. Then, the data were analyzed. The research data found that the largest group of subjects were those in the age group of 40–49 years. The sample also had a range of 32–69 years, a mean of 48, and the lowest group in the age range was more than 60 years.

Other studies have reported that the incidence of breast cancer increases with age, and doubles every ten years until menopause, and then decreases dramatically [12–15]. In contrast to the results of Lester’s study, breast cancer was more common in older females, with a peak incidence between the ages of 75 and 80. The mean age at diagnosis was 61 years in white females, 56 in Hispanic females, and 46 in African American females. Meanwhile, breast cancer is very rare before the age of 25 [16–19].

BMI is assessed by measuring the height and weight of the individual. It is used as a benchmark or a standard index to measure a person’s obesity level [20]. In this study, it was found that the most common BMI group were the obese subjects (57.7%), while the least common were those with low BMI (5.8%). In addition, one of the risk factors for breast cancer is obesity [21].

Various studies suggest that obesity is associated with an increased risk of breast cancer in postmenopausal females but not in premenopausal females. The relationship between body size and breast cancer prognosis has been examined in several studies, particularly Western ones. Increased body weight or body mass index is linked to survival rates of the disease. Furthermore, an increase in stomach size compared to waist size is associated with breast cancer mortality in postmenopausal females [5].

Under the cholesterol variable, this study’s results found increased cholesterol levels (70%) more often than a normal level (30%). Furthermore, it was found that cholesterol levels increased by 65.7% in premenopausal patients and 75% in menopausal subjects. Several studies have stated that the abnormal increase in the lipid profile components significantly influences the risk of breast cancer associated with obesity. However, in contrast to other studies, statistically, total cholesterol and triglycerides do not significantly influence breast cancer risk through high-density lipoproteins do [22–24].

The most common histopathological grading was in the moderate grade group (50%), followed by poor (38.3%), while the smallest was the good group (11.7%). Through pathology anatomy, the activity and aggressiveness of breast cancer cells can be observed. From these histopathological findings, grading can be used to determine the level of differentiation. Furthermore, research shows that histopathological grading is closely related to the prognosis. Breast cancer with good differentiation is always associated with a positive prognosis. The results of Spearman’s rank correlation coefficient were that there was no significant relationship between BMI status and breast cancer grading. Based on the data analysis, a p-value of 0.091 (>0.05) was obtained. However, further analysis on menopausal status obtained significant data, where the p-value was 0.018 (<0.05), which suggests a moderate relationship between BMI status and breast cancer grading, with a unidirectional correlation (r = 0.444). Meanwhile, in premenopausal subjects, the p-value of 0.938 (>0.05) was insignificant.

A research study by Ayoub et al. [25] concluded that obesity is related to the stage and grading of breast cancer in patients. Furthermore, it is also a poor prognostic factor, especially in menopausal patients [25].

Another study by Comenares et al. [26] found that 73.2% of subjects were obese and had to perform a histopathological grading examination. The data show that 49.1% of the subjects were well-differentiated, and most had normal or low nutritional status. The test results from analyzing the nutritional status and histopathological grading obtained a significant value of p = 0.017 [26]. Bougera discovered an association between BMI and breast cancer grading (p = 0.04 at premenopause and p = 0.01 at menopause) and that increased BMI was a predictor factor at grade 3 [11]. This is also in line with Prawirohardjo’s research [27] about the relationship between BMI and breast cancer grading. It was concluded that there was a tendency for patients with an obese BMI to have a higher risk of developing breast cancer (p = 0.045, <0.05) with a coefficient of r = 0.369 [27].

Kemal et al. [28] conducted a study that concluded there was no significant relationship between obesity and breast cancer grading. From the research results obtained, p-value = 0.221 (>0.05) [28]. This is in line with Biglia’s study, where there was no significant relationship between BMI and breast cancer grading (p-value = 0.181 in premenopausal subjects, with a p-value of 0.547 in menopausal subjects) [29]. Some researchers have stated obese females with breast cancer have aggressive growth tumors due to nuclear grading, invasive lymphovascular disease, and an increased proliferation index. Therefore, the tumor size grows faster compared to patients with average or normal nutritional status [28].

Obesity is associated with increased estrogen levels, although several other mechanisms can lead to changes in prognosis. Overweight females are usually associated with insulin-like growth factors and other growth factors such as leptin, TNF-α, IL-6, and VEGF, which trigger angiogenesis, tumor growth, and metastasis, and inhibit apoptosis [28].

Research by Li et al. [20] found that BMI is an independent factor that can increase the risk of breast cancer. BMI is closely linked to the incidence of breast cancer in females in China. The obese group with a BMI above 28 kg/m² had a higher risk than the undernourished group with a BMI below 18.5 kg/m². Therefore, obesity is also one of the unfavorable prognostic factors in cancer patients, which causes them to have a higher mortality rate than other patients with normal nutritional status [30].

Several studies have found no correlation between BMI and breast cancer risk at ages less than 49 years. However, in ages above 80 years, there was a significant correlation related to the patient’s menopausal status. This can be influenced by increasing the bioactivity of estrogen and aldosterone, the conversion of androgens to estrogen, decreased steroid hormone-binding globulin, increased growth factor receptors, hyperinsulinemia, increased fatty acids, and lipid profiles [31].

One study stated that the tendency of BMI to be a risk factor for breast cancer in premenopausal females is still controversial [32]. Another study found that BMI can be a prognostic factor in both menopausal and premenopausal patients suffering from breast cancer and can also be used to determine the rate of recurrence and mortality [33]. Furthermore, there is a relationship between BMI and tumor size, resulting in larger tumors in patients with an obese nutritional status [34–36]. In a study by Biglia et al., there was no relationship between BMI and breast cancer assessment; however, obesity was linked to cancer size and invasive lymphovascular disease [29].

Several meta-analyses found that for every 5 kg/m² increase in BMI, there was a 12% increase in breast cancer risk [37]. Therefore, BMI is a prognostic and can alter the course of therapy [38].

The molecular mechanisms underlying the relationship between obesity and breast cancer are still under investigation due to the complexity of obesity and the changing nature of each breast cancer subtype. Obesity is characterized by the development of reprogrammed metabolically active fatty tissue that induces local inflammation and altered cytokine/adipokine levels. These local changes contribute to changes in systemic physiology such as insulin levels, insulin-like growth factor IGF-I, steroid hormones, adipokines, and molecules associated with inflammation [30]. Obesity also triggers an increase in steroid hormones, including estrogen, which bind to the receptors at the core of breast cancer cells [39]. According to Kolb et al., the mechanism between obesity and breast cancer risk is influenced by several factors, such as adipocytes, adipokines, and adipose tissue inflammation [40]. Furthermore, chemokines and cytokines produced by adipocytes in obese patients increase the risk of breast cancer [41].

A meta-analysis mentioned that weight loss in menopausal females can reduce the risk of breast cancer. Another prospective cohort study stated that weight loss through bariatric surgery decreased the risk of breast cancer in menopausal females; however, this did not include men. The same research also discovered a reduction in the incidence of breast cancer at five years following bariatric surgery [42].

Meanwhile, our study found that the cholesterol levels of the subjects (70%) were higher than normal values (30%). Based on the overall statistical test on cholesterol levels and breast cancer grading, a significant p-value = 0.000 (<0.05) was obtained with moderate and unidirectional correlation (r = 0.440). Another statistical test on menopausal and premenopausal status yielded significant values of p-value = 0.048, (<0.05) and p = 0.009, (<0.05), respectively. Furthermore, r = 0.352 and r = 0.485 values were obtained for the two statuses, and each was moderate and unidirectional.

A Korean study found no correlation between increased cholesterol levels and breast cancer risk in menopausal females. However, it found a significant relationship between cholesterol levels and breast cancer risk in 31% of subjects with high cholesterol levels [43]. This is similar to a research finding in Africa of an association between increased cholesterol levels and the incidence of breast cancer (p-value = 0.001, r = 0.24) [44].

In studies on mice, it was found that dietary changes in cholesterol could alter tumor grading. And it could also influence the expression of proteins linked with advanced tumors in mammals [7].

Another study discovered a relationship between total cholesterol and breast cancer, particularly HDL cholesterol. Therefore, controlling cholesterol levels could help prevent the risk of developing breast cancer. Another study reported no significant relationship between cholesterol levels and breast cancer, with Europeans, however, appearing to be the exception [45].

According to research, reducing the risk of breast cancer can be accomplished by monitoring cholesterol levels in fat diets and performing routine exercises. The mechanism by which cholesterol causes breast cancer is still controversial, yet most studies say that it is influenced by cholesterol, which can trigger biomarkers in the 27-OHC pathway [46].

According to Martin et al., an abnormal increase in the lipid profile components elevate the risk of getting obesity-related breast cancer. In another study, total cholesterol and triglycerides had no significant effect on breast cancer risk, although high-density lipoprotein did [24].

In obese people, excess cholesterol usually accumulates in the liver. This will obstruct the activity of HMGCR (statins) and PCSK9 inhibitors, niacin, and the androgen that CYP27A1 can catabolize to 27-hydroxycholesterol (27HC) [22,47,48]. High expression of CYP27A1 in the liver will stimulate the infiltration of macrophages or breast cancer cells. Enzymes that catalyze 27HC and CYP7B1, are also expressed in breast cancer [49,50]. They are also associated with 27HC cell survival and bind to estrogen receptors (ER) to trigger the growth of breast cancer cells and hepatic X receptors, which cause metastasis [51–53].

5. Conclusion

Our study found no relationship between BMI and the histopathological grade of breast cancer. However, further analysis of menopausal status revealed significant data on histopathological assessment. Furthermore, a relationship does exist between cholesterol levels and the histopathological degree of breast cancer. This study showed that both premenopausal and menopausal states are associated with the histopathological degree of breast cancer. However, among the two groups, it was the menopause patients that had a greater relationship.

Footnotes

Acknowledgements

The authors do not have acknowledgments.

Conflicts of interest

None.

Funding

None.

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Relationship between body mass index and cholesterol levels with histopathological grading of breast cancer

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Methods

2.1. Data analysis

5. Conclusion

Footnotes

Acknowledgements

Conflicts of interest

Funding

References