Study of risk factors and marker status in women with breast cancer in Brunei Darussalam

Abstract

OBJECTIVE:

To investigate the associations between breast cancer staging and body mass index (BMI), menopausal status, and family history of breast cancer, as well as to assess the expression of tumor markers in women with breast cancer in Brunei Darussalam.

METHODS:

A retrospective cross-sectional study was carried out at The Brunei Cancer Centre. Cases of women with breast cancer between 2000 and 2013 were retrieved from the medical records section and entered into a clinical proforma. These were reviewed and analyzed using appropriate statistical methods.

RESULTS:

Overall, the mean age at diagnosis was 53.6 years ± 9.83. The postmenopausal women had a significantly higher risk of being diagnosed with late-onset breast cancer than premenopausal women (P = 0.022). The expressions of PR (P = 0.034), Her2 (P = 0.046), and CatD (P = 0.004) were significantly different in breast cancer staging. Other factors did not have a statistically-significant association with breast cancer staging.

CONCLUSION:

While most of the factors studied were not significantly different in breast cancer staging, our findings showed that it is recommended that high-risk women perform regular breast screening after the age of 40 years old. A future study highly appreciates comparing breast cancer risk factors among the Bruneian and Western populations.

Keywords

Breast cancer body mass index menopausal status family history tumor markers breast cancer staging

1. Introduction

Breast cancer is the most common malignancy among women in many countries. In 2020, an estimated 2.2 million new cases were diagnosed, and approximately 685,000 breast cancer deaths occurred worldwide [1]. In Brunei Darussalam, cancer is one of the leading causes of death, according to 19% of the total deaths in 2017. Most importantly, breast cancer is the leading cause of cancer deaths among women (18%) in the country [2]. Brunei Darussalam is a small country located in the northwest of the island of Borneo in Southeast Asia with a total population of 459,500 and a per capita Gross Domestic Product of US$29,433 in 2019 [3].

There are several risk factors associated with breast cancer. High body mass index (BMI) is a well-established risk factor for postmenopausal breast cancer [4,5]. Brunei has the second highest obesity prevalence rate among Southeast Asian countries, after Malaysia, at 14.1% for adults with a BMI of more than 30 kg/m² [2,6]. High BMI causes changes in hormone levels such as higher leptin levels and lower adiponectin levels. These changes affect tumor development, metastasis, and overall prognosis in pre-and postmenopausal women with breast cancer [7]. Most studies have concluded that the BMI index is associated with an increment in breast cancer risk in postmenopausal women [8,9]. However, limited studies have been conducted to investigate the association between BMI and breast cancer staging.

Moreover, a family history of breast cancer is a known predictive risk factor for breast cancer and is typically used to identify women at higher risk of the disease. Studies have shown that about 11% to 16% of women with breast cancer have at least one affected first-degree relative [10,11]. A strong family history of breast cancer may indicate an inherited predisposition through germline mutations in genes associated with breast cancer, such as BRCA1 and BRCA2. Roughly one-third of women with hereditary breast cancer have mutations in BRCA1 or BRCA2 [12]. A study in Brunei Darussalam showed 30% of Brunei breast cancer patients had at least one affected first and/or second-degree relative, and a higher number of family members in the first-degree relatives affected with breast cancer was significantly associated with an increased risk of having germline BRCA2 pathogenic mutations [13]. However, no data have been identified to show the relationship between a family history of breast cancer and breast cancer staging in Brunei Darussalam.

Tumour markers, often determined by immunohistochemistry, are critical in determining breast cancer progression. A few studies in Brunei Darussalam demonstrated the relationship between the expression of tumor markers and breast cancer outcomes [14,15]. The previous data [14,15] suggested that tumour markers such as estrogen receptor (OR), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) indicated their independent prognostic and predictive value, whilst; tumor suppressor protein (p53), apoptosis regulator protein (BCL2), epidermal growth factor receptor (EGFR), cell proliferation associated nuclear protein (Ki67), cell surface glycoprotein (CD34) and Cathepsin D (CatD) were also found to be affecting tumour progression and prognosis of breast cancer.

This study examined breast cancer cases in Brunei Darussalam to determine the prevalence between BMI and breast cancer staging, assess the relationship between menopausal status and family history of breast cancer and breast cancer staging as well, as assess the tumor markers such as OR, PR, Her2, p53, BCL2, EGFR, Ki67, CD34 and CatD in Brunei breast cancer patients.

2. Methods

This retrospective cross-sectional study looked at all breast cancer cases diagnosed and registered in The Brunei Cancer Centre (TBCC), Brunei Darussalam, over 14 years from 1st January 2000 to 31st December 2013. Data from male breast cancer cases were excluded from this study.

Clinical information data on BMI, date of first diagnosis of breast cancer, type of carcinoma, breast cancer staging, menopausal status, family history of breast cancer, and details of marker status given were extracted from the respective medical records and entered into a clinical proforma. The Medical and Health Research and Ethics Committee (MHREC) of Negara Brunei Darussalam approved the study.

Table 1
Distribution of women with breast cancer in the study

Variable Total (cases) n (%) Mean (SD^a )

Age (year) 53.6 (9.83)

Ethnicity 190

Malay 134 (70.5)

Chinese 40 (21.1)

Others 16 (8.4)

Types of breast carcinoma 213

Non-invasive 28 (13.1)

Invasive 143 (67.1)

Others 42 (19.7)

Age at diagnosis (years old) 216

<35 7 (3.2)

35–44 31 (14.4)

45–54 81 (37.5)

55–64 72 (33.3)

65–74 16 (7.4)

>75 9 (4.2)

Current status 219

Alive 200 (91.3)

Death 19 (8.7)

BMI^b at the age of diagnosis (kg/m²) 181

<18.50 7 (3.9)

18.50–24.99 66 (36.5)

≥25.00 71 (39.2)

≥30.00 37 (20.4)

Variable	Total (cases)	n (%)	Mean (SD^a )
Age (year)			53.6 (9.83)
Ethnicity	190
Malay		134 (70.5)
Chinese		40 (21.1)
Others		16 (8.4)
Types of breast carcinoma	213
Non-invasive		28 (13.1)
Invasive		143 (67.1)
Others		42 (19.7)
Age at diagnosis (years old)	216
<35		7 (3.2)
35–44		31 (14.4)
45–54		81 (37.5)
55–64		72 (33.3)
65–74		16 (7.4)
>75		9 (4.2)
Current status	219
Alive		200 (91.3)
Death		19 (8.7)
BMI^b at the age of diagnosis (kg/m²)	181
<18.50		7 (3.9)
18.50–24.99		66 (36.5)
≥25.00		71 (39.2)
≥30.00		37 (20.4)

^aSD = Standard deviation. ^bBMI = Body mass index.

BMI was calculated by using the formula $\frac{\text{Weight (kg)}}{\text{Height}^{2}(\text{m}^{2})}$ . Normal BMI was classified as BMI less than 25.0 kg/m², whereas high BMI was classified as BMI more than 25.0 kg/m² [16]. Premenopausal women were defined as those who claimed that they were still menstruating at the first visit and postmenopausal women were defined as those who claimed that they had no menstruation for more than six months before they had their first visit to TBCC. Breast cancer staging was defined as the breast cancer progression and classified into two categories: early onset (Stage I, Stage IIa, and Stage IIb) and late-onset (Stage IIIa, Stage IIIb, Stage IIIc, and Stage IV).

Statistical analysis was carried out using IBM SPSS version 20.0 software. Chi-square or Fisher’s exact test was used to assess the risk factors (menopausal status, family history of breast cancer, and BMI) and tumor markers (OR, PR, Her2, p53, BCL2, EGFR, Ki67, CD34, CatD) in women with breast cancer in TBCC. All hypothesis tests were two-sided, and a P value < 0.05 was considered statistically significant.

3. Results

3.1. Distribution of women with breast cancer

A total of 219 case notes were recruited for this study. Most of the women with breast cancer were among the Malays (70.5%), followed by the Chinese (21.1%) and others (8.4%). The most common type of breast carcinoma was invasive breast carcinoma, accounting for 67.1% of all cases. Most cases were presented with high BMI (59.6%). The mean age at diagnosis was 53.6 years ± 9.83. Details are shown in Table 1.

3.2. Associations between breast cancer staging and BMI, menopausal status, and family history of breast cancer

The association between breast cancer staging and BMI was not significantly different (P = 0.184) (Table 2). Nevertheless, this study demonstrated a significant association between later stages of breast cancer with postmenopausal women compared to premenopausal women (P = 0.022) (Table 2). On the other hand, breast cancer staging showed no significant correlation with family history of breast cancer (P = 0.800) (Table 2).

Table 2
Case characteristics and breast cancer staging

Variable n Breast cancer staging (Stage) 𝜒²statistic^a (df) P value^a

Early onset freq (%) Late onset freq (%)

BMI^b

Normal BMI^b 70 37 (52.9) 33 (47.1) 1.77 (1) 0.184

High BMI^b 95 60 (63.2) 35 (36.8)

Menopausal status

Premenopausal 72 52 (72.2) 20 (27.8) 5.24 (1) 0.022

Postmenopausal 69 37 (53.6) 32 (46.4)

Family histori^c

Absence 99 61 (61.6) 38 (38.4) 0.09 (1) 0.771

Presence 31 20 (64.5) 11 (35.5)

Variable	n	Breast cancer staging (Stage)	𝜒²statistic^a (df)	P value^a
BMI^b
Normal BMI^b	70	37 (52.9)	33 (47.1)	1.77 (1)	0.184
High BMI^b	95	60 (63.2)	35 (36.8)
Menopausal status
Premenopausal	72	52 (72.2)	20 (27.8)	5.24 (1)	0.022
Postmenopausal	69	37 (53.6)	32 (46.4)
Family histori^c
Absence	99	61 (61.6)	38 (38.4)	0.09 (1)	0.771
Presence	31	20 (64.5)	11 (35.5)

^aChi-square test for independence. ^bBody mass index. ^cFamily history of breast cancer.

Table 3

Tumour markers and breast cancer staging

Variable	n	Breast cancer staging (Stage)		𝜒²statistic^a (df)	P value^a
		Early onset freq (%)	Late onset freq (%)
OR^b
Positive	95	65 (68.4)	30 (31.6)	2.82 (1)	0.093
Negative	65	36 (55.4)	29 (44.6)
PR^c
Positive	88	62 (70.5)	26 (29.5)	4.51 (1)	0.034
Negative	72	39 (54.2)	33 (45.8)
Her2^d
Positive	73	40 (54.8)	33 (45.2)	4.00 (1)	0.046
Negative	81	57 (70.4)	24 (29.6)
p53^e
Positive	38	25 (65.8)	13 (34.2)	<0.00 (1)	0.969
Negative	81	53 (65.4)	28 (34.6)
BCL2^f
Positive	45	28 (62.2)	17 (37.8)	0.20 (1)	0.658
Negative	74	49 (66.2)	25 (33.8)
EGFR^g
Positive	11	5 (45.5)	6 (54.5)	–	0.199^h
Negative	106	70 (66.0)	36 (34.0)
Ki67ⁱ
Positive	67	41 (61.2)	26 (38.8)	0.57 (1)	0.450
Negative	47	32 (68.1)	15 (31.9)
CD34^j
Positive	19	13 (68.4)	6 (31.6)	0.04 (1)	0.834
Negative	88	58 (65.9)	30 (34.1)
CatD^k
Positive	63	34 (54.0)	29 (46.0)	8.14 (1)	0.004
Negative	53	42 (79.2)	11 (20.8)

^aChi-square test for independence. ^bOestrogen receptor. ^cProgesterone receptor. ^dHuman epidermal growth factor. ^eTumor suppressor protein. ^fApoptosis regulator protein. ^gEpidermal growth factor receptor. ^hFisher’s exact test. ⁱNuclear Protein and associated with cell proliferation. ^jCell surface glycoprotein. ^kCathepsin D.

3.3. Relationships between breast cancer staging and expression of tumor markers OR, PR, Her2, p53, BCL2, EGFR, Ki67, CD34, and Cathepsin D

Out of all the tumor markers investigated, only positive PR (P = 0.034), negative Her2 (P = 0.046), and negative CatD (P = 0.004) expressions were significantly associated with early stages of breast cancer, as shown in Table 3.

4. Discussion

The ethnic distribution of women with breast cancer in Brunei Darussalam was investigated in our study, showing the reflection of the general population distribution in the country. The mean age of breast cancer diagnosis was similar to previous studies in Brunei [14,15,17]. Furthermore, other Asian countries recorded the highest incidence rate of women with breast cancer diagnosed around 40 to 49 years old [18,19]. We may hypothesize that women with breast cancer are diagnosed at a younger age in Brunei Darussalam and Asia, in contrast to Western countries such as the USA, which recorded a mean breast cancer age of diagnosis at 62 years [20]. Factors such as genetics, environment, and culture may contribute to the differences.

High BMI is a common health condition, and its prevalence is increasing globally. It has been shown that a high BMI is associated with an increased incidence of particular diseases and certain cancers, such as digestive track and breast cancers [21]. Our study demonstrated that high BMI is a risk factor for breast cancer, as shown by the higher frequency of women with high BMI diagnosed with breast cancer in Brunei (Table 1). However, this study found a significant association between BMI and breast cancer staging. Contrary to other studies, a higher percentage of women with normal BMI diagnosed with late-onset breast cancer compared with high BMI (Table 2) [22,23]. This insignificant association with cancer staging may well reflect the limited number of cases that have been studied.

Our results showed that postmenopausal women had a significantly higher risk of being diagnosed late-onset breast cancer than premenopausal women, consistent with other studies [13,22]. The possible underlying cause may be the high BMI in Brunei in postmenopausal women. Interestingly, a survey of Brunei breast cancer patients also significantly showed postmenopausal women were associated with the age of onset of breast cancer at both 40 (early) and 50 (late) years old [13]. We also found a higher frequency of cases diagnosed with early stages of breast cancer in premenopausal women (Table 2). This result may be due to the disease affecting our country’s younger population, as mentioned in this study. Other aspects that lead to diagnosis at an earlier stage of the disease may include improved screening programs and increased breast cancer awareness.

This study demonstrated no significant association between a family history of breast cancer and breast cancer staging, comparable with other studies [11,24]. However, this finding contradicted a previous study of breast cancer that showed the presence of family history was correlated to a good prognosis [25]. Moreover, our findings presented a higher frequency of women without a family history of breast cancer. It might be multi-factorial, including the westernization of traditional diets and lifestyles in Brunei.

OR, PR, and Her2 are well-established predictor tumor markers in breast cancer prognosis and are widely used in Brunei [14,15]. Our study showed that PR had a significant association with breast cancer staging. This may indicate that PR-positive had a lower risk of reoccurrence and metastasis [26], which explained the high frequency of those cases in our study in the early onset of breast cancer. Her2, a proto-oncogene that encodes for a trans-membrane tyrosine kinase growth factor receptor, has been found to be associated with poor outcomes in breast cancer, consistent with another study [27]. Higher frequency of Her2-positive women diagnosed with late-onset of breast cancer suggested an increased risk of metastasis and reoccurrence in that particular category [28]. However, the present study could not establish a clear relationship between OR and breast cancer staging, inconsistent with the previous study [29]. This might be due to a limited number of cases recruited and uneven distribution of grouped data. Furthermore, the other markers, such as p53, BCL2, EGFR, Ki67, and CD34, failed to show significant associations with breast cancer staging in this study. However, some markers presented prognostic and predictive values by determining relationships with breast tumor grades [14,15]. Analysis of a larger number of samples in Brunei for p53, BCL2, EGFR, Ki67, and CD34 is warranted to demonstrate a clear relationship between those tumor markers and breast cancer staging and hence assist prognosis. Furthermore, these findings might be because not all women had the complete tumor markers tested. Thus, the number of cases recruited was less than those for OR, PR, and Her2. Therefore, insufficient data may affect our study. An important finding from this study was that more women with breast cancer were diagnosed with CatD-positive in the late onset of breast cancer, which was consistent with other studies [30,31]. In a France study, Masson et al. [32] found that CatD played a key role in controlling adipogenesis, suggesting that CatD may be a novel target in obese humans.

Additionally, several experimental studies demonstrated that adipocytes might play a supportive role in breast cancer [33,34].

As this study was hospital-based, there was a selection bias in the intake of cases, which might not be representative of all women with breast cancer. Furthermore, even with data on women over a fourteen-year period, there were trends in the association between some risk factors and breast cancer staging that suggested that data analysis from a larger sample population may show even more statistically-significant relationships. A much extended period will be consumed to collect a larger data set from Brunei Darussalam. Another limitation was that complete data was unavailable for all the women diagnosed with breast cancer in the fourteen year period.

5. Conclusions

In conclusion, a statistically significant association existed between menopausal status and breast cancer staging. Menopausal status is a well-known risk factor for breast cancer. BMI and family history of breast cancer did not show a significant association with breast cancer staging. However, associations have been shown to occur in most studies, as discussed above.

However, women are still encouraged to practice healthy lifestyles, for instance, a healthy diet and regular physical activity, to maintain an ideal BMI. It is recommended that postmenopausal women with high BMI and those with a family history of breast cancer perform regular breast screening, including monthly breast self-examinations, biennially clinical breast examinations, and mammograms after the age of 40 years. Surveillance of women at high risk is useful in detecting breast cancer at an early stage. Comparing breast cancer risk factors among Bruneian and Western populations is highly recommended. The expression of CatD in adipocytes from women with breast cancer and its purpose in controlling adipogenesis could be studied.

Footnotes

Conflict of interest

All authors declare no conflict of interest in the publication of this article.

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