|Ahead of print publication
Metabolic syndrome and breast cancer: Is there a cause-and-effect relationship?
Preety Negi1, Pamela A Kingsley1, Jubbin Jagan Jacob2, Jaineet Sachdeva1, Chinnu Jomi1
1 Departments of Radiation Oncology, Christian Medical College and Hospital, Ludhiana, Punjab, India
2 Departments of Endocrinology, Christian Medical College and Hospital, Ludhiana, Punjab, India
|Date of Submission||13-Jul-2022|
|Date of Acceptance||13-Jul-2022|
|Date of Web Publication||07-Oct-2022|
Departments of Radiation Oncology, Christian Medical College and Hospital, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
Background: Metabolic syndrome (MetS) has an important role in the development as well as the progression of breast cancer (BC). This syndrome is defined as having three or more central obesity, hypertension, insulin resistance, low low-density lipoprotein cholesterol, and high triglycerides (TGs). Multiple studies have demonstrated that early recognition of MetS may have a positive impact on decreasing BC incidence. We compared the prevalence of MetS in newly diagnosed carcinoma breast patients with controls in the general population and thereby provide insight into its role as an emerging risk factor for BC. Patients and Methods: A prospective, case–control study was conducted at Christian Medical College and Hospital, Ludhiana, between September 2018 and October 2019. One hundred and four subjects each of BC and age-matched controls were enrolled. The measurement of waist circumference (WC), blood pressure (BP), fasting blood glucose levels, and lipid profile was performed for women with newly diagnosed BC and controls. Results: MetS was significantly more prevalent among BC (65.4%) compared to controls (30.8%). On assessing each component of MetS, it was evident that the prevalence of WC and BP, as well as the metabolic parameters, namely fasting blood sugar, TGs, and high-density lipoprotein cholesterol, was higher in Group A as compared to Group B. The majority of the women with BC and MetS were postmenopausal. The majority (66.2%) of BC patients with MetS were receptor positive. Conclusions: This study unveils a hidden link between MetS and BC, and hence, BC awareness programs should stress the need for lifestyle changes and healthy living to nip this evil in the bud. Opportunistic screening should be undertaken for women presenting to the medical facility with MetS. Future studies are required to design effective strategies to raise the possibility of MetS as an established risk factor in BC.
Keywords: Breast cancer, metabolic syndrome, obesity, prevalence, risk factors
|How to cite this URL:|
Negi P, Kingsley PA, Jacob JJ, Sachdeva J, Jomi C. Metabolic syndrome and breast cancer: Is there a cause-and-effect relationship?. J Radiat Cancer Res [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.journalrcr.org/preprintarticle.asp?id=358107
| Introduction|| |
The incidence of breast cancer (BC) in women has varied from 25.9 cases/100,000 in South-Central Asia to 94.2 cases/100,000 in Australia/New Zealand in 2018. Approximately 45% of more than 1 million new cases of BC diagnosed each year, and more than 55% of BC-related deaths, occur in low- and middle-income countries like India. The “Westernization” of the developing world is the most widely cited reason for the global increase in BC which could comprise both desirable factors such as improved socioeconomic factors, reproductive control, and undesirable habits such as sedentary lifestyle, lack of exercise, and junk food consumption. Risk factors related to diet, obesity, and exercise are also often blamed for increasing BC rates. The role of modifiable risk factors, such as obesity and metabolic syndrome (MetS) need to be addressed and measures need to be taken to circumvent the increasing incidence of this deadly peril. It is becoming increasingly evident that metabolic disorders such as obesity and hyperinsulinemia are involved in carcinogenesis and progression of BC.,, MetS also called syndrome X, the insulin resistance syndrome, the deadly quartet, or the obesity dyslipidemia syndrome, consists of a conglomerate of metabolic abnormalities including abdominal obesity, hypertriglyceridemia, and the associated hyperinsulinemia, hyperglycemia, and hypertension have been contemplated as risk factors for the development of various cancers.,
Almost every component of MetS has been associated with a higher risk of liver, colorectal, and bladder cancer in men and endometrial, pancreatic, colorectal, ovarian, and postmenopausal BC in women.,, Various suggested mechanisms include extragonadal estrogen production, decreased sex hormone-binding globulin (SHBG) resulting in increased estrogen bioavailability, and increased insulin biosynthesis, causing mitogenic effects on both nontransformed and malignant breast epithelial cells.
It is interesting to observe that the westernization of lifestyle and environmental factors are mainly responsible for international and interethnic differences across various countries. A better understanding of how modifiable risk factors as mentioned above, can affect the BC incidence may have a considerable contribution to our present knowledge leading to the development of new preventive and therapeutic strategies for this malignancy. To examine this link between MetS and BC, we conducted this case–control study to compare the prevalence of MetS in newly diagnosed carcinoma BC patients with age-matched women in the general population.
| Patients and Methods|| |
This prospective, observational, case–control study was conducted between December 2018 and January 2020 on biopsy confirmed newly diagnosed BC women with age ≥18 years and those with measured MetS variables at the time of diagnosis of cancer. The prevalence of MetS in these newly diagnosed BC patients and their casual relationship was analyzed by comparing the same with age-matched normal healthy women. Those with carcinoma in situ or Stage IV BC at diagnosis were excluded from this study.
The enrolled study participants were categorized into two groups, Group A constituting of newly diagnosed patients with BC and Group B as the control group of age-matched normal adult women, i.e., relatives accompanying the patient or faculty working in our hospital. The individuals in the control group were apparently healthy women with no personal history of cancer. All volunteers in the control group were individually matched to cases by age. Anthropometric measurements (body weight, height, and waist circumference [WC]) and blood tests, including fasting blood glucose levels, triglycerides (TGs), total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein cholesterol (HDL-C) were evaluated for all the study participants in both groups.
All patients with the clinical diagnosis of BC underwent trucut biopsy for confirmation of diagnosis, and biopsy-proven BC patients were enrolled in the study Group A. Detailed history related to the established risk factors, namely age at menarche, regularity of menstrual cycle, parity, age at menopause, duration of menstrual cycle were elicited. Additional information on body mass index (BMI), disease stage, and hormone receptor status were documented. Detailed personal history of metabolic and cardiovascular disease was elicited. Interviews included family history of BC in first- and second-degree relatives, and other comorbidities related to MetS. Information regarding the history and/or treatment of medical conditions such as high blood pressure (BP), diabetes, and prior/concomitant medications were extracted.
Body mass index
BMI was calculated as the weight (in kilograms) divided by the square of the height (in meters). Weight was measured on a weighing scale in summer clothing without footwear to the nearest 0.1 kg. Height was measured with a calibrated wall-mounted Seca stadiometer to the nearest ± 1 cm, as per the norms by the World Health Association 1995. The World Health Organization defines “overweight” as a BMI of 25–29.9 kg/m2, “obese” as a BMI >30 kg/m2, and “normal” as between 18.5 and 24.9 kg/m2.
Before measuring WC, each subject was asked to relax and take a few deep, natural breaths. WC was measured with the subject standing with arms at the sides, feet positioned close together, and weight evenly distributed across the feet. The lowest reading of this measurement was taken at the end of the normal expiration using stretch-resistant, flexible measuring tape centered at the level of the umbilicus, just above the iliac crest, and parallel to the floor.
Before checking BP, the participant was made comfortable and relaxed for at least 5 min. BP was measured in a sitting position with both feet on the floor using a pneumatic sphygmomanometer. The BP cuff of approximate size was placed on the study participant's bare right arm. Systolic pressure was recorded as the point at which auscultatory pulsations were heard as the cuff was deflated. The disappearance of the auscultatory pulsations defined the diastolic pressure. Two BP readings were taken 5 min apart, and an average of these two was considered to ensure accuracy in measurement (checked by the same person).
A 12-h fasting venous blood sample was collected and analyzed for fasting blood glucose, and complete lipid profile (TGs, total cholesterol, LDL cholesterol, and HDL-C). Quantitative estimation of glucose was analyzed from plasma using enzymatic assay on Cobas 6000 (c 501 module). Lipid profile was estimated using enzymatic volumetric assay and analyzed on Cobas 6000 (c 501 module). HDL-C was estimated using an HDLC3 kit (based on the homogeneous enzymatic colorimetric assay) and analyzed on Cobas 6000 (c 501 module).
Definition of metabolic syndrome
MetS is defined as having three or more of the following: Central obesity, hypertension, insulin resistance (adipose, muscle, and liver cells do not respond appropriately to insulin, resulting in high circulating glucose levels which leads to hyperinsulinemia), low LDL cholesterol, and high TGs.
The modified National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria for Asian Indians were implemented for the diagnosis of MetS. High BP was defined as ≥130 mm Hg systolic BP or ≥85 mm Hg diastolic BP or patient under antihypertensive treatment with a history of hypertension. As per this criterion, the presence of any three risk factors constituted a diagnosis of MetS [Table 1].
Sample size calculation
The minimum sample size required for the study was calculated as follows:
n = Z2 P (1 − p)/d2, where
n = sample size
p = expected prevalence or proportion
d = precision rate
According to a study on MetS and BC risk in India, the prevalence of MetS in BC patients was found to be 40%.
Z = 1.96 (approximately = 2, for level of confidence of 95%)
P = 40% (=0.163)
d = 10% (=0.1)
n = 96
However, taking an attrition rate of 10%, we included 104 cases in our study. Taking case: control ratio as 1:1, we included 104 controls in this study.
Data were collected on a pretested and prevalidated questionnaire from the study subjects who satisfied the inclusion criteria. Data were analyzed using Microsoft Excel and SSPS version 20.0 (IBM SPSS, Chicago, Illinois, USA). Chi-square was applied to analyze the association between the two attributes and P ≤ 0.05 was taken as significant (confidence interval = 95%).
| Results|| |
Demographic and clinical characteristics at baseline for newly diagnosed patients with BC are shown in [Table 2]. Family history of BC was statistically more prevalent in Group A (6 cases, 5.8%) than in Group B (2 cases, 1.9%) (χ2 = 1.17, NS).
We demonstrated the prevalence of the modified NCEP-ATP III-defined MetS in Group A as 65.4% (68 cases), whereas it was 30.8% (32 cases) for Group B and the difference was significant statistically with the P < 0.00001. On assessing each component of MetS, it was evident that the prevalence of WC and BP, as well as the metabolic parameters namely, fasting blood sugar, TGs, and HDL-C, was higher in Group A as compared to Group B [Figure 1]. Obese/overweight patients with MetS had a higher risk of BC than those without MetS [Table 3].
|Figure 1: Comparison of MetS components in Group A versus Group B. MetS: Metabolic syndrome, WC: waist circumference, TGs: Triglycerides, FBS: Fasting blood glucose, HTN: Hypertension, HDL-C: High density lipoprotein cholesterol|
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|Table 3: Grade of body mass index and metabolic syndrome in breast cancer patients|
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On substratification of BC patients with MetS based on menopausal status, it was found that postmenopausal women with MetS had a greater risk of developing BC (75%) as compared to premenopausal women (25%). We observed that MetS is an independent risk factor for BC irrespective of the disease stage at presentation. In addition, our data were pointing toward the fact that BC patients with MetS have a higher risk of developing hormone receptor-positive BC (66.2%) than their counterparts (33.8%) [Table 4].
|Table 4: Correlation between disease characteristics and metabolic syndrome variables|
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| Discussion|| |
MetS (constituting at least three of the following, namely central obesity, hyperglycemia, hypertension, dyslipidemia, and insulin resistance) is associated with various health conditions, such as cardiovascular disease, type 2 diabetes mellitus, and diverse types of cancers, particularly breast, pancreatic, colorectal, and prostate cancers.,, Each component of MetS may or may not increase the risk of cancer more than the whole spectrum of MetS.,
BC is a biologically distinct disease with multifactorial etiology. It is unquestionably impossible to identify a specific risk factor for the majority of BC patients. Among the various risk factors, MetS serve as an important emerging risk factor influencing BC etiology. Treatment strategies for BC are continuing to evolve at a greater pace, but definitely, BC prevention has received far less attention to reducing the incidence of BC. This is indeed partly attributable to inconsistent information concerning the role of modifiable risk factors such as obesity and MetS. An area of concern is the markedly increasing the prevalence of these modifiable risk factors in various countries worldwide.
We estimated the prevalence of MetS to be 65.4% for newly diagnosed BC patients compared to 30.8% for controls, which is higher than that previously reported. The difference in the prevalence of MetS noted could be explained by the vast variations in geographic and genetic factors. The present study contemplates an important observation of the high prevalence of each component of MetS in BC patients as compared to the general population (P < 0.00001).
It is well established that obesity is not a single disease and is commonly associated with metabolic disorders. Multiple molecular mechanisms proposed to connect BC and obesity include hyperinsulinemia and insulin resistance, increased inflammatory cytokines, leptin and adiponectin signaling, and elevated bioavailability of estrogen. Hyperinsulinemia (a hallmark of insulin resistance) by direct mitogenic effects and indirect effect of increased circulating levels of bioavailable insulin-like growth factor-1 (IGF-1) may result in a higher risk of cancer development. Therefore, IGF-1 exerts both mitogenic and antiapoptotic effects, thereby promoting cancer initiation and progression in insulin-resistant patients. Insulin and IGF-1 inhibit the hepatic synthesis of SHBG. Both these hormones stimulate the ovarian synthesis of sex steroids that can promote cellular proliferation and inhibition of apoptosis [Figure 2].
|Figure 2: Mechanism proposed to connect MetS and BC. MetS: Metabolic syndrome, BC: Breast cancer|
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On further analyzing the data for menopausal status separately, we could correlate those postmenopausal patients MetS (75%) had a greater risk of developing BC as compared to their premenopausal counterparts (25%). Our results corroborate with previous studies reporting a strong association of BC risk and MetS; being limited to postmenopausal women.,, In the present study, however, menopausal status was not associated with BC risk, indicating that the effect of MetS is independent of receptor status. Our data points toward the fact that menopausal status is independent of receptor status in patients with BC. In addition, we found that majority of BC patients with MetS were receptor positive (66.2%). Dibaba et al. reported that MetS is associated with a somewhat lower risk of hormone receptor-negative compared to hormone receptor-positive BC among American women.
Our results should be interpreted in light of some limitations. Relatively, a small number of cases and controls; therefore, the results should be cautiously interpreted. This study has several strengths, in terms of age-matched case–control design and inclusion criteria limiting enrollment of only newly diagnosed BC cases.
| Conclusions|| |
The prevalence of MetS in BC patients in our study was higher than the rates reported in the literature. Our work sheds light on the importance for clinicians to embark on opportunistic screening for women with MetS and guide them toward regular screening for BC. We conclude, based on our findings that clinicians should grab the opportunity to circumvent this deadly peril by guiding these cohorts of women with MetS to embrace healthy lifestyle modifications, thereby leading to the ultimate goal of BC prevention; prevention is better than cure.
I would like to acknowledge Dr. Urvashi Grover for helping with the statistics work.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]