Cancer represents the second main cause of death worldwide, behind only cardiovascular diseases (CVD).¹ Projections for 2030 expect around 24 million cases of cancer and 14.6 million deaths.² This disease represents a global health challenge that has been increasing in low-and middle-income countries with the globalization of the economy and lifestyles.³ Among various neoplasm types, breast cancer (BC) is the one that affects women the most each year, being responsible for 23% (1 380 000) of all new cancer cases and 14% (458 400) of all deaths due to cancer.⁴

The number of long-term cancer survivors is increasing. A better organization of cancer care, more effective treatment options, and evidence-based tumor-specific protocols are factors that have contributed to this increase.^{5 - 7} However, 2 out of 3 cancer survivors are prone to suffering from complications in the long term. ⁸ A wide spectrum of late adverse effects such as CVD, diabetes, dyslipidemia, arterial hypertension, osteoporosis, and metabolic syndrome (MS) components are likely to develop among cancer survivors. For this reason, it is important to design appropriate health management strategies for these patients.^{7 , 9 - 10}

Studies show a high prevalence of MS in the Brazilian population. One of these population studies found a MS prevalence of 29.8% in adults (95% confidence interval [CI]).⁴ In a study performed with 50 women with BC aged between 40 and 80 years and 50 age-matched controls, the prevalence of MS was 40.0% among patients with BC and 18.0% in the control group (P = 0.02). A positive independent association was observed between MS and risk of BC (odds ratio [OR] = 3.037; 95% CI 1.214–7.597).¹¹

In MS, adipocytes and adipokines derived from the perivascular adipose tissue such as leptin, resistin, IL-6, and tumor necrosis factor-α are potent pro-inflammatory molecules that may promote oxidative stress in the endothelium and affect endothelial function,¹² leading to a predisposition to CVD.^{13 , 14} In this context, a new subspecialty has emerged within the cardiology field: cardio-oncology, where cardiologists participate in a multidisciplinary team dedicated to cancer treatment. Before initiating treatment, it is important to identify patients at increased risk for cardiac toxicity so that alternative, less cardiotoxic treatment options can be considered.^{15 , 16}

The aim of the present study was to verify the prevalence of MS and CVD risk in female BC survivors (BCS).

Mixed-race participants and those with secondary education were the most prevalent in both groups. Considering family income, we observed that participants of this study had a low socioeconomic status, since 40% of the control group had a family income of ½ to 1 minimum wage and the same percentage earned 1 to 2 times the minimum wage in the BCS group. Most women reported not practicing regular physical exercise or having a family history of cancer, as well as not smoking or drinking; this last variable presented a statistical difference from the control group, as did the presence of menopause ( Table 1 ).

Table 1

Characteristics	Control group (n = 60)	BCS group (n = 60)	p
Race
White	10 (17%)	10 (17%)	0.849b
Black	16 (27%)	19 (32%)
Mixed-race	33 (55%)	29 (48%)
Asian	1 (2%)	2 (3%)
Schooling
Incomplete primary/lower secondary education	8 (13%)	3 (5%)	0.543b
Primary/lower secondary education	5 (8%)	4 (7%)
Incomplete secondary education	5 (8%)	6 (10%)
Secondary education	33 (55%)	34 (57%)
Incomplete tertiary education	3 (5%)	2 (3%)
Tertiary education	6 (10%)	11 (18%)
Family income
< ½ MW	3 (5%)	6 (10%)	0.222b
½ to 1 MW	24 (40%)	14 (23%)
1 to 2 MW	22 (37%)	24 (40%)
2 to 5 MW	10 (17%)	16 (27%)
> 5 MW	1 (2%)	0 (0%)
Physical activity
Yes	47 (78%)	42 (70%)	0.297a
No	13 (22%)	18 (30%)
FH of cancer
No	40 (67%)	36 (60%)	0.448a
Yes	20 (33%)	24 (40%)
Menopause
No	29 (48%)	9 (15%)	<0.0001 a
Yes	31 (52%)	51 (85%)
Smoking
No	55 (92%)	58 (97%)	0.439c
Yes	5 (8%)	2 (3%)
Drinking
No	38 (63%)	56 (93%)	0.0001 c
Yes	22 (37%)	4 (7%)

BCS: breast cancer survivors; MW: times the minimum wage; FH: family history; a: chi-squared test; b: G test; c: Fisher’s exact test.

Regarding the characteristics of tumors and the performed treatment ( Table 2 ), the right breast had been affected in 60% of female BCS. Considering staging levels, the most prevalent was stage II (43.3%). As for treatment, 86.6% underwent a complete protocol (surgery, chemotherapy, and radiotherapy), with varying orders according to clinical characteristics and the tumor’s anatomopathological aspects. The mean follow-up time, representing the end of treatment and follow-up, was 4 years.

Table 2

Characteristics	n	%
Tumor location
Right breast	36	60.0
Left breast	24	40.0
Staging
I	11	18.3
II	26	43.3
III	23	38.3
Treatment
C + S + R	21	35.0
C + S + R	25	41.6
C + R + S	5	8.3
C + R + S	1	1.7
C + S	5	8.3
C + R	1	1.7
C + S	1	1.7
S	1	1.7
Follow-up time (years)	4 ± 2.44

C: chemotherapy, S: surgery, R: radiotherapy

When comparing anthropometric parameters and metabolic risk factors among female BCS and the control group ( Table 3 ), we observed that both groups presented overweight (mean BMI of 26.08 kg/m²in the control group and 29.27 kg/m²in the female BCS group). The WHR in both groups was over 0.86, which is the threshold for identifying high cardiovascular risk. Cholesterol levels were above normal values for women, with mean values of 200.46 mg/dL and 213.98 mg/dL in the control and BCS groups, respectively. Some variables presented statistically significant differences between groups, such as weight, BMI, AC, HC, and LDL-cholesterol.

Table 3

Variables	Control group (mean ± SD)	BCS group (mean ± SD)	p
Age (years)	49.06 ± 6.22	48.86 ± 7.23	0.871a
DAP (mmHg)	86.08 ± 14.11	83.5 ± 14.24	0.320a
Weight (Kg)	62.15 ± 11.45	69.36 ± 13.01	0.002 a
Height (m)	1.54 ± 0.05	1.53 ± 0.05	0.703a
BMI (Kg/m 2 )	26.08 ± 4.40	29.27 ± 5.18	0.0004 a
AC (cm)	86.18 ± 15.33	92.08 ± 13.56	0.021 a
HC (cm)	93.63 ± 9.33	99.89 ± 11.49	0.001 a
HDL (mg/dL)	49.73 ± 14.9	49.43 ± 13.02	0.907a
LDL (mg/dL)	118.87 ± 35.54	132.5 ± 30.20	0.020 a
VLDL (mg/dL)	32.10 ± 12.53	28.86 ± 10.90	0.134a
Triglycerides (mg/dL)	159.83 ± 59.07	143.25 ± 61.98	0.136a
	Median / IQR (25–75)	Median / IQR (25–75)
SAP (mmHg)	120 110–132.5	120 110–130	0.636b
Cholesterol (mg/dL)	202 181–238.3	197.5 178.5–221.5	0.271b
WHR	0.92 0.84–0.95	0.93 0.89–0.97	0.207b
Glycemia (mg/dL)	95.5 89–104.5	90.5 85–102.25	0.096b
Insulin (µUI/mL)	5.79 3.50–12.3	6.81 3.40–1.03	0.603b
HOMAR- IR	1.42 0.84–2.93	1.65 0.74–2.71	0.437b

SD: standard deviation; IQR: interquartile range; BCS: breast cancer survivors; SAP: systolic arterial pressure; DAP: diastolic arterial pressure; BMI: body mass index; AC: abdominal circumference; HC: hip circumference; WHR: waist:to-hip ratio; HDL: high-density lipoprotein; LDL: low-density lipoprotein; VLDL: very low-density lipoprotein; HOMAR-IR: Homeostasis Model Assessment for Insulin Resistance; a: Student’s t-test; b: Mann-Whitney test. p < 0.05 (significance).

Variables that presented statistically significant differences between groups were analyzed by a logistic regression model. Through this model, we identified that isolated variables did not increase the OR for MS, except for HC ( Table 4 ).

Table 4

Variables	p	OR	(95% CI)
Menopause	0.630	0.684	0.15 to 3.12
Weight (Kg)	0.598	1.037	0.91 to 1.19
BMI (Kg/m2)	0.658	0.918	0.63 to 1.34
AC (cm)	0.455	1.056	0.91 to 1.22
HC (cm)	0.028	0.000	0.00 to 0.13
LDL (mg/dL)	0.853	0.998	0.98 to 1.20

OR: odds ratio; CI: confidence interval; BMI: body mass index; AC: abdominal circumference; HC: hip circumference; WHR: waist-to-hip ratio; LDL: low-density lipoprotein.

The identification of MS in both groups, according to NCEP-ATP III criteria, is demonstrated in Graph 1 . In this graph, we observe a higher occurrence of MS in the BCS group, with 27 women (45%), in contrast to 19 (32%) in the control group. When comparing groups, we did not observe a statistically significant difference.

Graph 1

In the 10-year CVD risk stratification according to Framingham scores ( Table 5 ), we obtained a high prevalence of low cardiovascular risk in both groups (73% in the control group and 72% in female BCS), with no statistically significant differences between groups according to Student’s t- and Mann-Whitney testing of the obtained scores.

Table 5

Cardiovascular risk	Control group		BCS group		p
	n	mean risk	n	mean risk
Low	43 (73%)	4.48 %	44 (72%)	4.34 %	0.411b
Intermediate	15 (22%)	13.13 %	13 (25%)	14.48 %	0.750a
High	2 (5%)	29.50 %	3 (3%)	27.66 %	0.640a

A: Student’s t-test; b: Mann-Whitney test. p < 0.05 (significant). Note: the Student’s t- and Mann-Whitney tests assessed differences between scores obtained in both groups in the Framingham scale (continuous variable). On table 5, such scores were transformed in percent values for risk stratification.

For assessing the mean cardiovascular risk in both groups ( Graph 2 ), we obtained a 10-year risk for developing CVD of 7.48% in the control group and 7.70% among female BCS. When comparing groups, we did not observe a statistically significant difference ( p > 0.05).

Graph 2

Women in both groups presented similar socioeconomic and clinical characteristics, such as low schooling levels and low socioeconomic status ( Table 1 ). These factors influence the level of knowledge on diseases in general and the adoption of healthy lifestyles,⁵ which could explain the low prevalence of regular physical activity among women in this study. This fact directly impacts MS and CVD risk factors.¹ However, female BCS had less damaging life habits, such as lower levels of smoking and drinking, when compared to the control group. The higher prevalence of menopause among BCS may be related to chemotherapy treatment, which favors its early development.⁷

The anthropometric parameters and metabolic risk factors directly related to obesity (weight, BMI, AC, HC, and LDL-cholesterol) were elevated in female BCS, with statistically significant differences when considering the control group ( Table 3 ). Results of a controlled and well-designed study with some of these variables demonstrated that cancer survivors were more dyslipidemic than the control population.¹⁶ The increase in BMI among post-menopausal women mainly results from an associated increase in estrogens.¹⁸ In addition, the pain, fatigue, and weakness associated with chemotherapy may cause physical inactivity, leading to abdominal obesity. Moreover, an unhealthy diet and lack of exercise increase visceral fat, leading to MS and chronic diseases such as obesity, hypertension, and diabetes.¹⁹

A prospective study performed in Denmark with women with BC revealed that those who had a BMI of 30 kg/m² or higher presented more advanced disease at diagnosis when compared to those who had a BMI of less than 25 kg/m.²⁴ Another study performed in the United States observed that, in women who gained weight after a BC diagnosis, each 5-kg gain was associated with a 13% increase in specific mortality, concluding that an elevated BMI was associated to higher mortality rates due to BC.¹⁸ The presence of visceral adipose tissue can lead to MS due to its hyperlipolytic state and contribution of free fatty acids to the increase in insulin resistance.¹⁶ Therefore, it is extremely important to routinely assess the nutritional status of women with BC with easily obtainable anthropometric measures such as BMI and AC.⁴

Female BCS face approximately twice the risk of death due to CVD and other chronic diseases than age-matched women with no cancer history.²⁰ In this study, we observed that almost half of our sample (45%) of BCS were diagnosed with MS. Similar results were observed in another study, where MS was present in 50% of female BCS and in 37.5% of participants in the control group. In this study, the most frequently observed diagnostic criteria were abdominal obesity (62.5%) and dyslipidemia (45.2%).¹⁰ Another study, also performed with women with BC, reported that 69.2% of post-menopausal women had MS and 53.8% had advanced cancer stages, demonstrating that MS could influence a worsening of the BC prognosis.⁴

In a prospective study with 2092 patients followed-up due to BC, MS was significantly associated with menopause, HOMA-IR index, HC, and hypertension.²¹ This corroborates findings from this study, where our logistic regression ( Table 4 ) identified a higher risk of developing MS in women with increased HC. The occurrence of MS is 2.2 to 4.4 times higher in BCS than in the general population. These findings may reflect a lack of interest and education on MS among BCS.⁵

Drugs commonly used in cancer treatments, such as anthracyclines, camptothecins, epipodophyllotoxins, and platin-based agents, interrupt DNA replication and protein transcription and synthesis, thus compromising cell regeneration and growth. These agents may interact with receptors or second messengers, inducing gonadal hormone deficiencies, and produce reactive oxygen species leading to mitochondrial dysfunction. Anemia, apoptosis, and cell lysis may lead to tissue hypoxia, causing the liberation of pro-inflammatory cytokines and macrophage activation. All these effects may contribute to the development of obesity, insulin resistance, and dyslipidemia, and ultimately to MS.¹⁰

Female BCS in this study had a mean Framingham risk score of 7.70%, thus being stratified as at low risk for CVD in 10 years ( Graph 2 ). On the other hand, the WHR (which identifies the current cardiovascular risk according to an individual’s body fat distribution) was above the threshold in both groups ( Table 3 ), classifying them as at high CVD risk. Although the mean Framingham score in this study was lower than that reported by other studies, evidence shows that patients who underwent cancer treatment had a subsequent increase in CVD risk. The risk of developing CVD among patients with BC who underwent chemotherapy was 3 times higher than in patients who underwent surgery only, and it was 4.22 times higher in patients who had chemotherapy and radiotherapy.²²

According to cardio-oncologists, cardiotoxic therapies (including chemotherapy or radiotherapy) are the main contributors to an increase in CVD risk in BCS.²³ In a case-control study with 2168 women from Northern Europe with breast adenocarcinoma treated with radiotherapy,²⁴ each 7 Gy of radiation corresponded to an increase in cardiovascular risk of 7.4%. The risk was observed 5 years after receiving radiotherapy and persisted for 30 years.²⁵ Moreover, depression, anxiety, and stress and/or anguish were associated with a 30% increase in MS prevalence among cancer survivors. Many subjacent pathophysiological associations may also be driven by psychological health. Stress involving the exposure to treatment may cause interruptions in the production of hormones and neurotransmitters, which influences cardiovascular risk.²⁶

A meta-analysis of data from 289 109 patients demonstrated that mortality due to CVD was higher among women who underwent radiation therapy for BC in the left breast in comparison to those who had it in the right breast.²⁷ This way, our findings indicating that the right breast was more affected and a mean follow-up to the end of treatment of only 4 years (according to Table 2 ) may explain the low 10-year risk for CVD in female BCS and the absence of statistical differences when compared to the control group ( p > 0.05).

Despite some limitations, such as the difficulty in establishing a causal association between the analyzed variables and MS due to the sample size and cross-sectional nature of the study, our work provided important clinical information on cardiometabolic factors present in BCS. This is the first step for identifying the frequency of risk factors in BCS, allowing the allocation of important subsidies for elaborating public health policies and personalized treatment plans that are less harmful and cardiotoxic.^{28 - 29}

This study demonstrated a higher prevalence of MS among female BCS, possibly due to overweight. Although the studied population presented a low risk for CVD, we recommend that female BCS adopt healthy lifestyles, as well as rigorous screening and control of cardiometabolic risk factors. However, longitudinal cohort studies with these women are still needed for the development of more accurate risk prediction models for MS and CVD.