Is There a Relationship Between Insulin Resistance and Breast Cancer-Related Lymphedema? A Preliminary Study

Abstract

Background:

High blood insulin levels, insulin resistance (IR), and obesity are components of metabolic syndrome (MetS). The literature has indicated a high risk of breast cancer in patients with MetS. However, no studies have been conducted evaluating the relationship between breast cancer-related lymphedema (BCRL), one of the most frequently encountered postbreast cancer treatment conditions, and IR. Therefore, the aim of this study was to evaluate whether there is a relationship between BCRL and IR.

Methods and Results:

A total of 28 patients diagnosed with breast carcinoma were included in this preliminary study. Patients were divided into BCRL (n = 15; mean age: 55.2 ± 11.2 years) and non-BCRL (control) groups (n = 13; mean age: 55.17 ± 6.57 years). Body mass index (BMI), waist and hip circumference, and fasting blood glucose and blood insulin levels of all patients were recorded. The Homeostasis Model Assessment (HOMA) test was used for the calculation of IR measurement with a value of 2.5 taken as an indicator of IR. Parameters were compared between groups. BMI, waist circumference measurements, blood insulin, and HOMA-IR levels were statistically significantly higher in the BCRL group than the control group (p < 0.05).

HOMA-IR values >2.5 were found in 14 patients in the BCRL group. In the control group, only three patients had IR based on HOMA-IR criteria (p = 0.000).

Hip circumference measurements and fasting blood glucose levels were similar between the groups (p > 0.05).

Conclusions:

BCRL appears to be associated with waist circumference, fasting blood insulin level, and HOMA-IR levels. In routine clinical practice, evaluation of IR may be important in the follow-up of this patient population.

Introduction

Breast cancer is the most common female neoplasm and the second cause of cancer mortality in women in industrialized countries. However, improvements in survival rates in recent decades have led to an increased incidence of long-term treatment-related complications. Breast cancer-related lymphedema (BCRL) is one of the most frequent issues faced by breast cancer survivors treated with surgery with or without radiotherapy and has a tremendous impact on quality of life and social costs. BCRL results from an iatrogenic impairment in the transport capacity of the local lymphatic system, which leads to the interstitial accumulation of lymph fluid in the upper limb.^1–8 This lymphatic insufficiency leads to a progressive inflammatory process that ultimately manifests as discomfort and recurrent infections. Patients with BCRL in the ipsilateral upper extremity suffer from swelling, heaviness, pain, numbness, stiffness, immobility, physical changes, and limitations on range of motion, daily living activity, function, personal care, and recreational and social relationships. These problems can lead to work and financial problems in patients with BCRL.^9,10

Several studies have suggested that high blood glucose and other aspects of metabolic syndrome (MetS), such as postmenopausal obesity, abdominal/central obesity, insulin resistance (IR), and high levels of insulin and insulin-like growth factor 1 (IGF-1), are associated with malignancy risk, including breast cancer. Metabolic and hormonal parameters may also be related to breast cancer pathophysiology and prognosis.^11–18

Although several studies have been conducted on breast cancer and IR, to the best of our knowledge, there are no studies in the literature evaluating the relationship between BCRL and IR. For this reason, the aim of this study was to evaluate whether there is a relationship between BCRL and IR.

Materials and Methods

This preliminary study was approved by the Baskent University Institutional Review Board and Ethics Committee (project no: KA16/90) and supported by the Baskent University Research Fund. Written informed consent was obtained from all participants.

The study population was categorized into two groups. The inclusion criterion of the BCRL group (n = 15; mean age: 55.2 ± 11.2 years) was diagnosis of unilateral upper extremity BCRL. The non-BCRL group (n = 13; mean age: 55.17 ± 6.57 years) consisted of patients diagnosed with unilateral breast cancer without lymphedema and served as the control group. All patients were treated surgically, including axillary lymph node dissection, and received chemotherapy and radiotherapy.

Exclusion criteria were bilateral breast carcinoma, bilateral BCRL, and history of MetS, diabetes mellitus, or IR.

Age, body mass index (BMI) (body weight [kg]/height² [m²]), education level, work status, dominant extremity, affected breast, duration of malignancy diagnosis, and waist and hip circumference were recorded for both groups.

None of the participants had signs of acute skin and subcutaneous inflammation.

There was no information about the BMI of the patients in each group at the time of diagnosis of cancer, and the body weight change during the anticancer treatment.

Waist circumference was measured at the midpoint between the lower border of the rib cage and the iliac crest. Hip circumference was measured at the maximum circumference at the level of the buttocks, corresponding to the symphysis pubis.¹⁹

Fasting blood glucose and blood insulin levels of all patients were recorded for the evaluation of IR. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) Index was used to assess IR. This index is calculated using the formula developed by Matthews et al.²⁰:

HOMA-IR measured using the formula: fasting plasma insulin (μU/mL) × fasting plasma glucose (mg/dL)/405. A HOMA-IR value of 2.5 was taken as an indicator of IR.^14,21,22 These parameters were compared between groups.

Measurements of differences in upper limb volume and size were used for the evaluation of BCRL. Diagnostic criterion for BCRL was identified as a difference of >200 mL in upper limb volume or a circumferential difference of ≥2 cm at any of these points between the affected and nonaffected upper limbs.^23,24 Patients meeting one or both of these criteria were defined as having lymphedema.

Patients were asked to remove all jewelry and watches from their hands and wrists before measurement. Volumetric measurement differences between the upper extremities were made using the water displacement method. A larger water container with an overflow pipe that drains into another smaller container was filled with warm water up to a mark at the lower border of the overflow pipe. Each arm was placed in the container in turn and the volume of water that was displaced was recorded. The circumferential measurement differences method was performed using a narrow, flexible nonstretch tape measure.

Measurements were performed at the following levels: metacarpophalangeal joint, wrist, 10 cm distal to the lateral epicondyle, 10 cm proximal to the lateral epicondyle, and 20 cm proximal to the lateral epicondyle.

The lymphedema stage of all BCRL patients was evaluated. Stage I presents with pitting edema and is reversible. Stage II occurs as the edema progresses and becomes more intense, nonpitting, and irreversible. Stage III is characterized by advanced lymphedema. Cartilaginous hardening can be observed in conjunction with papillomatous outgrowths and hyperkeratosis of the skin in this stage.²⁴

Statistical analysis

Statistical analysis was performed using the statistical package SPSS software (Version 17.0; SPSS, Inc., Chicago, IL). For each continuous variable, normality was checked using the Kolmogorov–Smirnov test, the Shapiro–Wilk test, and histograms. All numerical data are expressed as median values (minimum–maximum) or as proportions. The categorical variables between the groups were analyzed using the chi square test or the Fisher exact test. Comparisons between groups were applied using the Student t test for normally distributed data and the Mann–Whitney U test for data that were not normally distributed. Values of p < 0.05 were considered statistically significant.

Results

Clinical characteristics of the study population did not show statistically significant differences between groups (p > 0.05) with the exception of the duration of malignancy, which was significantly higher in the control group than the BCRL group (p = 0.007). Clinical characteristics of each group are summarized in Table 1.

Table 1.

Clinical Characteristics of the Study Population

Characteristics	BCRL group (n = 15)	Control group (n = 13)	p
Age, mean ± SD (years)	55.2 ± 11.2	55.17 ± 6.57	1
Duration of malignancy, mean ± SD (months)	25.53 ± 12.03	49.08 ± 28.93	0.007^a
Dominant extremity, right/left (n)	14/1	12/1	0.697
Affected breast, right/left (n)	6/9	8/5	0.225
Work status
Housewife/active working/retired (n)	13/2/0	10/1/2	0.224
Education level
No school/elementary school/middle school/high school/college/master (n)	1/1/6/2/4/1	1/2/4/1/4/1	0.518

Statistically significant.

BCRL, breast cancer-related lymphedema; SD, standard deviation.

In the BCRL group, nine patients were evaluated in lymphedema stage I, five patients in stage II, and one patient in stage III. Lymphedema evaluation results are given in Table 2.

Table 2.

Lymphedema Evaluation Results of the Breast Cancer-Related Lymphedema Group [Median (Minimum–Maximum)]

Characteristics	Values
Duration of BCRL (months)	5.6 (3–25)
Interlimb volume difference measurements (mL)	380 (105–1180)
Interlimb size difference measurements (cm)
Metacarpophalangeal joint	3 (0–4)
Wrist	4 (3–5)
10 cm distal to the lateral epicondyle	3.5 (3–5)
10 cm proximal to the lateral epicondyle	3 (3–7)
20 cm proximal to the lateral epicondyle	3.5 (3–4)

Mean BMI value was within the obesity-grade I range in the BCRL group (mean BMI: 32.37 ± 6.05) and the overweight range in the control group (mean BMI: 28.08 ± 4.35).

BMI, waist circumference measurements, blood insulin, and HOMA-IR levels were significantly higher in the BCRL group than the control group (p < 0.05).

Fourteen patients in the BCRL group had HOMA-IR values >2.5. In the control group, only three patients had IR based on HOMA-IR criteria (p = 0.000).

Hip circumference measurements and fasting blood glucose levels were similar between groups (p > 0.05).

Metabolic parameters of study population are given in Table 3.

Table 3.

Metabolic Parameters of the Study Population

Characteristics	BCRL group (n = 15)	Control group (n = 13)	p
Body mass index, mean ± SD (kg/m²)^a	32.37 ± 6.05	28.08 ± 4.35	0.043^b
Waist circumference (cm)^a	105.07 ± 19.02	92.15 ± 11.33	0.022^b
Hip circumference (cm)^a	116.67 ± 19.07	109,38 ± 10.38	0.08
Fasting blood glucose level (mg/dL)^a	103.33 ± 9.49	96.62 ± 9.52	0.118
Blood insulin level (μU/mL)^a	15.58 ± 5.7	9.31 ± 4.69	0.003^b
HOMA-IR index values^a	4.07 ± 1.52	2.2 ± 1.27	0.003^b
HOMA-IR index situation (n)
HOMA-IR >2.5	14	3	0.000^b
HOMA-IR <2.5	1	10	0.000^b

Mean ± standard deviation.

Statistically significant.

HOMA-IR, Homeostasis Model Assessment of Insulin Resistance.

Discussion

To our knowledge, this is the first study evaluating the relationship between BCRL and IR. For this purpose, we compared IR-related parameters among patients with and without BCRL. Most significantly, the number of patients with IR was higher in the BCRL group. In addition, numerical HOMA-IR index values were significantly higher in the BCRL group. Our main opinion is that IR appears to be related to the presence of BCRL. Our results correlate with the literature on BCRL pathogenesis and on genetic, metabolic, and physiologic studies of lymphedema.

Visser et al. evaluated BCRL and genetic predisposition in a systematic review and found that patients with BCRL had genetic variations in 18 genes,²⁵ including the forkhead transcription factor (FOXC2) gene, an essential regulator of lymphangiogenesis. Mutation or absence of FOXC2 may cause abnormal lymphangiogenesis and lymphedema.²⁶ In addition, the FOXC2 gene is an important regulator of IR, hyperglycemia, and adipocyte metabolism. The presence of FOXC2 in adipose tissue is correlated with increased insulin sensitivity, lower plasma glucose, and insulin levels, and appears relatively resistant to IR and obesity.^27–30

Although the mechanism of IR is unknown, alterations in adipocyte metabolism may be related. Previous studies have demonstrated that IR is promoted by increased adipocyte expression of interleukin-6 (IL-6) and tumor necrosis factor-α or reduced expression of adiponectin and leptin. Several studies have shown that the abovementioned factors are related to lymphedema. One of these factors, IL-6, a known regulator of adipose tissue homeostasis, has been shown to be increased in patients with lymphedema. Regulating the level of IL-6 and/or leptin may reduce the incidence of postoperative lymphedema.^30–32

In vitro studies have demonstrated that lymphatic fluid alone has the ability to cause adipose tissue differentiation. Recent studies have reported increased adipose deposition after lymphatic fluid leakage and dysfunction, and that adipose tissue proliferation is, in part, due to lymphatic fluid leakage. In the literature, studies have proved that the adipose deposition was increased after the lymphatic fluid leakage and dysfunction in a transgenic mouse model. Researches have demonstrated that lymphatic fluid stasis can initiate adipose tissue differentiation. Upregulation of adipose tissue differentiation marker (adiponectin) in a mouse tail model of lymphedema has also been reported.³¹ Such data lead to the question of whether the relationship between IR and BCRL has a more complicated mechanism.

BMI of 25 to 29.9 kg/m² is categorized as overweight and a BMI >30 kg/m² as obese (30.0–34.9, grade I; 35.0–39.9, grade II; and ≥40, grade III).^33,34 Substantial epidemiological evidence has shown that excessive adiposity strongly influences the risk, prognosis, and progression of various malignancies, including breast cancer.^18,34–36 In the present study, mean BMI values of both groups was >25 kg/m². Mean BMI value was within the obesity-grade I range in the BCRL group and the overweight range in the control group. High BMI scores in the pathogenesis of lymphedema have been shown in previous studies.¹⁰ Our study supports previous data indicating that obesity is associated with both breast carcinoma and lymphedema.

Elevated lipid accumulation in the body can be either due to the result of surgical procedures or due to the pathological accumulation of fluid, matrix remodeling, and adipose expansion in the affected extremity.³⁷ Chakraborty et al.³⁷ reported the crucial role of the lymphatic system in transportation of dietary lipids and the close relationship with the adipose tissue. Based on the data about the detection of the accumulation of fat, most apparently around lymph nodes and near mesenteric lymphatic vessels, the lymphatic leakage proposed as a major mechanism by promoting adipocyte hypertrophy or ectopic adipogenesis via the lymphatic defects. The lymphatic transport system has the ability to be regulated to optimize the mainstream flow of the lymphatic system. This particular flow rate depends on factors such as intrinsic and extrinsic forces, pumping regulation, nitric oxide release, and adjustment of the basal tone of the lymphatics. However, in animal experiments, mesenteric lymphatics were found to be less sensitive to these changes.³⁷

Lymphatic system dysfunction can lead to changes of lipid transport and fat deposition, as well as lymphedema and progression of MetS-related metabolic risk factors. MetS includes dyslipidemia related with atherogenesis, prothrombosis, high blood pressure, IR related with high glucose level of plasma, central obesity, and proinflammation.³⁷ Abdominal/central obesity is defined as waist circumference ≥90 cm for women in the Turkish population.^38,39 While the mean value of waist circumference was high in both groups in the present study, it was higher in the BCRL group.

Despite the exclusion of patients with a medical history of MetS, we found that IR markers, BMI, and waist circumference were higher in patients with BCRL. According to our results, we believe that BCRL may be related with MetS because of the relationship of BCRL with IR and central and total obesity. However, we were unable to evaluate all components of MetS for this study. For this reason, we cannot definitively determine the relationship between BCRL and MetS in our study population.

The presence of statistically significant results about these three entities (IR; BMI, and waist circumference) in patients with BCRL may linked with each other. However, we are unable to determine the primary component of these entities.

The main limitation of our study is the small sample size and preliminary nature. To reach clearer conclusions, this issue may be evaluated in studies with larger populations. In addition, as most patients in our study group had low-grade BCRL, we were unable to analyze the relationship between BCRL stage and metabolic parameters. Finally, we could not evaluate all components of MetS. Future studies with larger, more diverse populations would contribute to this question.

Conclusion

BCRL appears to be associated with HOMA-IR level, fasting blood insulin level, BMI, and waist circumference. In routine clinical practice, evaluation of IR and abdominal and total obesity may be important in the follow-up of this patient population. Lifestyle changes and preventive or therapeutic modalities to prevent the development of IR and related entities may be effective in reducing the risk of developing lymphedema and treating lymphedema. This issue can be better elucidated by studies that include all of the components of MetS with a larger population.

Footnotes

Ethical Approval

All procedures involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

This controlled study was approved by the local ethics committee.

Acknowledgments

The authors would like to thank Cagla Sarıturk for performing biostatistical analysis and Prof. Mehmet Adam, MD, for the primary idea, and contribution to the design and methodology of the present study.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This preliminary study was approved by the Baskent University Institutional Review Board and Ethics Committee (project no: KA16/90) and supported by the Baskent University Research Fund.

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