Background
Due to better breast cancer screening modalities and cancer treatment options [
1], the number of breast cancer survivors (BCS) in the United States is expected to increase from ~3 million survivors in 2012 to 3.8 million by 2022 [
2]. Although more women are surviving this disease, a higher prevalence of depressive symptoms exists among BCS compared to the general female population, often persisting more than 5 years after diagnosis [
3]. BCS also are at high risk for the development of obesity and associated cardiovascular disease risk, including metabolic syndrome, type 2 diabetes mellitus (T2DM), and hypertension [
4,
5]. Depression and heightened metabolic dysfunction in chronic cancer BCS are often attributed to cancer diagnosis and treatment side effects, including emotional distress, pain, sleep disturbances, and excessive adiposity [
6,
7].
Depression may affect the ability to make positive lifestyle changes and comply with medical therapy [
8], while antidepressant treatment is associated with weight gain [
9], possibly placing BCS at even greater metabolic risk. Indeed, a recent meta-analysis concluded that depression is associated with worse glycemic control, poor adherence to medication and diet regimens, and a reduction in quality of life in adults with T2DM [
10]. Large waist circumference and low high-density lipoprotein cholesterol (HDL-C) also show associations with depression in subjects with an unknown cancer history [
11]. Thus, determining the presence of depression in BCS may have implications for clinical care in the chronic phase of recovery.
The tendency for weight gain with aging places postmenopausal women at increased risk for metabolic dysfunction [
12]. In addition to abdominal obesity, significant risk factors for breast cancer in postmenopausal women are elevated fasting glucose, hypertension, hyperlipidemia [
13], all components of the metabolic syndrome. Less is known about whether cancer survivorship increases metabolic risk during long-term recovery. Only a few studies have matched postmenopausal BCS to postmenopausal non-cancer controls [
4,
14,
15], finding that BCS are more likely to have metabolic abnormalities than age-matched women without prior breast cancer. However, several limitations are present in these studies, including differences in BMIs between cases and controls and/or lack of consideration of differences in racial profiles between groups, which could affect interpretability of the results. Thus, this study evaluated metabolic risk and depression in postmenopausal BCS compared to postmenopausal women without a prior diagnosis of breast cancer matched for age, race, and BMI. We hypothesized that women with previous breast cancer have worse depression scores and poorer metabolic profiles compared to women without a history of breast cancer, and that this difference is independent of age, race, and obesity. Further, we anticipate that BCS with depression will have greater metabolic dysfunction than BCS without depression.
Discussion
While numerous studies have identified weight gain as a consequence of breast cancer treatment extending into the chronic phase of recovery [
23,
24], fewer studies have examined the prevalence of metabolic dysfunction in BCS. Although studies have reported that postmenopausal BCS have more metabolic abnormalities than non-cancer controls [
4,
14], ours is the first to show that this is independent of age, race, and obesity. We find that fasting glucose is higher, with a trend for higher cholesterol, in BCS compared to non-cancer controls. We also determined that BCS are more likely to be treated for depression than non-cancer controls and that BCS with depression have more metabolic abnormalities. Thus, understanding the consequences of breast cancer diagnosis and treatment on risk for depression and metabolic dysfunction may aid in medical monitoring to optimize health during the survivorship phase of cancer recovery.
The pathophysiological response linking depression and metabolic dysfunction is inconclusive with regard to causal factors. It is postulated that depression is associated with increased stress and activation of the hypothalamic–pituitary–adrenal (HPA) axis, which is involved in the pathogenesis of central adiposity and metabolic syndrome [
25]. Greater metabolic dysfunction is associated with higher proinflammatory cytokines [
26], many of which are elevated in BCS [
27,
28]. Conversely, there is evidence that many cancer treatments, including radiation and chemotherapy may activate an immune response [
29,
30], leading to dysregulation of the HPA axis and, ultimately, depression [
31]. Further, development of central adiposity also increases secretion of endogenous steroid hormones in obese, postmenopausal women [
32]. High levels of circulating estrogen and testosterone are associated with an increased risk of breast cancer in peri- and postmenopausal women [
33,
34]. Although, we do not believe estrogen concentrations have been compared between BCS and non-cancer controls, no differences in hyperandrogenic status (testosterone concentrations >1.2 ng/ml) were found between these groups previously, despite observed metabolic differences [
15]. Studies, including ours, suggest that as many as 50–55 % of BCS are depressed [
35‐
37], which is ~20–25 % more than that observed in postmenopausal women without a history of cancer [
38]. Further, our results agree with previous reports [
14,
39] that metabolic syndrome is prevalent in ~50 % of postmenopausal BCS. This is ~1.5 higher than what is observed in postmenopausal women of comparable age and BMI in NHANES [
40] and our postmenopausal non-cancer controls. The presence of metabolic abnormalities and depression following breast cancer diagnosis are associated with elevated cancer recurrence and mortality rates [
39,
41,
42], highlighting the importance of understanding the mechanism linking depression and metabolic dysfunction in BCS.
Often the failure to recover after breast cancer treatment (i.e. low quality of life persisting for years following completion of cancer treatment [
43]) is attributed to lifestyle choices, including low activity levels and suboptimal nutrient intake. However, our results suggest that the metabolic abnormalities and depression observed in BCS may not be attributable to low cardiorespiratory fitness, as these risk factors were present even though a higher VO
2max was observed in BCS than non-cancer controls. Despite this finding, many studies suggest that depressive symptoms and metabolic dysfunction improve with exercise in BCS [
44‐
46].
This study is limited by a small sample size, which prevented stratification by breast cancer treatments and the control of length of time post-cancer treatment. As there is evidence that breast cancer treatments, including chemical variations in drugs used for chemotherapy, may have varying effects on metabolism [
47], future studies should attempt to stratify by treatment. There is limited data available on the impact of duration of survivorship on the observed relationships; however, there is evidence that subjective outcomes (i.e. quality of life and depression) remain lower than pre-diagnosis or may even continue to decline during the survivorship phase [
3,
48]. The cause of this continued failure to recover is not elucidated and may be influenced by factors other than the cancer diagnosis and treatment (i.e. financial and emotional support) during the survivorship phase. Although the gold standard for depression evaluation is the use of a clinician rated interview technique, such as the Structured Clinical Interview for DSM-IV Axis I Disorders and the Hamilton Depression Rating Scale, these methods require substantial subject time and trained clinical interviewers [
49]. Self-report questionnaires, such as the CES-D, have strong validity and reliability [
50] and are less burdensome [
51] when compared to interview techniques. Further, because of the pilot nature of this study, body composition assessments of the BCS were limited to anthropometric measurements. While more sophisticated measures of body composition may provide additional insight as to the role of cancer survivorship on metabolism, these tests can be expensive and often require radiation exposure, which may decrease participant interest in and compliance to the study protocol. However, some of these limitations are balanced by our strong study design, where BCS were matched for age, race, and BMI to non-cancer controls. BMI of the subjects spanned from normal weight to morbidly obese, while most studies examining metabolic dysfunction in BCS only includes those who are obese; thus, these findings may be more representative of the general BCS population.
In summary, our results support the need to monitor weight gain, depression, and the progression of metabolic abnormalities during treatment and longitudinally in BCS, as their development may affect long-term survivorship. Further studies into the mechanistic links between depression and metabolism are necessary to identify strategies that can offset their impact on survivorship following a breast cancer diagnosis.
Authors’ contributions
MCS was involved in study design, data collection and analysis, and writing the manuscript and ASR and APG in the study design, data interpretation, and manuscript review. All authors read and approved the final manuscript.