This meta-regression summarizes the best available evidence regarding the effects of MSE on mediators of inflammation, anthropometric data, and further perspective for interventions to improve treatment outcomes among BCS survivors at risk for metabolic diseases, such as CVD. The pooled evidence from RCTs conducted to assess the effects of exercise programs on mediators of inflammation in postmenopausal BCS susceptible to metabolic syndrome, such as CVD, showed moderate level of evidence to recommend less than three inflammatory markers (IL-6, CRP and TNF-alpha) for evidence-based personalized therapy. In light of the present evidence, clinical, chemical, and genetic factors should be incorporated in therapeutic models. A comprehensive literature search highlighted the research gaps with regards to the effect of MSE programs on anthropometric predictors and associated mediators of inflammation in postmenopausal BCS likely exposed to a number of treatment-induced adverse events. A number of studies identified that lifestyle interventions are the adjuvant therapies in improvement of body composition, including HRQOL, reduction in BMI, and decreased body fat 41, 49, 50, 51. Changes in insulin-like growth factor I (IGF-I) were also identified to play a role in pathogenesis of both cancer and metabolic syndrome, such as diabetes 51. The association between obesity and inflammation, and between chronic conditions and cancer subtypes, was described in literature based on known biological pathways. Changes in the adipose tissue, modulated by gene-environment interactions, in the cases of cancer and metabolic diseases such as CVD, modulation of adipocyte levels, hypoxia, drugs interactions, and oxidase stress, might lead to a chronic state of inflammation in predisposed patients such as postmenopausal BCS with additional comorbidities. The increased risk of obesity-related cancers could be mediated, in part, by these changes in the adipose tissues 52.
Elevated CRP is associated with increased response to proinflammatory cytokines (IL-6, TNF-alpha) following immune response, infection or inflammation. CRP concentration has been shown to increase with elevated BMI, smoking status, and HRT in post-menopausal women. CRP can be decreased with physical activities, healthy diet, and higher alcohol intake 53, 54. Although reverse causality induced by acute inflammatory process in oncogenic patients could be over- or under-estimated in this review, based on study heterogeneities included in meta-analysis, new studies with rigorous methodologies and larger sample sizes may change our actually level of evidence. Additionally, a body of knowledge on the safety and effectiveness of exercise programs in improving general quality of life in cancer survivors are available in literature 14, 18, 34−37, 55, 56. Most of these studies were able to provide the level of evidence on the efficacy and effectiveness of MSE in reducing treatment related adverse events and the effects of exercise programs on serum cytokines changes in postmenopausal BCS. Zaidi et al., (2018) discussed the chronicity of the disease and it produces long-term physiological and psychological manifestations, which adversely affect the quality of life of BCS and the options for personalized exercise programs to mitigate the potential side effects 57. The implementation of these strategies is different in continents, such as Africa, which still have a health systems challenge. The committee highlighted the needs for addressing gaps in knowledge on screening, monitoring, prevention, and management of various cardiovascular toxicities among BCS with CVD58. These limitations were due to lack of enough clinical trials and the meta-analyses and novel studies are warranted on this topic. A review investigating the effects of exercise interventions on CVD risk factors during and after completion of BC treatment suggested that MSE may be an effective strategy to control treatment-associated CVD effects in BCS and more studies are needed to define the effects of exercises on CVD and cancer outcomes 59. Further, a review by Lucius and Trukova (2015) on assessment of lifestyle interventions, including nutrition and exercises, on cardiotoxicity and predictors of treatment failure in postmenopausal BCS with CVD was conducted. The authors identified that weight management is a key adjuvant therapy for these patients. This is because many postmenopausal women had already exhibited CVD risk factors at diagnosis of BC 60. Although obesity is a consistent risk factor for CVD, other risk factors are not yet studied in literature, such as diabetes and hypertension, and contributions of genetic risk factors need further assessment toward lifestyle interventions.
Nowadays, few studies have examined the effects of exercises on inflammatory markers in BCS with CVD risk factors. Also, most of these studies have minimal sample sizes and low power; by the way, the evidence level is not quantified by levels of Evidence and Grades of Recommendations because of lack of meta-analyses (Unclear). It is difficult to evaluate whether the type of exercises and dose of exercise may influence the mediators of inflammation similarly or differently. Current level of evidence is inconclusive whether BCS with CVD risk factors have similar exercise-induced inflammatory responses compared with healthy individuals towards are also on targeted drugs. In addition, lack of objective tools, such as accelerometers, to measure exercise regimens and examine the effects of exercises on disease outcome for the patients participating in community based programs were not mentioned in many studies. Result discrepancies identified through different reviews may be due to the wide range of disease stages, as well as, the various treatment options recommended for BCS. Moreover, exercise modalities have been very diverse, with studies ranging from resistance, aerobic, mixed doses, and even non-conventional exercise interventions, such as Tai-Chi. Further, exercise modes, intensities, and follow-up periods differ from study to study, all resulting in no generalizability of findings for cytokines response. Another limitation is that some studies could not be included in the meta-analysis because of lack of sufficient RCTs.
Even though cytokines (CRP, IL-6 and TNF-alpha) seem to have a better concentration over time, misclassification is likely because only one measurement of CRP or IL-6 was assessed at study baseline and endpoint. Furthermore, only three markers were considered in this review. Additional inflammatory markers were reported in other reviews to be associated with different metabolic syndrome, such IGFBP-3. Other subclasses of proinflammatory cytokines, monocyte chemoattractant protein 1 (MCP-1), CD40 ligand and lipoprotein-associated phospholipase were not assessed in this study. Thus, dose-response meta-analysis assessing the effects of different lifestyle interventions on phenotypes and genotypes of inflammatory profiles in postmenopausal BCS could be needed in different population subgroups. This could provide evidence-based generalized recommendations. Lastly, many countries, especially those of Africa, and races were not represented in light of the present findings.
Obesity and weight gain have been identified as the most important risk factors for development and progression of postmenopausal BC 61, 62. AIs reduce the production of estrogen, decreasing stimulation of hormone receptor-positive BC 20. AIs may be less effective in obese women, due to the greater quantity of aromatase in peripheral fatty tissue. A review conducted by Ioannides et al., (2017) supported the evidence of a negative effect of obesity on AI efficacy in postmenopausal hormone receptor-positive BCS 63. The metabolic syndrome characterized by central obesity, glucose intolerance, hypertension and dyslipidaemia, is a common feature linked to inflammation in cancer subtypes also reported among BCS on AIs. This may raise some concerns especially in the adjuvant setting where the aim of treatment is to cure, and for postmenopausal patients who are already at risk for CVD. As discussed early on, the effects of endocrine therapy, such as AIs, interfere with BC and obesity related biological pathways 4. Other comorbidities, such as diabetics and CVD, are indirectly induced by gene-environmental risk factors and interactions of drugs used to manage these complex diseases. Overweight and obesity, as well as, postmenopausal status are well-known risk factors for CVD 4. A meta-analysis by Saadat et al., (2012) suggested that the apolipoprotein E (APOE) gene allele is a low-penetrant risk factor for development of BC 64. One study revealed that BC patients with the APOE4 allele have low plasma triglyceride levels when receiving tamoxifen therapy 65. The authors concluded that tamoxifen therapy increases serum triglyceride levels and may induce severe hypertriglyceridemia in BCS. A study examining the change in lipid profile produced in response to TAM therapy established the relationship between ApoE genotype and menopausal state in BCS. The final analysis showed that TAM treatment induced similar plasma triglyceride increases in patients with positive or negative APOE genotype. Compared to premenopausal patients, postmenopausal BC patients demonstrated a more beneficial lipid profile change in response to treatment 66.
ApoE genes involved in lipoprotein synthesis and metabolism are considered as promoters of chronic heart diseases 67. ApoE gene is part of a broader paradigm in clinical research, highlighted to play a role in gene-environmental risk factors interactions, as a predictor for common metabolic diseases such as CVD, via unifying obesity related intermediate phenotype, Alzheimer’s disease (AD), dementia, atherosclerosis, multiple sclerosis, peripheral artery diseases, diabetes, stroke, and cancer subtypes, as recently reported in molecular epidemiology of BC 67. ApoE is a normal small molecule composed of very low-density lipoproteins (LDL) and high-density lipoproteins (HDL), and is involved in various metabolic functions. These include lipoproteins metabolisms, cholesterols transport, tissue repair, immune response and regulation, as well as cell growth and differentiation. The localization, frequencies and biological pathways in both CVD and cancer patients have been studied elsewhere in terms of CVD, neurological dysfunction, neuromuscular diseases and different types of diabetes 67, 68. However, while many studies have tried to examine the role of the ApoE gene as molecular intermediate risk predictor for a number of conditions in multi-ethnic populations, few authors have evaluated its contribution in BC patients associated CVD 65, 66. Only one study evaluated the association between ApoE gene and the risk of BC in both non-Hispanic white and African-American women 65. The evidence is not sufficient to recommend its utility for personalized medicine. Additionally, APOE ε-4 status has been associated with greater cortical amyloid deposition, whereas exercise has been associated with less in cognitively normal adults 69. Head et al., (2012) examined whether physical activity moderates the association between ApoE gene and amyloid deposition in cognitively normal subjects. The authors identified a significant interaction between ApoE gene and exercises (p = 0.008), such that a more sedentary lifestyle was significantly associated with higher PIB binding for ε-4 carriers (p = 0.013) but not for ε-4 non-carriers (p = 0.208). All findings remained significant after controlling for age, gender, education, hypertension, BMI, diabetes, heart problems, history of depression and interval between assessments 69. A study conducted by Lückhoff et al., (2015) to compare the genotype distribution and allele frequencies of APOE ε-2 (rs7412) and ε-4 (rs429358) in 537 South Africans participating in a chronic disease screening algorithm with the goal to establish the causal pathways between AD related familial predisposition and dyslipidemia. The authors identified a statistically significant differences in the genotype distribution for APOE ε-2 (p = 0.034), as well as, APOE ε-4 (p = 0.038) in patients with the family history of AD 68. In addition, LDL cholesterol levels were inversely associated with physical activity among the study participants with familial history of AD (p < 0.001), but the association was not found in patients without family history of AD (p = 0.257). Moreover, these results may lead to the application of personalized medicine in patients clinically diagnosed with familial hypocholesteremia to exclude APOE gene as an important determinant of CVD risk factors. The authors concluded that APOE genotyping, as risk prediction for dyslipidemia in the South African population, should derive the greatest benefit from early lifestyle-based interventions intended to decrease CVD recurrence in AD susceptible patients 68. Also, its incorporation in diagnosis of postmenopausal BCS with CVD risk factors may play a role in preventing cancer drug-related adverse events and may positively impact on HRQOL of the patients. Although many studies have tried to assess the effects of MSE on obesity-induced side effects in BCS, to date, the evidence is lacking on the effects of current lifestyle interventions on ApoE in postmenopausal BC survivors with additional comorbidities, such as CVD and diabetes.