Most of the current studies on the effects of exercise on inflammatory factors and IGF systems in breast cancer survivors involve IL-6, IL-10, IL-1β, TNF-α, CRP, IGF-1, IGFBP-3, etc. Some researchers used meta-analysis to quantify the effects of exercise on the levels of inflammatory factors and IGF systems [28, 29], but no quantitative analysis was performed in terms of exercise period and type, and our article refines the effects of different intervention period and different intervention type on the combined effects of outcomes based on previous studies. Further quantitatively evaluate the effects of exercise on inflammatory factors and IGF systems, so as to provide a basis for more individualized studies.
Our meta-analysis showed that exercise intervention significantly reduced IGF-1 levels in breast cancer survivors, and further subgroup analyses showed significant improvements in IL-6 levels in the exercise group compared with control group when the intervention period was longer than 12 weeks, and a significant effect of exercise on CRP and IL-10 when the intervention period was less than or equal to 12 weeks; in addition, aerobic exercise plus resistance training significantly reduced IL-6 levels. Sensitivity analysis showed that exercise had a significant effect on TNF-α levels in breast cancer survivors after excluding highly heterogeneous studies.
4.1 Exercise improves the prognosis of breast cancer patients
The American Cancer Society (ACS) and the American Society of Clinical Oncology (ASCO) in their breast cancer survivorship care guidelines suggests that breast cancer survivors should engage in regular exercise consistent with ACS guidelines, should avoid lack of exercise, and should engage in at least 150 minutes of moderate or 75 minutes of vigorous aerobic exercise per week plus strength training at least two days per week .
A meta-analysis involving 16 breast cancer survivors showed that the mean relative risks of breast cancer mortality and all-cause mortality for breast cancer survivors who participated in exercise were 0.72 (95% CI, 0.60-0.85) and 0.52 (95% CI, 0.42-0.64) , respectively. Another strong piece of evidence comes from a prospective evaluation involving 8 cohorts breast cancer patients. There is an association between post-treatment exercise and breast cancer-specific mortality and various mortality rates. 8-9 Met-hours of exercise per week associated with a 50% reduction in mortality from cancer and all causes . A meta-analysis also found that exercise was negatively associated with all-cause, breast cancer-related mortality, and risk of breast cancer recurrence in breast cancer survivor . In addition, numerous studies [34-36] have shown that lack of exercise is also associated with postoperative fatigue, psychological distress, and poor overall quality of life in breast cancer patients. Therefore, exercise is one of the better prognostic rehabilitation tools for breast cancer patients.
4.2 Inflammatory factors
Tumor-associated inflammation is one of the hallmarks of breast cancer ,IL-6, TNF-α and CRP are widely recognized as biomarkers of breast cancer-associated systemic inflammation .IL-6, TNF-α and CRP are all pro-inflammatory factors that have been widely studied. In addition, IL-1β is also a pro-inflammatory cytokine that plays a role in the pathogenesis of cancer [39, 40].IL-1β levels are significantly higher in tumors of breast cancer patients than in normal breast tissue . Studies have shown that increases in chronic pro-inflammatory factors, particularly IL-6, are associated with elevated levels of fatigue and psychological symptoms in breast cancer survivors [42-44]. The mechanism may be the ability of pro-inflammatory cytokines to affect brain function through various signaling modalities (vagal activation, hormonal effects, direct interactions between circulating cytokines and brain cytokines), leading to complex cancer complications such as fatigue and depression [42-45]. In addition to pro-inflammatory cytokines, anti-inflammatory cytokines are also important in the development of tumors, such as IL-10. IL-10 is a powerful anti-inflammatory cytokine that promotes the formation of a microenvironment, then inhibits anti-tumor immune responses and promotes the growth of cancer cells [46-48]. Studies have shown that serum levels of IL-10 are significantly higher in breast cancer patients than in healthy individuals . Given these characteristics of inflammatory factors, these biomarkers can be used to diagnose female breast cancer and identify patients with a poorer prognosis.
Studies have shown that exercise is associated with lower levels of various pro-inflammatory cytokines [50, 51]. A study on breast cancer patients found a negative association between exercise and IL-6 levels; other meta-analyses have also shown a significant decrease in IL-6 and CRP levels after exercise intervention . However, in our meta-analysis we only found that exercise intervention significantly reduces TNF-α levels after excluding highly heterogeneous studies, but we did not found significant correlation between exercise and other inflammatory factors. Further subgroup analyses showed that exercise significantly reduced IL-6 levels when the intervention period >12 weeks, but exercise had a nonsignificant effect on IL-6 levels when the intervention period ≤12 weeks. In contrast, the exercise significantly reduced CRP and IL-10 levels when the intervention period ≤12 weeks. This suggests a possible effect of different intervention period on the experimental results. There was significant heterogeneity in the results of the intervention period subgroup analysis (91.3%, 99.5%, 98.0%, 60.7%), suggesting that the effect of exercise on IL-6, CRP, TNF-α, and IL-10 levels in breast cancer patients with different intervention period is a high probability of being a source of heterogeneity in the currently included studies. Therefore, we hypothesized that there may be a complex correlation between the period of intervention and changes in inflammatory factors. A study analysis  concluded that for the elderly population, short-term intervention training hardly leads to significant changes in the organism at the level of indicators. However, long-term exercise may not show changes in inflammatory markers, as older adults are susceptible to other uncontrolled environmental factors, which in turn affect the levels of inflammatory factors. In addition, we found that aerobic plus resistance training significantly reduced IL-6 levels. Previous studies [53, 54] have identified the benefits of aerobic plus resistance training, which improves the overall functional capacity of breast cancer patients. As a result, a growing number of studies have now evolved from just one type of exercise to a more complex exercise prescription of aerobic exercise combined with resistance training. However, we included too few studies on other inflammatory factors to analyze the effects of other intervention types on outcomes. More studies should be included in the future to analyze the effects of exercise intervention period and type on inflammatory markers in breast cancer patients and to determine the most appropriate intervention period and intervention type for breast cancer patients.
4.3 IGF system
The IGF system is one of the important mechanisms in breast cancer pathogenesis. IGF -1 has anti-apoptotic effect on breast cancer cells [55, 56] and IGFBP-3 is a highly relevant binding protein for IGF-1. IGFBP-3 is able to inhibit IGF-1 binding to IGF-1R (IGF-1 receptor) by competitive binding to IGF -1 to exert activity [57, 58].Studies have shown that high circulating levels of IGF-1 and low levels of IGFBP-3 are associated with an increased risk of premenopausal breast cancer [9, 59, 60]. In addition, a meta-analysis of prospective studies on the relationship between IGF-1 and breast cancer incidence in premenopausal women showed a statistically significant positive association between IGF-1 and breast cancer risk . The IGF signaling system plays an important role in breast cancer development and progression [62, 63]. In addition, the IGF signaling system is an important mediator in tumorigenesis more than 90% of breast cancer patients have overexpression of IGF-1R . So targeting the IGF system is a better option.
Studies have shown that exercise can reduce IGF-1 levels and increase IGFBPs levels . Exercise is thought to cause physiological changes in systemic IGF ligand and binding protein bioavailability, which may indirectly affect IGF-1R signaling . In our meta-analysis, we included three studies on IGF-1, and all three studies reported that exercise significantly decreased IGF-1 levels. In a meta-analysis  involving 7 studies of breast cancer patients also found a trend towards decreased IGF-I levels after exercise, but this was not statistically significant (WMD, -5.23 ng/mL; 95% CI, 13.00 to 2.53; p=0.19).However this meta-study found no significant effect of exercise on IGFBP-3 (WMD, 0.01; 95% CI, -0.96 to 0.98; p=0.99) levels. This is similar to the findings of our study, in which although there was a tendency for exercise to improve IGFBP-3, the results were not statistically significant. Among the studies on IGFBP-3 that we included, two of them [21, 25] reported elevated IGFBP-3 levels after exercise, while in another 6-month aerobic exercise study  found a significant reduction of 4.1% (p=0.006) in IGFBP-3 levels in the intervention group compared to the control group. The results showed a significant discrete pattern, which may be related to intervention type. In a 6-month study  of prostate cancer patients with aerobic or resistance exercise programs significant increase in serum IGFBP-3 of 12.1% (P≤0.05) was observed in the resistance exercise group, while IGFBP-3 was reduced by 23.7% (P≤0.05) in the aerobic exercise group. However, this may be only a conjecture, as baseline levels of IGFBP-3 were significantly higher in the aerobic exercise group than in the resistance training group in this study, and participants in this study also differed significantly from those in our study.
4.4 Limitations of the study
The article included fewer studies and included only English and Chinese studies, which may have incomplete study inclusion; second, this study did not adjust for potential confounders such as age, BMI, and gender, which may have a potential effect on the study results; third, due to the small number of included studies and the lack of available data, the subgroup analysis only discussed the effect of different exercise period and type on the result in some studies, and did not analyze the effects of all studies on the type and intensity of the intervention. A comprehensive subgroup analysis of the characteristics of exercise intervention is warranted for future studies.
This study affirms the trend that exercise positively affects the inflammatory factors and IGF system in breast cancer survivors. Exercise is feasible for breast cancer survivors, and exercise not only reduces side effects, but also improves survival rates in breast cancer patients. However, the most beneficial exercise period, type and intensity for inflammatory factors and IGF systems in breast cancer patients are not clear. Future studies should include more randomized controlled trials to analyze the appropriate exercise intervention for breast cancer patients to improve inflammatory factors and IGF systems, and to provide a basis for developing individualized exercise prescriptions for breast cancer patients.