There is a bidirectional relationship between chronic low-grade inflammation and breast cancer, as a tumor can produce an inflammatory environment and therefore a systemic immune response, but chronic inflammation can also both precede and promote the development of cancer [1]. There is even talk of considering inflammation to be an enabling feature of breast cancer, or the seventh hallmark of the disease along with the six hallmarks already identified by Hanahan and Weinberg [2,3]. Inflammation is a process, or bodily response, secondary to infection or sudden injury, and it is associated with the activation of various molecular mechanisms [4]. This response can be local or systemic, depending on the severity, and both indicate an imbalance of the metabolism of the affected tissues. This metabolic imbalance in the lesion is produced by an increase of immune cells as well as inflammatory parameters of great clinical importance, such as C-reactive protein (CRP) and its inducer interleukin-6 (IL-6) [4,5].

Once the inflammatory response ends, tissue metabolism is normalized. If this process of remission is interrupted by some circumstance, such as pathogens, toxins or other stimuli, healthy tissue could be damaged and produce what is known as persistent low-grade inflammation, or chronic inflammation [6]. It is the result of an immune system that overreacts so that the concentrations of inflammatory factors are higher than in a healthy population [5]. This systemic and chronic inflammation is widely associated with chronic diseases [6] and even symptomatology, as there is a positive association between increased levels of CRP and excess of adipose mass (excess weight and obesity), which is a factor that could be potentially modified with physical activity and diet [4,7]. Moreover, inflammatory markers such as IL-6 have also been associated with the malignant transformation of epithelial cells and tumor progression, associating low-grade inflammation with a higher risk of cancer and recurrence in the survival phase. Thus, these factors are considered valuable prognostic biomarkers in the population of those with cancer [1,8,9]. Therefore, knowing and finding appropriate primary prevention strategies to modify these parameters is a major challenge in the field, so as to reduce the risk of cancer recurrence and increase survival.

Different therapeutic strategies have shown efficacy in the modification of these and other biological parameters, but with contradictory results. The beneficial effects of physical exercise as a means of controlling low-grade inflammation have been amply demonstrated [10,11], even in breast cancer survivors (BCSs). A study conducted by Jones et al, in which they used a physical exercise program in BCSs, found a significant reduction of IL-6 [12]. Additional studies have evaluated other strategies, such as manual therapy [13], tai chi [14], mindfulness [15], or yoga [16], to reduce inflammation markers in different cancer populations. However, scientific evidence about strategies based on telemedicine are scarce, and they are practically nonexistent for cancer. A study conducted by Haggerty et al assessed two technology-based, 6-month, lifestyle interventions (telemedicine or text messaging) in obese women with endometrial hyperplasia, showing a reduction of some biomarkers such as IL-6 after the intervention [17]. Another study by Frank et al examined the effectiveness of telehealth coaching promoting nutrition and exercise in soldiers, evaluating biomarkers of bone health [18]. There are also some clinical trial protocols with no published results at present [19-21]. Therefore, at the moment there are no strategies in which telemedicine, and specifically mobile health (mHealth), are used as a delivery mechanism for interventions that could cause biological changes.

Low-grade inflammation is highly influenced by aspects such as obesity, fatigue or a sedentary lifestyle [22-24], and its relationship with chronic pathologies has been demonstrated. However, the issue of association, or the factors that influence its regulation through nonpharmacological and distance-based intervention strategies, remain unresolved [6]. In the biopsychosocial context that encompasses a subject with cancer, promoting changes through mHealth strategies in psychological, physical or social aspects is not entirely complicated (eg, quality of life) [25]. However, biological parameters have a high intersubject variability and are not usually addressed in these types of studies [24]. Therefore, understanding what factors can influence these parameters can help to develop mHealth-based strategies, thus increasing patient empowerment in regard to their health.

To the best of our knowledge, scientific evidence is scarce in regard to mHealth-based strategies related to tracking biomarkers of inflammation, and the importance of low-grade inflammation in cancer recurrence has already been demonstrated. Thus, the objectives of this study were to:

The objective of this study was to determine the preliminary results of the possible association between the use of an mHealth strategy app as a delivery mechanism to monitor energy balance in cancer and the reduction of systemic inflammation markers, as well as to suggest possible predictors of this change. Current findings suggest that after two months of use of the app, a significant reduction of these markers can be observed. Thus, there could be a possible association between the two. In addition, the change in weight, pain and quality of life, as well as the type of tumor removal surgery, hormone therapy and the uMARS score, can have a contribution in the changes found in the concentrations of CRP and IL-6.

A system of monitoring energy balance through an mHealth app seems to reduce the biological parameters of systemic inflammation (CRP and IL-6). Our results suggest that after two months of use of the mHealth app, based on the monitoring of energy balance (in terms of diet and physical activity), the concentration of CRP and IL-6 are significantly reduced in BCSs. In fact, this change has a moderate effect size in CRP (Cohen d=–0.640; 95% CI –0.985 to –0.293) and a high effect size in IL-6 (Cohen d=–0.805; 95% CI –1.225 to –0.379). A study by Skogstad et al was the only one found with a design similar to ours, as it used a virtual internet physical activity motivation strategy in which some biological parameters were measured [43]. In this study, participants were included in a motivational physical activity program in which they measured their steps using a wrist-band accelerometer. However, unlike our study, no differences were found in CRP concentration after the intervention, perhaps because their study target population were healthy workers without pathology. The effect size reported for both our biomarkers supports the hypothesis that these changes are not due to time, but it is important to remark that the quasi-experimental pre-post design of our study does not allow us to affirm that the changes found are only attributable to the use of the app. Therefore, a controlled and randomized clinical trial should be carried out in the future.

Biological parameters of systemic inflammation can be mediated or modified by lifestyles changes such as physical activity and diet [4,6,7]. This study is the first to examine clinical and anthropometric factors that affect changes in these biological parameters, after using a mobile strategy to monitor energy balance in breast cancer survivors. Because rehabilitation strategies focus on face-to-face or distance physical activity and diet programs, understanding the potential determinants of reducing inflammation markers can help design more effective intervention strategies.

The results of our study show that possible moderators of a reduction in CRP concentration include not receiving hormonal therapy, as well as having higher satisfaction and changes in quality of life (the higher quality of life change, the lower the CRP concentration). The role of estrogen in inflammation is poorly understood, the mechanism is not well studied, and its relationship is very complex [44], and different studies show contradictory results depending on different pathologies, with some showing they are associated with an inflammatory activity, while others show a proinflammatory role [44]. The differences found in pre and postmenopausal women suggest that the peripheral production of estrogens plays an important role in these differences [44-47]. Our results provide new evidence in this regard, since not having received hormone therapy may be a predictor of a greater reduction in CRP concentration in female survivors of breast cancer. However, estrogen’s relationship with quality of life has been considered from another point of view. We understand that it is not that a higher perception of quality of life is a predictor of a reduction of proinflammatory markers but rather the other way around, that the diminished inflammatory state is associated with an increase in the quality of life [48,49]. Ultimately, our results suggest a higher score in uMARS as a predictor of the change in CRP concentration. In addition, there is a strong association between satisfaction and quality with the amount of time spent on the mHealth app. If women with the highest score in uMARS use the mHealth app more, then the reduction in inflammatory markers could be due to the direct relationship caused by a healthier lifestyle [6,50,51].

The results of our study also show possible moderators of the reduction in IL-6 include the type of tumor removal surgery (less invasive surgery), as well as changes in both weight and pain (the greater the reduction of these factors, the greater the reduction of IL-6). These results are consistent with the known bidirectional relationship between obesity and low-grade inflammation, which contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders [4]. In the same way, an inflammatory reaction is also mediated by the classic cardinal signs of inflammation (eg, pain) [52]. Therefore, it is logical to think that a reduction in pain reported by breast cancer survivors can be a predictor of a reduction in IL-6 concentration such as that observed in our results. Finally, there is a lot of scientific evidence to support the use of minimally invasive surgical techniques since they don’t raise inflammatory reactants as much, and these findings may support the relationship between IL-6 and the type of tumor removal surgery found in our results [53-56].

It is worth highlighting some strengths and limitations of the present study. The main strength lies in the nature of the study. To the best of our knowledge, this is the first study that proposes a mobile strategy to monitor energy balance as a mediator in the reduction of proinflammatory markers in BCSs. If future research supports our results, we will have found another support strategy for cancer survivors that is low cost and accessible to everyone and which could reduce markers highly related to the risk of recurrence. However, there are also many limitations to be noted. The main limitation lies in the design of the study, as well as the sample size, which prevents us from speaking in terms of causality and effectiveness. In addition, the r² obtained in the multiple regression models was low. However, we must not forget that we are trying to explain biological parameters with nonbiological variables. Our results may support the biopsychosocial model, since it shows how biology can be modified through these variables. Other biological parameters that can justify the rest of the variability that has remained to be explained should be taken into account in the future.

In conclusion, through the results of this study, we hypothesize that there is a possible association between an mHealth energy balance monitoring strategy app and biological changes in BCSs. These changes could be explained by different biopsychosocial parameters such as the use of the application itself, quality of life, pain, type of tumor removal surgery, hormonal treatment or obesity. Future studies should be carried out with a specific focus on all these biological parameters, and with an appropriate study design, to support these findings.