The importance of physical exercise in cardiovascular fitness in breast cancer survivors. A cross-sectional study: women in Motion 2.0

To compare the cardiovascular fitness of breast cancer (BC) survivors with an active lifestyle to those with a sedentary lifestyle. A cross-sectional study was conducted. Participants were classified into four groups: two groups of active women who performed more than 150 min/week of physical exercise, active with BC (Act-BCW) and active without BC (Act-HW); and two groups of sedentary women who performed less than 90 min/week of physical exercise, sedentary with BC (Sed-BCW) and sedentary without BC (Sed-HW). VO2max was estimated by the 6-min walking test (6MWT); speed, isometric strength, lower body maximum strength, explosive strength, balance, and body composition were also measured. ANOVA was used to analyze group differences and post hoc comparisons were developed with the Bonferroni test. A total of 92 women were recruited. Significant differences were found in VO2max between the Act-BCW and Sed-BCW groups (MeanDif = 5.86, p < 0.001). No differences in VO2max were observed between the active groups (MeanDif = 0.42, p = 0.753). Related body composition and fat mass levels were significantly lower in the Act-BCW group than in the sedentary groups (Sed-BCW MeanDif =  − 6.78; p = 0.012; and Sed-HW MeanDif =  − 12.07; p < 0.001). Women who are Act-BCW can achieve similar values in physical condition as women who are Act-HW and have better values than women who are sedentary. Furthermore, our results suggest than physical activity level may have a greater impact in body composition than a previous history of BC.


Introduction
Breast cancer (BC) is the most common tumor in women worldwide. In 2020, 34,088 new cases were estimated in Spain, assuming a 3.81% increase from 2018. Approximately 130,000 women have been living with a breast tumor diagnosis in the last 5 years [1]. Despite this, BC treatments lead to long-term side effects such as physical impairments (i.e., cardiorespiratory fitness reduction) [2] and changes in body composition (i.e., fat gain) [3]. These effects may negatively impact quality of life and survival rates of these women [4,5] In this sense, obesity has been described as a promoter of different cancer biomarkers, especially those related to general inflammation, such as IGF-1 [6,7], C-reactive protein [8,9], some interleukins, estradiol, and TNF-α [10][11][12], and can impair immune function, altering leucocyte counts, and cell-mediated immune responses [13,14].
For this reason, obesity is becoming an important topic of interest due to the possible relationship with cancer prognosis by the role of inflammatory cells in tumor proliferation, survival, and migration [15,16]. This highlights the relevance of obesity and weight control in breast cancer patients [17]. Severe obesity is associated with a significant increase in relapses and deaths in patients with operable breast cancer receiving adjuvant chemotherapy [18].
In the last 10 years, there has been a strong interest in the role of exercise for breast cancer patients as an effective tool to prevent different side effects resulting from cancer treatments [19], in particular, reducing obesity, [20] fatigue and depression levels and increasing cardiovascular fitness (VO 2max ), functional capacity, and strength [21]. These benefits have been observed in patients during any stage of the illness, including in survivors [22], and are related to the improvement of the quality of life of BC patients [23].
In addition, multiple studies have observed that physical exercise helps to rebalance the alterations in body composition resulting from cancer treatments, reducing fat mass levels, and increasing lean mass. These factors prevent different metabolic diseases and reduce relapse risk, which are associated with obesity [20,24].
It is important to note that VO 2max has been described as an independent parameter of better survival in BC [25] patients as well as in healthy women [26,27]. However, several treatments used in breast cancer patients reduce VO 2max , increase fatigue perception, and reduce functional capacity, having a negative impact on patients' QoL and survival. [28,29].
Despite the relevance of VO 2max in cancer survivors, little is known about the extent to which physically active BC survivors are able to recover and achieve similar VO 2max values compared to their healthy counterparts and whether the impact of sedentary behavior on women's VO 2max and health is similar in cancer patients and healthy women.
With this in mind, we developed a cross-sectional study to compare the VO 2max of BC patients to the VO 2max of controls with active and sedentary behaviors.

Study hypothesis
BC patients can achieve the same level of VO 2max as paired healthy women performing the same level of exercise.

Study design
A cross-sectional study was designed to include active and sedentary adult women with and without a diagnosis of BC. The study was approved by the ethics committee at the Carlos III Health Institute. The study was conducted following the principles of the Declaration of Helsinki. Participants received all necessary information, and they signed written informed consent forms to participate.
In total, 92 women were recruited on an ongoing basis from April to June 2018 at a sport center in Madrid, Spain (Tigers Running Club). The patients were divided into four groups meeting the following inclusion criteria: Two groups of active women were defined as those who performed more than 150 min of exercise per week, with a minimum of 60 min of resistance exercise and 90 min of cardiovascular exercise [30]: The exclusion criteria included women with bone metastatic disease, as well as any musculoskeletal, cardiovascular, or neurological disorder that could constitute a contraindication to exercise, and women who had the first diagnosis of the disease more than 5 years ago. Eligible women were scheduled for their testing appointment.
The participants underwent initial testing in the following order: body composition, the 6MWT, 35-m test, dynamometry tests, balance test, Sargent jump test, and squat test. The women completed the following questionnaires: the quality of life, depression, fatigue, memory, and oncology physical exercise questionnaires. All tests were performed in a single session.

Primary objective
To compare the VO 2max of BC patients with an active lifestyle to those with a sedentary lifestyle. VO 2max was estimated using the 6MWT, collecting the final distance. VO 2max was estimated using the following formula [31]: 22.506 − 0.271 * weight + 0.051 * distance(6MWT) − 0.065 * years.

Secondary objectives
To compare the fitness conditions and body compositions of BC patients with an active lifestyle to those with a sedentary lifestyle.
To assess the participants' fitness conditions, the following tests were developed: a 35-m test (speed); dynamometry tests (isometric strength); a 60″ squat test (lower body maximum strength); a Sargent jump test (explosive strength); and a 30-s balance test (balance).
Body composition was measured by bioimpedance (Tanita BC-601) at the beginning of the assessment to determine weight, fat mass, lean mass, water percentage, bone mass, and visceral fat. All women had to follow the same dietary recommendations before the test.
Physical activity was measured using the International Physical Activity Questionnaire Short Form (IPAQ-SF), which contains 7 questions. The total energy expenditure per week (measured by METS) and the sitting time per day (measured by minutes) were assessed by International Physical Activity Questionnaire (IPAQ) [32].

Sample size
The sample size of 23 participants per group was estimated with a statistical power of 80% to detect a minimum difference in VO 2max of 3.39 ml/kg/min** (1.67-5.1 ml/kg/min) between groups, assuming a total sample of 92 women **This value was selected based on the results of the meta-analysis by McNeely et al. [32], showing that a difference of 3.39 ml/kg/min, which is almost a met (metabolic equivalent), corresponds to a 12% improvement in survival in men.

Statistical analyses
Descriptive analyses using the mean and standard deviation for continuous variables and percentages for categorical variables were used.
Analyses of variance (ANOVA) were used with continuous variables to compare the groups. Post hoc comparisons were calculated using the Bonferroni test. Comparisons between categorical variables were performed using the chi-square test.
All statistical analyses were performed using SPSS version 21 software (SPSS Inc., Chicago, IL). Confidence intervals were set at 95%, and the significance value was set at p < 0.05.

Results
Of the 106 participants who were contacted at the beginning of the study, fourteen refused to participate after initial acceptance (Fig. 1).

Patient characteristics
Baseline demographic and medical profile of cancer patients participating in the study are shown in Table 1. Patient age was the first considered variable. All women were paired with a ratio of ± 3 years of age. There were no differences in age between the BC patient (49.48 vs 50.57; p = 0.687) or healthy women groups (52.26 vs 47.43 years, p = 0.076).
In terms of employment, more than 60% of the patients were working at the time. Almost 70% of the BC patients were receiving endocrine therapy at the time of the analysis.
The participants reported different comorbidities: osteoporosis, cholesterol problems, high sugar levels, high fat levels, high blood pressure, cardiac problems, and thyroid problems. Interestingly, significant differences were found between the breast cancer groups (p = 0.017).
Related to treatment side effects, large differences between patients with lymphoedema were observed between the sedentary (33.4%) and the active (50%) group. However, no significant differences between groups were observed (Chi 2 = 1.080; p = 0.299). Table 2 presents fitness profile, body composition, and physical activity levels of each of group of women.

Cardiovascular fitness
In terms of the cardiovascular fitness of active women, VO 2max levels were significantly better in comparison with the sedentary groups (p < 0.001). No significant differences were found between the Act-HW and Act-BCW groups (p = 0.75). No differences were found between the sedentary groups (p = 0.214). However, there were significant differences in VO 2max between the Act-BCW and Sed-BCW groups (p = 0.000). These results are presented in Tables 3  and 4 and in the box plot graphic in Fig. 2. Women in the Sed-BCW group did not show significant differences compared with their healthy counterparts (p = 0.21).

Body compositions, physical conditions, and physical activity levels
In terms of body composition, the Act-BCW group showed significantly better results in total weight, body mass index, lean mass, water percentage, and visceral mass compared to the sedentary groups. Moreover, the Act-BCW group had a significantly lower body fat percentage than the Act-HW group (p < 0.001). No significant differences were found in the rest of the measured variables between the active groups ( Table 3) or between the sedentary groups (Table 4).
Regarding physical conditions, the Act-BCW group showed significantly higher results than the sedentary groups in the 35-m test, dynamometry tests (right hand, left hand, legs, and back) squat test, and Sargent jump test. There were no differences between the Act-BCW and Act-HW groups.
No significant differences were observed between patients undergoing any type of treatment (chemotherapy, radiotherapy, endocrine therapy, and targeted therapy) compared with those that were not under treatment, neither in physical test results and in body composition status.
In terms of physical activity levels (IPAQ), there were no significant differences between the active groups (p = 0.055) but there were significant differences between Act-BCW vs Sed-BCW (p = 0.002) and Act-HW vs Sed-BCW (p < 0.001). Regarding to sitting time, there were no significant differences between any groups (p = 1.00 for all of them) (Tables 3  and 4).

Discussion
In this work, we found that women who are Act-BCW can achieve the same values in cardiovascular fitness, physical condition and body composition as active healthy women and significantly better values than sedentary women with BC.
Our results confirm that women who were Act-BCW presented an 11.8% higher V0 2max than their counterparts who were Sed-BC, a significant difference that might impact not only BC patients' health but also the survival of women with BC. In addition, the results of this investigation confirm the main hypothesis of the study, showing that women who are Act-BCW can achieve the same values in V0 2max , or even higher values, than women who are Act-HW.
Bearing in mind that cardiovascular capacity is an independent predictor of mortality in cancer [33] and is 25% lower than the V0 2max (relative to age and sex) in healthy individuals, the results of our trial are an important scientific contribution that once again emphasizes the importance of physical exercise in improving cancer patient health during and after treatments, which can lead clinicians to consider approaching the treatment of cancer patients in an integral way.
Related to body composition, our results show that physical activity is an effective, supportive care method in BC patients to achieve fat mass and lean mass levels that are similar to healthy active women. In contrast, body composition values were not significantly worse in sedentary patients than in their healthy counterparts, suggesting that BC by itself does not imply a body composition imbalance. Therefore, physical exercise is a stronger determinant of a balance or imbalance in body composition than a previous history of BC. This study aligns with previous evidence [34] showing that approximately 65% of all breast cancer survivors are overweight or have obesity; it is also known that a sedentary lifestyle and obesity are associated with poorer outcomes after a BC diagnosis and a significant increase in recurrence and elevated total mortality [35], possibly through their relationships with some biomarkers that are promoters of inflammation [36].
Findings from a recent report suggested that BC patients with obesity had a 35% higher risk of BC-related death [18,37]. Additionally, BC treatment is related to an increase in body fat as well as a decrease in lean body mass and bone mineral density. These changes can put these women at increased risk for frailty fractures and osteoporosis, as well as further risk for comorbid chronic diseases and cancer recurrence [38].
Apart from maximum oxygen consumption and body composition, we observed that active women had a better functional capacity than sedentary women, again showing the importance of exercise to maintain body functionality and prevent the most common physical disabilities in these patients, such as arthralgia or muscle pain, which might promote medication withdrawal [39].
In terms of lymphedema, despite the active group presenting an incidence of 16.6% higher than the sedentary ones, different studies have shown that exercise is not only safe for patients with lymphedema but also may be an effective therapy to manage lymphedema symptoms [40,41].
Related to sitting time, considering the Spanish population average (330.6 ± 184.8 min/day) [42], our four groups of patients, regardless they were active or sedentary groups, were within this average. Considering this data, future studies could be interesting to measure the participants' NEAT "non-exercise activity thermogenesis," a novel concept, which has demonstrated that not only include an extra calories expenditure but also reduce the occurrence of the metabolic syndrome, cardiovascular events, and all-cause mortality [43]. In this way, we could know the total caloric expenditure of each participant in a more accurate way.
When analyzing patients' limitations in being more active, a lack of time was the main barrier to performing physical exercise, given the impression that they do not perceive exercise as a key factor in maintaining and recovering their health. Therefore, this could be an aspect to be considered in future studies. Developing strategies that include oncologists, nurses, other care providers, and exercise-oncology specialists not only encourages patients to practice exercise but also highlights the importance of patients having an active lifestyle because it has been demonstrated that BC survivors who maintain an active lifestyle can achieve the same values in physical condition as active healthy women.

Strengths and limitations
The main strength of this study is its originality since no previous studies were found comparing the physical condition of these four groups of women. Moreover, using field tests added a pragmatic element to the study, making it a more real-life scenario than a research laboratory.
The main limitations include the small sample size, the cross-sectional nature of the study, and the lack of financial resources. With more resources, we would be able to increase the sample size by engaging more participating hospitals and to include other gold standard tests such as DEXA for body composition or breath-by-breath for VO 2 max analyses. Another limitation that should be considered was that some patients of the sedentary group were exercising up to 90 min/week, so they were not entirely sedentary subjects.
Despite the limitations of the study, we can conclude that performing at least 150 min/week of physical exercise is crucial for BC patients, given that there is an improvement in their physical capacity and V0 2max , which is directly linked with better survival.
Moreover, exercise helps breast cancer patients recover a healthy body composition, increasing lean mass, and decreasing body fat. This effect counteracts the negative impact of several treatments on women's weight a characteristic that is associated with a worse prognosis.
Future clinical trials should focus on changes in body composition in patients receiving hormone therapy according to different levels of physical activity and evaluate the impact of physical activity on cardiorespiratory fitness depending on the type of chemotherapy received, given the influence of obesity and cardiorespiratory fitness on breast cancer patients' survival.