Functional Capacity Predictors in Breast Cancer Women: a Cross-sectional Study

Purpose: Functional capacity (FC) declining has been poorly evaluated and characterized in women with breast cancer (BC). It is expected that FC declining may have an impact on survival, and also compromise quality of life and independence. This study aimed to evaluate the FC of women with BC and identify predictors of obtained results. Methods: A cross-sectional study including women with BC consecutively referred for a physical medicine and rehabilitation consult between October and December 2019. Glittre-ADL Test (TGlittre), maximal respiratory pressure tests [maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP)] and Modied Fatigue Impact Scale were used in order to assess FC, respiratory muscle strength and fatigue, respectively. Age, professional status, smoking habits, comorbidities, body mass index, duration and status of disease, previous and ongoing treatments were also registered. Results: A total of 42 women with non-metastatic BC were enrolled with a disease duration of 11.50 months (71), mostly in stage II (53.60%) and under hormone therapy (38.10%). TGlittre performance time was 3.13 minutes (8.72). TGlittre performance time correlated with MIP (r = -0.373; p <0.01) and MEP (r = -0.414; p = 0.007) values and age (r = 0.711; p < 0.010). Patients with CV and endocrine comorbidities had higher TGlittre time values (p <0.01 and p = 0.019, respectively). Age was the only statistically signicant predictor (p=0.041) of TGlittre variation. Conclusions: Women with BC presented decreased FC with mean values of TGlittre duration higher than those described in the literature in healthy subjects.


Procedures
All the assessments were conducted on the same day by a physician, including the assessment of functional capacity, the respiratory muscle strength and fatigue. All the procedures were explained previously.

Functional capacity
TGlittre was used to evaluate functional limitation and to assess the capacity of patients to performing activities of daily living. It consists of a standardized circuit of 10 meters which must be performed ve times, in the shortest possible time, while carrying a backpack weighing 2.5Kg, with de following sequence [14]: 1. From a sitting position, the patient stands and walks along a at course; crossing a two-step staircase at the midpoint (17 cm height + 27 cm width) and then walks again; 2. At the end, there are two shelves with three objects weighing 1Kg each, positioned on the top shelf (at the shoulder height) to be moved down, one by one, to the lower shelf (at waist height) and subsequently to the oor; then the objects must be placed again on the bottom shelf, and nally moved to the top shelf; 3. The patient walks back, sits again, and immediately starts the next lap, following the same circuit, until ve laps are concluded.
Heart rate and peripheral oxygen saturation were recorded using a pulse oximeter, and perceived dyspnea was assessed by the Modi ed Borg Scale [15], at the beginning and end of the test. The total time to complete the test was also registered.
Even though there are no age-matched reference values of TGlittre in women with BC, Reis CM et al [16] developed a reference equation for the time to complete TGlittre based on age and height in apparently healthy individuals. In order to compare our results, the predicted TGlittre time was calculated considering the formula 3.049 + (0.015 × age years ) + (-0.006 × height cm ). [16] Respiratory Muscle Strength The measurement of maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) was performed with a manovacuometer (MicroRPM®, Carefusion, Basingstoke, UK), according to the American Thoracic Society/European Respiratory Society guidelines. [17] The maneuvers were performed 3 times and the best value was considered. The lower limit of normality of MIP and MEP was calculated considering the age and sex, according to the formulas 62 -(0.50 × age years ) and 95 -(0.57 × age years ), respectively. [18] Fatigue The level of fatigue was assessed using the Modi ed Fatigue Impact Scale (MFIS) -Portuguese version. [19] MFIS is subdivided into physical (10 items) and cognitive (11 items) subscales and assesses the impact of fatigue on daily functioning during the last four weeks. Each item is rated on a ve-point scale, ranging from 0 to 4. [20] A total score equal or higher than 38 was considered as the cut-off of fatigue [21].

Statistics
Continuous variables are expressed as means and standard deviations (SD) or medians with interquartile ranges for variables with skewed distributions. Categorical variables are presented as frequencies and percentages. Normal distribution was checked using Shapiro-Wilk test or skewness and kurtosis.
Differences in categorical and continuous variables were tested with the use of Kruskal-Wallis or Mann-Whitney tests. Spearman's coe cient (ρ) was used to assess the strength and direction of the linear relationships between pairs of continuous variables.
The predictor variables of TGlittre variability were determined using a multiple linear regression model. All reported p-values are two-tailed, with a p-value of 0.05 indicating statistical signi cance. Statistical analyses were performed using Software Statistical Package for the Social Sciences (SPSS) Version 23 (© IBM, Armonk, NY) Results: A total of 42 women were included, with an average age of 59.62 ± 9.99 years. The majority (76.19%) of patients had other comorbidities, mostly cardiovascular (CV) and endocrine. Demographic and clinical characteristics are summarized in Table I. the TGlittre reference equation [16], 73.81% of the population spent more time to complete the test than the predicted value, according age and height. About 14% (n = 6) and 24% (n = 10) of patients had MIP / MEP values below lower limit of normal according to age and sex, respectively. Fifteen women (35.71%) had a total score of MFIS ≥ 38, considered the cut-off of fatigue [21].   Cancer treatment is associated with numerous adverse side effects, including pain, fatigue, cachexia, reduced strength and lung capacity, diminished range of motion, among others. A signi cant percentage of women will keep some of these symptoms for months after the end of treatments and will experience treatment-related late effects that may in uence not only their quality of life, but also morbidity and mortality. [4,6,7,24] A reduction of lower limbs muscle strength and endurance, associated with compromised walking ability, have been reported in women with BC. [12,25] In addition, Kokkonen et al. [12] reported poor balance, especially dynamic balance, in 78,1% of women with advanced BC. Impaired muscle strength associated to peripheral neuropathy, induced by neurotoxic chemotherapy agents, can compromise balance and disturb walking, leading to a further decline in FC. [12].
TGlittre was initially developed and validated to assess FC and the ability to perform ADL in patients with chronic obstructive pulmonary disease (COPD). [14] However, the evidence is limited about the performance in patients with other diseases such as cancer. Reis CM et al. [16] proposed a reference equation for TGlittre based on anthropometric and demographic variables in apparently healthy subjects. Although the reliability of the equation in women with BC cannot be established, when we applied it in our population, we found that 73.81% of women had higher values than the predicted ones, suggesting the FC compromise among our sample. In another work, Reis CM et al. [26] reported the shortest time to complete TGlittre of 2.03 minutes and a mean time of 2.62 minutes in healthy subjects. Similarly, Skumlien et al [14], found that the shortest time to perform TGlittre by healthy subjects was 2 minutes. However, it is known that FC decreases with age, and in the study of Côrrea et al. [27] with 10 healthy subjects with a mean age of 64 years, the mean time to complete TGlittre was 3.3 minutes. In our study, BC women were younger (59.62 ± 9.99 years) and needed 3.13 minutes to perform TGlittre, suggesting that other factors may play an important role in FC.
Kokkonen et al used six-minute walk test (6MWT) to determine functional impairment in women with advanced BC and found that FC was signi cantly lower compared with healthy subjects. [12] Comparing TGlittre and 6MWT, the last one includes only walking, which may imply a different metabolic pro le compared with daily activities. In a study with heart failure patients, Almeida MP et al. [28] showed that TGlittre elicited higher ventilatory and cardiovascular responses than 6MWT. On the other hand, TGlittre simulates several daily activities, such as walking, sitting-standing, climbing up and down stairs and moving objects in different heights. It seems to be more representative of ADL and could re ect more faithfully real-life situations and the limitations experienced in a daily basis. Despite an overall correlation of TGlittre with 6MWD in COPD, Skumlien et al [14] found a substantial variability, especially in more debilitated patients, showing that TGlittre provided additional information about functional status, particularly in more disabled patients. To our knowledge, this is one of the rst studies that evaluate FC in women with BC using TGlittre. We only found a published abstract by Cakmak et al [23], which had similar results. They evaluated fteen BC survivors without any metastasis or active disease, that took a mean time of 3.1 minutes to complete TGlittre.
In our study, age was the only predictor of variation in TGlittre time. As previously described, FC tends to decrease with aging, due to a gradual reduction of muscle strength and oxygen uptake. [29] Women with cardiovascular and endocrine comorbidities spend more time to complete TGlittre. A fundamental condition for many ADL is the ability to perform mainly aerobic, i.e. oxygen-using, work. Such activities require the integrated work of the heart, lungs, and circulatory system to carry oxygen to the metabolically active muscles. [30] The presence of cardiovascular and some endocrine comorbidities, represented in our study by hypertension, diabetes mellitus, dyslipidemia, valvular disease, interatrial communication, arrhythmia and peripheral venous insu ciency, may compromise this mechanism and lead to the limitation of FC. Nonetheless, age was the only predictor of TGlittre variation, regardless of the presence of these comorbidities.
It is important to mention that women with BC may had the di culty of using the backpack, due to pain caused by the catheter implantation, scars and/ or lymphedema in the upper limb caused by previous surgery. TGlittre was not initially developed to this population, and it would be interesting to report and quantify the impact of these limitations in future studies, in order to adapt it to these population characteristics.
Also, our work revealed that expiratory and inspiratory muscle strength were decreased in 24% and 14% of the patients, respectively. The analysis showed that TGlittre time was inversely correlated with MIP and MEP, suggesting generalized muscle weakness and deconditioning. This respiratory muscle impairment is considered one of the underlying mechanisms of exercise intolerance. [31] We found that 35.7% of women reported fatigue, which did not correlate with TGlittre time. Fatigue is one of the symptoms most frequently reported by women with BC, with a high variability in prevalence.
Besides, it is a multifactorial and subjective symptom, involving biological and psychological aspects, and the physiopathology is not completely understood. [3,[32][33][34] In another cross-sectional study, with 215 BC women, 72.09% were fatigued, while physically active women showed lower symptoms of fatigue and higher scores for quality of life scales, compared with sedentary ones. [3] Although fatigue did not correlate with TGlittre time, other studies show that feeling tired has a direct impact on functionality and compromises quality of life. [32,33] The absence of correlation between fatigue and FC reinforces the importance of evaluating FC, which may be compromised even in the absence of self-reported fatigue.
There are limitations in this study. Firstly, it included only patients with criteria to be referred for a physical medicine and rehabilitation consult, and who wanted to participate in an exercise program, which may induce selection biases. It is possible that more vulnerable women or less motivated women may not be referred to our center, and it could overestimate FC and underestimate fatigue of this population.
Secondly, the tests used were not validated for breast cancer patients. The lack of sex and age-matched reference values of TGlittre for this population may compromise the clinical results interpretation. Since it is a relatively new test, more studies are needed to determine the reference values according age groups in healthy people. Additionally, MFIS was originally developed to assess fatigue in patients with chronic diseases, and it is not speci c for this population.
Some rehabilitation needs of women with BC are still poorly recognized. Currently, exercise is recognized as a key element in cancer treatment to reduce symptoms and improve physical functioning, mood and quality of life. [35] In order to promote and validate physical and functional improvements during the recovery process, an adequate FC evaluation to assess the physical abilities of BC women could facilitate and optimize the development of exercise-based rehabilitation programs. Despite time-consuming, TGlittre may be a valid test to assess FC in this group of patients.

Conclusion:
Women with BC presented a decreased FC, with mean values of TGlittre duration higher than those described in the literature in healthy subjects. Due to the sedentary lifestyle that characterizes this population, the presence of comorbidities and the multisystemic attainment of BC and different treatments used, we consider that it is essential to evaluate the FC and factors associated with its decline, allowing the optimization of intervention in a rehabilitation program. Declarations: Con icts of interest: the authors certify that there is no con ict of interest with any nancial organization regarding the material discussed in the manuscript.
Funding resource: none.
Code availability: N/A Availability of data and material: research data are not shared.
Ethics approval: N/A Consent to participate: All patients gave their informed consent prior to their inclusion in the study.

Consent for publication:
All authors consent to the publication of the manuscript