Associations between Physical Exercise, Quality of Life, Psychological Symptoms and Treatment Side Effects in Early Breast Cancer

Background Identifying and understanding modifiable factors for the well-being of cancer patients is critical in survivorship research. We studied variables associated with the exercise habits of breast cancer patients and investigated if the achievement of exercise recommendations was associated with enhanced quality of life and/or psychological well-being. Material and Methods. 311 women from Finland, Portugal, Israel, and Italy receiving adjuvant therapy for stage I–III breast cancer answered questions about sociodemographic factors and physical exercise. Quality of life was assessed by the EORTC C30 and BR23 questionnaires. Anxiety and depression were evaluated using the HADS scale. Results At the beginning of adjuvant therapy and after twelve months, 32% and 26% of participants were physically inactive, 27% and 30% exercised between 30 and 150 minutes per week, while 41% and 45% exercised the recommended 150 minutes or more per week. Relative to other countries, Finnish participants were more likely to be active at baseline and at twelve months (89% vs. 50%, p < 0.001 and 87% vs. 64%, p < 0.001). Participants with stage I cancer were more likely to be active at twelve months than those with a higher stage (80% vs. 70%,p < 0.05). The inactive participants reported more anxiety (p < 0.05) and depression (p < 0.001), lower global quality of life (p < 0.001), and more side effects (p < 0.05) than the others at twelve months. Accordingly, those who remained inactive or decreased their level of exercise from baseline to twelve months reported more anxiety (p < 0.01) and depression (p < 0.001), lower global quality of life (p < 0.001), and more side effects (p < 0.05) than those with the same or increased level of exercise. Conclusion For women with early breast cancer, exercise was associated with a better quality of life, less depression and anxiety, and fewer adverse events of adjuvant therapy. Trial registration number: NCT05095675. Paula Poikonen-Saksela on behalf of Bounce consortium (https://www.bounce-project.eu/).


Introduction
Breast cancer is the most common malignancy in women and its' prognosis is generally excellent [1]. To facilitate ofering interventions and education to promote quality of life and mental health in survivors, it is important to recognize the modifable factors related to the well-being of these patients. Physical inactivity is a known risk factor for breast cancer [2] and many observational studies suggest an inverse association between physical activity and exercise after breast cancer diagnosis and breast cancer and/or all-cause mortality [3][4][5][6][7]. Exercise interventions [8][9][10][11][12][13][14][15] or physical activity in general [16] have resulted in positive efects on the well-being of breast cancer patients. Small-to-moderate benefts of exercise have been noted concerning the quality of life, physical ftness [8,11,12], fatigue [11,12,17], and depression [11,18].
In 2010, the American College of Sports Medicine convened a roundtable to explore the literature on the safety and efcacy of physical exercise both during and after adjuvant cancer therapy and to provide guidelines on appropriate exercise [19]. It was concluded that exercise training is safe both during and after cancer therapies and improves physical functioning, quality of life, and cancerrelated fatigue in cancer survivors [19]. Te scale of these benefts to physical functioning and quality of life has led to recommending cancer survivors to follow the 2008 US Department of Health and Human Services (US DHHS) Physical Activity Guidelines for Americans [19]. Te US DHHS guidelines state that patients with chronic conditions such as cancer should be as physically active as their abilities and conditions allow [20]. Recommended periods of aerobic activity are 150 minutes of moderate-intensity exercise or 75 minutes of vigorous exercise a week. Strength training was recommended 2-3 times per week, along with stretching after each exercise session [19]. Tese recommendations are in line with the World Health Organization's recommendations on physical activity and sedentary behavior that were updated in 2020 [21]. However, a recent prospective cohort study of US cancer survivors (60% female) showed that physical inactivity is still highly prevalent as only 28% of the survivors reported the recommended 150 minutes or more of leisure time physical activity per week. Moreover, especially a combination of lack of physical activity and prolonged sitting was associated with heightened risks of all-cause and cancer mortality [22].
In this study, we described the exercise habits of early breast cancer patients during the frst year from the start of oncological treatments and explored sociodemographic and cancer-related variables that are associated with such factors. Furthermore, we studied whether exercise according to current recommendations had an association with the quality of life or mental well-being of the patients one year after the start of adjuvant therapy.

Materials and Methods
Te BOUNCE project (European Union's Horizon 2020 Research and Innovation Programme under grant agreement No 777167) studies the resilience of early breast cancer patients. Between 2019 and 2020, 816 participants from Finland, Portugal, Israel, and Italy were recruited and gave their consent to be involved in the BOUNCE project. According to the WHO statistics (https://gco.iarc.fr/today/), all the participating countries belong to the category with the highest age-standardized breast cancer incidence worldwide.
Of the 816 participants, 555 were retained in the study after one year. To examine the relationships between aerobic exercise and quality of life and psychological symptoms, we used the data of 311 participants who had completed all the relevant questionnaires at study entry and after one year. Participants with incomplete data were more likely to have less years of education, and to have received chemotherapy or radiotherapy in comparison to those who provided complete data on all variables of interest at baseline and one year later (p < 0.01). No other diferences in sociodemographic or medical variables between participants with complete and incomplete data were found. Te study protocol was approved by the ethics committee of each participating institution and was conducted in accordance with the Declaration of Helsinki. Participants were screened from hospital records, received oral and written information about the study, and provided written informed consent.

Participants.
Te population of this substudy comprised women aged 40-70 years who were recently diagnosed with histologically confrmed stage I-III breast cancer and received either adjuvant or neo-adjuvant therapy in addition to surgery. Patients received chemotherapy, endocrine therapy, and/or anti-HER2 therapy according to the biological profle of their breast cancer, and radiotherapy according to local guidelines. Patients were eligible if they did not have a history of early onset mental disorder, other serious concomitant diseases diagnosed within the last 12 months, major surgery for severe disease, trauma within 4 weeks prior to study entry, or lack of complete recovery from the efects of surgery or other malignancy within the last fve years.

Instruments.
We collected participant data regarding sociodemographic factors, lifestyle, and psychological wellbeing using questionnaires via the online Noona tool or paper. Noona is an electronic patient-reported outcome (ePRO) software for patients with cancer. A trial assistant collected medical information from hospital records. In the BOUNCE project, data was collected from the participants every three months for up to 18 months. In the current substudy, we used data from the baseline and 12 months (M12) after beginning adjuvant therapy.

Te Breast Journal
Te participants reported the time, in minutes, spent in aerobic moderate-intensity exercise such as walking, and in vigorous exercise such as running. In accordance with the US DHHS guidelines and for the purpose of our analyses, vigorous exercise was converted to moderate exercise so that one minute of vigorous exercise corresponded to two minutes of moderate exercise. In accordance with a recent British exercise survey (Active Lives Adult Survey May 2020/ 21 Report, https://sportengland.org/), the patients' physical activity was categorized into three levels: "inactive," if the amount of exercise was less than 30 minutes a week; "fairly active," if the amount of weekly exercise ranged from 30 to 149 minutes and "active," if the amount of weekly exercise was 150 minutes or more.
QOL and adverse efects were measured by the EORTC QLQ-C30 [23] with the breast cancer module supplement BR-23 [24]. Te Global health/QOL scale describes patients' subjective quality of life and is based on two questions about physical condition and overall QOL. Te Hospital Anxiety and Depression Scale HADS [25] was used to assess the psychological symptoms. Patients with a severe anxiety HADS score of 13 or more at baseline were ofered psychological support according to the participating hospital's local practice.

Analyses.
To examine the relationships between the level of exercise and sociodemographic and medical factors, we used a series of chi-square tests and ANOVAs. Also, a series of MANOVAs were used to examine the association between the level of exercise at baseline and at one year (M12), as well as the potential change in the level of exercise from baseline to M12 (as the independent variables), and the indices of psychological health and quality of life (i.e., symptoms of anxiety, depression, global quality of life, side efects, arm and breast symptoms; as the dependent variables). Tese analyses were performed after controlling for several sociodemographic and medical variables. Specifcally, we controlled for the country of origin; age; education level (0-9 vs. > 9 years of education); marital status (married/ living with a partner vs. single/widowed); employment (employed vs. nonemployed/retired); income (very low/low vs. average/high), as reported by the participants, and after adjusting to the GDP income level of each country; tumor grade; tumor stage (I vs. II and III); therapy type (i.e., lumpectomy vs. mastectomy, radiotherapy, endocrine therapy, chemotherapy, and HER2-directed therapy) coded as a series of dummy variables; body mass index (BMI); receiving vs. not receiving psychotropic medication; receiving vs. not receiving formal psychological support/ counselling.
Tests of multicollinearity and multivariate normality (by determining the Mahalanobis distance from the available data and calculating the relevant chi-square values) were performed. Seven outliers were identifed, which were excluded from the fnal sample (i.e., not included in the fnal sample of 311 participants). A post hoc examination revealed a statistical power of over .90 at an alpha level equal to 5% and a medium efect size, for the analyses performed. Te level of statistical signifcance was defned at p < 0.05. Te Bonferroni correction for multiple comparisons was used whenever relevant.

Type of Exercise, Sociodemographic, and Medical Factors.
Patient characteristics are presented in Table 1. At baseline, 32% of the participants were inactive (i.e., exercised less than 30 min per week), 27% were fairly active (i.e., exercised 31-149 min per week), and 41% were active (i.e., exercised 150 min or more per week). Twelve months later (M12), 26% of the participants reported being inactive, 30% fairly active, and 45% active. In addition, 36% reported that they stayed inactive or decreased their level of exercise from baseline to M12, whereas 64% reported that they maintained or increased their level of exercise. Of the "inactive" participants at baseline, almost half (49%) exercised more at M12; of the "fairly active" participants at baseline, 22% decreased and 37% increased their level of exercise; of the "active" participants, 34% decreased and 66% maintained their level of exercise. Overall, it was more likely for the participants to maintain or increase their level of exercise than to remain inactive or decrease their level of exercise [64% vs. 36%; χ 2 (4) � 69.97, Regarding the country of origin and sociodemographic variables (see also Table 2), participants from Finland were more likely to be fairly active or active at baseline (89% vs. 50% on average for all other countries; χ 2 (6) � 67.51, p < 0.001). No statistically signifcant diferences existed across education level, marital status, income, tumor stage or grade, type of treatment, and receiving (vs. not receiving) any type of psychotropic medication or formal psychological support at baseline or at M12 (χ 2 s < 5.76, p > 0.05), as well as BMI and age, (Fs(2) < 1.90, p > 0.05).
Finally, when comparing the change of exercise habits from baseline to M12, the likelihood to maintain or increase the level of exercise was higher in participants from Finland (72% vs. 57% on average for all other countries), with an average or high income (69% vs. 52% for low income), grade I tumor (76% vs. 61% for higher grades), and who were not undergoing chemotherapy (72% vs. 57% for those treated with chemotherapy; χ 2 s > 5.90, p < 0.05). Also, participants who maintained or increased their level of exercise were older (M = 55.34, SD = 0.63 years) than those who were inactive or decreased their level of exercise (M = 52.96, SD = 0.84 years; F(1) < 5.13, p > 0.05).

Discussion
Our fndings showed that women with early breast cancer were more likely to maintain or increase their level of exercise than to stay inactive or decrease their level of exercise over one year from the start of oncological treatments (64% vs. 36%; χ 2 (4) = 69.97, p < 0.001). Tis is in line with fndings of the largest prospective exercise intervention study on breast cancer survivors BREX, whereby physical activity increased both in patients randomized to exercise intervention and control groups during the early rehabilitation period [26]. However, other evidence suggests that women with early breast cancer signifcantly decrease their physical activity and exercise levels from one-year prediagnosis to one-year postdiagnosis when types of sports and household activity were assessed with an interview [27]. It is important to consider that the BOUNCE study period overlapped with the beginning of the COVID-19 pandemic era which could have had an impact on the results. According to a recent review, however, physical activity levels decreased, and  [29], which was also true in our study as a signifcant correlation was found between exercise activity at baseline and after one year (Spearman rho = 0.54, p < 0.001). Despite the participants being more likely to maintain or increase than to decrease their activity level, only 45% of them did aerobic exercise according to the given recommendations after one year. Tis fact emphasizes the need for patient education to promote their physical activity from the start of oncological treatment. Patient education could help breast cancer patients to prevent maladaptive lifestyle behaviors, such as weight gain or sedentariness, and lower the risk of cancer relapse or even death [30].
In the current study, the Finnish participants were physically more active than participants from Portugal, Inactivity at twelve months was signifcantly related to several outcomes, namely to more symptoms of anxiety and depression, lower global quality of life, and more side efects. According to the available literature, exercise intervention has positive efects on several of these outcomes [31]. Te positive efects of exercise mainly apply to exercising according to the recommendations of at least 150 minutes of aerobic exercise per week divided into 2-3 times [31]. Our study suggests that also exercising for 30-150 minutes per week, or increasing the amount of exercise may also have positive efects on the quality of life and mental health. Te efect size of the impact of the exercise level (inactive, 30-149 minutes, 150 minutes, or more) on the outcomes after one year was medium to small. However, the efect size of the change in exercise level was medium to high (especially regarding depressive symptoms), indicating that a stable level of moderate or high exercise or an increased level of exercise activity is signifcantly related to better well-being. Tus, motivating patients to exercise according to general recommendations is also pertinent due to other demonstrated health benefts [20]. Accordingly, people are able to transfer skills (e.g., a person-centered perspective) from sports to other life domains, such as oncological health management. Te positive attitude and behaviors learned during sports activities may be transferred to other life contexts, helping patients in coping with mixed feelings, such as uncertainty and fear of recurrence [32].
Te strength of the present study is that its participants represent a typical breast cancer population receiving various breast cancer treatments while coming from diferent cultural backgrounds. In the context of the BOUNCE project, extensive background material was available from a breast cancer cohort who received standard treatment, without any additional exercise intervention that could lead to the selection of more active patients for the study [26]. Te literature about the physical activity of breast cancer patients concerns mainly randomized trials with some type of exercise intervention [9,10,[12][13][14][15]33], which can also afect patients' activity in the control group [26]. One limitation of our study is that measuring physical activity was based on participants' self-reports, without any objective digital activity measurements. Another limitation is the suboptimal sample size with a large number of drop-outs and thus a possibility of a selection bias. Te study was prospective, yet correlational; therefore, no causal efects can be inferred.

Conclusions
Exercise after diagnosis of breast cancer was associated with a better quality of life, less depression, and fewer adverse events of adjuvant therapy. However, one year after beginning adjuvant therapy, less than half (45%) of the women diagnosed with breast cancer exercised according to current guidelines. Promoting motivation for physical activity among breast cancer patients from the time of diagnosis throughout the treatment phase and the frst-year postdiagnosis is vital for improving their mental health and quality of life.

Data Availability
Te data that support the fndings of this study are available upon request from the corresponding author PPS. Te data are not publicly available due to restrictions e.g., they are Table 4: Te means and standard deviations (in parenthesis) of psychological well-being and quality of life indices across the change in the level of exercise from baseline to month 12 (n � 311). Only the indices with a statistically signifcant diference across the changes in levels of exercise are included in the

Ethical Approval
Tis study involves human participants and the experiments comply with the current laws of the countries in which they were performed.

Consent
Te patients received oral and written information and written informed consent was obtained from all patients.

Conflicts of Interest
Te authors declare that they have no conficts of interest.