In this secondary analysis of the WHIP Study examining cross-sectional and longitudinal associations among PA, daily sitting time and QOL, we found significant associations between activity levels (and sitting time) with endocrine symptoms and general and BC specific QOL. Self-reported PA increased each year, while sitting time stayed consistent. Endocrine symptoms significantly increased (worsened) while general and BC specific health-related QOL declined slightly over the same period. Importantly, higher levels of baseline PA or change in PA were not associated with changes in endocrine symptoms or health-related QOL over time. We did however find that worse endocrine symptoms were associated with a slower rate of increase in sitting time while having better QOL scores at baseline was associated with a significant increase in the rate of sitting. Overall, both PA and sitting appear to be important behaviors among BC survivors undergoing AET.
A number of previous studies examining the relationship between PA, endocrine symptoms and QOL among women with BC have predominantly examined arthralgias or musculoskeletal concerns that develop as a result of aromatase inhibitor (AI) therapy for HR + BC. A recent meta-analysis, focused specifically on musculoskeletal symptoms, examined 9 trials that included 743 participants who were randomized to exercise or usual care [28]. Overall, findings supported exercise as an effective approach for managing pain, stiffness and grip strength. However, another study did not find improvements in QOL domains such as fatigue, endocrine symptoms or total quality of life, despite significant improvements in PA behaviors as a result of intervention. Nyrop and colleagues encouraged women on AIs (n = 20) to walk for at least 30 minutes per day for 5 days a week over a 6-week period, to address arthralgia [29]. While total walking time per week significantly increased over the study, decreases in joint pain, stiffness and fatigue were not significant suggesting the need for a larger sample. The duration of the intervention may be critical however with that study only being 12-weeks [30]. While not all symptoms that result from AET are musculoskeletal in nature, their presence is also linked to reductions in PA among women who take them [31]. Other factors linked to declines of PA following use of AIs included BMI. In the HOPE study [32], a 12-month clinical exercise trial among women with AI-induced arthralgia, 121 BC survivors with at least mild arthralgias were randomized to a supervised exercise or control group. At 12 months follow up, women who participated in aerobic and resistance training reported greater improvements in overall, BC-specific and endocrine symptom subscales compared to the control participants. Study authors concluded that given the frequency of side-effects from AIs and the risk for treatment non-adherence, that non-pharmacological approaches like exercise training could be valuable. Interestingly our results did not show an improvement in QOL (general or BC-specific) or endocrine symptoms to be associated with total PA, perhaps due to the fact that the most common activity reported in the current analyses is walking. This is likely due to the non-specific nature of the IPAQ regarding resistance training, which was a primary component of the exercise intervention in the HOPE study. It is well established that resistance training is critical for the maintenance of physical functioning, including among older persons and those who experience chronic pain. Therefore, guidance to increase physical activity should specifically include the guideline-based recommendations of at least 2-days of resistance training per week in addition to 150 minutes of aerobic training. It should be noted that a barrier to recommending resistance training relates to access to facilities and supervision in the safe performance of certain exercises. However, the recent COVID-19 pandemic has increased the availability of remote and online programs at low cost and these may be valuable in this regard.
A unique aspect and strength of this study is the examination of sitting time and its association with QOL and endocrine symptoms cross-sectionally and over time. The fact that more sitting time at baseline was associated with worse general, BC-specific, and endocrine symptoms at baseline but reduced endocrine symptoms over time was somewhat unexpected. Hartman and colleagues [33], examining both moderate to vigorous PA (MVPA) and sedentary time measured with accelerometry among 134 post-menopausal BC survivors, found that more time spent sitting in longer bouts was associated with worse physical QOL, especially in women who did little MVPA. While we did not specifically assess whether there was effect modification in our analyses, it may be that women who were doing more PA were also resting more outside of those bouts of activity. A separate study [34], conducted among 195 post-systemic therapy BC survivors (50% on hormonal therapy), found that more time spent in accelerometer-assessed sitting was associated with worse pain, fatigue and depression, especially among women with low levels of PA. Women with better QOL at baseline may have increased their sitting as they began to experience side-effects of treatment. Women who experience pain at either at rest or at onset of activity, are likely to attribute this discomfort to activity and therefore do less. Unfortunately, this only serves to further reduce their functional capacity increasing the likelihood that when they engage in activity, they will experience discomfort. Similarly, it is often counter-intuitive that women who are fatigued can benefit from activity. Most often patients who are fatigued believe they should do less and rest, which again leads to declines in function and worsening fatigue over time. The only way to combat this is to engage in activity to strengthen the musculoskeletal system. Indeed, our prior findings indicated that women who were the most adherent to AET had the highest levels of sitting time [35], perhaps suggesting that these women would experience side effects of AET early and these symptoms would then level off or increase more slowly over time. These findings highlight that both behaviors are independently important for the management of symptoms in BC survivors and they should be advised to both increase exercise and also reduce long periods of sitting time. Other strengths of our study are the inclusion of a racially diverse sample of HR + BC survivors.
This study does have a few limitations. First, only self-reported measures were used for collecting PA and sitting data. While important for clarifying context, there are known issues with over-reporting of PA and under-reporting of sitting time in the IPAQ questionnaire, particularly for BC survivors [36–38]. Furthermore, use of objective measures of PA would allow for the assessment of lower intensities of PA in the range of 1.5–2.9 METs, capturing movement and daily activities of living which are lost in self-reported measures but still important for health among BC survivors [16]. Fortunately, because the primary outcome of interest in the WHIP parent study was adherence to AET and not specifically PA there may have been less inclination to overreport activity. Nevertheless, the use of accelerometers would have improved the accuracy of data capture in that regard. Second, there were a relatively large number of participants who were lost to follow up in this study. We did find that certain baseline characteristics (race, education and income) seemed to be correlated with missingness of study variables; however, in sensitivity analyses the primary findings were not altered after excluding those with two or more missing visits. Thus, we cannot fully rule out the possibility of survival bias where the missingness may be related to the symptoms or prognosis after treatment. Further, we only included the treatment type at the time of the baseline visit in these models and did not explore whether women changed the type of therapy used over time such as in a switch strategy. This implies that caution is needed, particularly when interpreting the results from an unconditional LGCM showing the shape of longitudinal changes in study variables over time. Lastly, the model-data fits of the LGCMs were below or marginally above the acceptable levels for model fit parameters in structural equation modelling frameworks. The greater model-data fits are necessary to obtain the valid parameter estimates from the LGCM model, and thus future studies are warranted to test the proposed LGCM model in different settings.
In summary, our findings from a large and diverse cohort of BC survivors undergoing AET, shows that both PA and sitting time were important with respect to managing symptoms and maintaining QOL. Clinician guidance towards the adoption of PA that includes both aerobic and resistance exercise and a reduction of sedentary behaviors should take into account the patient-level variations in symptoms such as fatigue or pain, that may make activity challenging. Regular activity can also help with weight management efforts, which is important for a population of women who are at risk for weight gain and therefore further comorbid conditions. Given baseline levels of activity/sitting are more strongly associated with baseline symptoms and QOL, it is important that women are encouraged to adopt appropriate activity behaviors as early as possible, despite the challenges they may face as a result of treatment and associated side-effects. Future research is needed to more accurately delineate the optimal prescription of PA (e.g., type, dose, intensity, volume) coupled with management of prolonged periods of inactivity (sedentary behaviors), especially in consideration of the types of treatment a women may receive for HER + BC.