This study examined the association of treatment and cancer-related factors with function in patients with a history of breast cancer and are receiving rehabilitation care. While many factors influence ability to participate in desired and needed activity, these findings provide valuable insight that may help identify patients most at risk for functional decline.
Within the NED cohort, the presence of CIPN was most strongly associated with decline in physical function. CIPN is prevalent in the breast cancer population, particularly with the use of taxane-based therapy, and leads to higher risk of falling, anxiety, depression, insomnia, and psychological distress. Results of this study further demonstrate the association of CIPN with lower physical function in breast cancer survivors, thus supporting the need for effective cancer rehabilitation intervention. In addition to CIPN, age was associated with higher patient reported fatigue; this may indicate less resilience to treatment effects, possibly due to frailty or pre-morbid non-cancer impairments. Age and CIPN were most predictive of decreased social participation, perhaps in part due to age-related functional decline or fear of ambulating in the community. Since all treatment factors analyzed can potentially cause functional decline, identifying CIPN as the strongest predictor of reduced function in this subgroup helps identify at-risk patients.
While CIPN was also associated with reduction in function in patients with active disease (physical function and fatigue domains), active chemotherapy was not. Possible explanations for this include that active chemotherapy does not necessarily mean a patient has or will develop CIPN and that there are different chemotherapy regimens depending on disease status that may cause greater toxicities. This underscores the importance of evaluating toxicities in the context of a person’s global function; intervention studies based on the development of CIPN are warranted.
Conversely, radiation was found to have a small but significant association with increased physical function in the NED cohort, though no effect on fatigue or social participation. This is an unexpected finding and may be the result of selection bias. For example, the inclusion of patients who had higher performance status or given the risk of complications from radiation had received physical rehabilitation prior to this study (e.g., physical therapy, lymphedema therapy). Another possible explanation is that radiation in the absence of surgery portends better function than surgery alone or a combination of the two; this is consistent with prior data suggesting that surgery and chemotherapy has a greater impact on quality of life than radiation.
Radiation was again found to have a small positive effect on function in those with active disease, similar to the NED cohort. For this group, it may reflect the benefits on pain and function conveyed by radiation in the setting of metastatic disease. As a symptom modulator, radiotherapy improving function is not necessarily unexpected, although this cohort also includes women receiving curative-intent treatment who already completed radiation. Of note, only 30.1% of patients receiving curative intent treatment in this cohort had received prior radiation, compared to 82.4% of those with metastatic disease, suggesting that radiation may have provided symptom relief in this cohort. The lack of active radiation patients in this study, due to a low accrual number, suggests that acute toxicities of radiation are not well accounted for, but that the benefits of radiation in those with active tumors is.
Interestingly, a combination of surgery, radiation, and chemotherapy was not associated with a greater decline in function in patients with NED in this analysis. One explanation for this includes that simply having one of these treatments was enough to reduce function (e.g. chemotherapy causing CIPN); having a combination of treatments may not have a significant additive effect on reduced function. In addition, endocrine therapy, which can cause arthralgia as well as other musculoskeletal and neuromuscular impairments (e.g., trigger finger, carpal tunnel syndrome) was not significantly associated with reduced function. This may be because impairments from endocrine therapy, while bothersome and limiting in some ways, may not reduce a person’s overall function and ability to participate in social roles.
For those with active disease, brain metastases were most associated with decline in physical function and greater fatigue. Although the association was strong, the underlying cause of this finding is uncertain. It could be the result of neurologic deficits and/or the fact that brain metastases signify later stage disease and, thus, overall increased disease/treatment-related burden and, in turn, impacting downstream physical function, such as increased sedentary activity and deconditioning.
Of note, only 10% of patients in this cohort had brain metastases. This is consistent with previous research reporting that less than 10% of breast cancer patients with metastatic disease are clinically identified as having brain metastases.22 That said, brain metastases are far more prevalent in breast cancer patients evaluated post-mortem with prevalence ranging from 15–30% The impact of hidden brain metastases may underlie a rapid decline in health and therefore low number with brain metastases presenting to rehabilitation clinics. Alternatively, there may be breast cancer patients with small and asymptomatic central nervous system disease that do not require rehabilitation related to the metastases.
The presence of metastatic disease in the “active disease” subgroup alone did not independently predict low function in patients with active disease, nor did active or prior chemotherapy, or prior surgery. This warrants investigation of additional factors leading to functional decline in patients within this population. Such unexplored factors may cause impairment and reduced function in this population to a higher degree than these treatments, which are often more remote since patients with metastatic disease have many more recent treatments and disease-related factors contributing to their decline.
Cancer rehabilitation care must be held to rigorous evidence-based standards to demonstrate value to patients, payers, and the oncology providers. This poses a challenge in a heterogenous population to which care is often individualized. The results in this study have multiple strengths towards that end. First, it includes patients from multiple sites increasing the generalizability and external validity of the findings. The data included high quality and complete information regarding participants’ demographic characteristics and cancer histories. Additionally, the independent variables were assessed with a well-validated PROM instrument vetted specifically for this population. As PROMs become essential for cancer research, this paper enhances understanding function as an endpoint for future clinical trials. With performance status so closely linked to treatment decision-making, understanding treatment effects on function is essential in oncology practice and clinical trials.
The findings reported in this manuscript are generally consistent with other studies evaluating functional decline in cancer patients, while adding greater detail to the breast cancer population. Additionally, this study is novel in that it uses an item-response theory-based PROM specific to function in cancer patients. This approach is widely accepted as the gold standard for PROM use, and previous studies often use instruments specific to only one aspect of function (e.g. activities of daily living) or subsets of larger quality of life instruments (e.g. the physical function component of the SF-36). Two of the strongest predictors of functional decline, age and systemic chemotherapy, have consistently been associated with functional decline across multiple cancers.,,,, This manuscript, however, provides breast-cancer specific functional information stratified by those actively receiving treatment and long-term survivors, which is a novel and potentially important contribution to the literature. Additionally, our findings that both surgery and radiation therapy are not strongly linked to functional decline are in line with other studies that evaluated these treatments in other cancer types. Of note, the existing data about surgery and radiation therapy are limited, enhancing the importance of these findings. Few studies exist evaluating the effect of surgery on function, including in esophageal cancer or patients already experiencing functional decline and admitted to nursing facilities. Studies on radiation do not include breast cancer nor anatomic-specific information, with authors of a recent review article to concluding that radiotherapy is “…likely to have less impact on functional status than their systemic counterparts.” Though not evaluated in breast cancer, brain metastases have been linked to functional decline in lung cancer patients.
This study has several limitations. First, its focus on patients already referred to cancer rehabilitation clinics narrows its scope and creates the potential for selection bias. The results should not be interpreted to suggest, for example, that patients receiving endocrine therapy are not at risk for impairment or functional decline. Rather, the results only draw associations between what treatment- and disease-related factors are most strongly associated with low function in patients already experiencing symptoms requiring rehabilitation. Second, treatment covariates were binary. For example, the data only reflected whether a patient had previously had surgery, not how many, what type of surgery, if there was breast reconstruction, among other characteristics. The radiation covariate did not distinguish the effects of active from prior radiation or quantify radiation fields or dosage. Additional research is needed to determine the effect of more specific surgical or radiation interventions on function. Third, use of PROMs as the only functional measure may be a limitation. While patients’ perceptions are a crucial dimension of functional assessment, PROMs are susceptible to recall bias and differential item functioning. Their pairing with objective measures of function (e.g., activity monitors) may offer a more comprehensive assessment of a patient’s capabilities. Last, the cross-sectional nature of this study provides only a snapshot of participants’ function. Longitudinal evaluation would potentially provide greater clarity into the mechanisms of functional decline. A larger and longitudinal study may confirm these results and add additional detail.