br Methods Female patients N age
Methods: Female patients (N = 144; age ≥ 50) with stage I-III breast cancer scheduled to receive chemotherapy and age-matched non-cancer controls (N = 142) were included in this secondary analysis and assessed pre- and post-chemotherapy. Controls were assessed at equivalent time-points. Frailty was assessed using a modified Fried's score (0–4) using self-reported measures of weakness, exhaustion, walking speed, and physical activity. Serum levels of interleukin (IL) 6, and soluble tumor necrosis factor-alpha (sTNFR) I and II were measured. Asso-ciations between pre-chemotherapy cytokine and receptors level (median as cutoff) and post-chemotherapy frailty were evaluated using t-tests.
Conclusions: Both cancer and chemotherapy were associated with frailty. Higher pre-chemotherapy inflamma-tory cytokine levels were associated with post-chemotherapy frailty. This supports the utility of inflammatory cytokines to identify patients who develop worsening of frailty characteristics with chemotherapy.
Frailty, a state of vulnerability to stressors, is a clinically important age-related syndrome that increases risk of adverse outcomes such as disability and mortality [1,2]. The phenotypic manifestations of frailty, as characterized by Fried et al.—weakness, fatigue, low physical activity, slow walking speed, and unintentional weight loss—are associated with decreased quality of life, and functional and cognitive decline in com-munity dwelling older adults [1,3,4]. Over 50% of older patients with cancer are frail or pre-frail . A diagnosis of cancer and its treatments
Corresponding authors at: University of Rochester Medical Center, 265 Crittenden Blvd, Rochester, NY 14627, United States of America. E-mail addresses: [email protected] (N. Gilmore), [email protected] (M. Janelsins).
are known stressors and contribute to the frailty phenotype. As such, frail patients with cancer, including breast cancer, are more susceptible to negative outcomes including increased morbidity, mortality, chemotherapy-related toxicity, and decreased chemotherapy tolerance [6–8]. Understanding the predictors of frailty in the cancer TAK242 is of particular importance to help better understand the etiology of cancer-related frailty, and to ultimately guide decisions about treat-ment. Identifying frail patients or those at risk of developing frailty prior to initiating treatment would provide oncologists with guidance for early interventions that can reduce the risk of negative outcomes associated with treatment.
Inflammation plays a vital role in the process of aging . Older adults have dysregulated immune function, chronic systemic low-grade inflammation, and reduced ability to recover from insults [10,11]. This heightened inflammatory state has been shown to be a
contributing factor to frailty in community dwelling older adults. Inflammatory markers are also associated with functional decline and mortality [12–14]. While research suggests that inflammation may play an important role in the development of frailty, the pathogenesis of inflammation in aging and the underlying mechanism of frailty are poorly understood. Furthermore, whether inflammation can predict which older patients with cancer are at increased risk of developing frailty after receiving cancer treatment is still unknown.
Older adults with elevated frailty measures often have increased cir-culating serum levels of white blood cells, interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and tumor necrosis factor receptor I and II (TNFRI and II) [13,15]. The pleiotropic cytokine IL-6 is a soluble molecule involved in acute and adaptive immunity and functions to maintain homeostasis [16,17]. Prior studies have shown that serum levels of IL-6 increase with age and that IL-6 may contribute to morbid-ity [15,18]. In addition, IL-6 has been established as the main cytokine positively associated with Fried's markers of frailty [13,18]. Lippitz et al. found that higher levels of serum IL-6 were highly correlated with mortality independent of cancer type and stage . IL-6 has also been found to increase after chemotherapy in breast cancer patients . TNF-α, another pleiotropic cytokine, mainly produced by activated macrophages and monocytes, is a potent mediator of inflammation and is associated with frailty in older adults . TNF-α mediates its pro-inflammatory effects through the binding of its cognate receptors TNFRI and TNFRII. Soluble TNFRI and TNFRII (sTNFRI and sTNFRII), which are released via proteolytic cleavage of the membrane bound TNFRI and II, have been reported to be indicators of TNF-α pro-duction . It has been shown that frail individuals have elevated serum levels of sTNFRI and sTNFRII , and this elevation is associated with chemotherapy treatments [23,24].