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    r> Studies evaluating frailty in patients with breast cancer have typi-cally focused on patients over the age of 65 and have demonstrated that pre-frail and frail patients have increased long-term mortality [7]. Most breast cancers, are diagnosed at an early stage and the mean age of diagnosis is 62 years old [32]. Because cure rates after treatment are high in younger patients (b65 years) with early stage breast cancer, many of these patients will become cancer survivors [33] living to ages ≥65 years, when frailty is more common. Our findings support prior studies that have demonstrated that cancer and cancer treatment
    Fig. 3. The associations of pre-chemotherapy cytokines with post-chemotherapy frailty for patients with breast cancer. Post-chemotherapy frailty scores were stratified by pre-chemotherapy cytokine level (below vs above median). a. IL-6, b. TNFRI, c. TNFRII.
    Fig. 4. The associations of pre-chemotherapy cytokines with post-chemotherapy frailty for non-cancer controls. Post-chemotherapy frailty score were stratified by pre-chemotherapy cytokine level (below vs above median). a. IL-6, b. TNFRI, c. TNFRII.
    results in accelerated aging and early-onset frailty [34,35]. In this sam-ple of patients with breast cancer (mean age 60), we found that they U46619 were more frail than their age-matched non-cancer controls prior to starting chemotherapy, thus physiologically older. These results dem-onstrate the importance of evaluating frailty in a breast cancer popula-tion as part of treatment planning, even in younger patients (b65 years). Treatment comes with risk for toxicity, functional decline, and increased morbidity and mortality. Therefore, early identification of patients who are frail or at risk for increased frailty with treatment would allow for individualized assessment risks and benefits and for
    guidance of early interventions to prevent functional decline with treatment.
    Frailty in patients with cancer is not always apparent on initial as-sessment. Therefore, there has been increasing interest in identifying measures that can accurately and efficiently assess frailty and func-tional reserve across the aging spectrum. Due to the interplay between aging, frailty, and inflammation, age-related immunologic cytokines may serve as potential markers to help identify which patients with cancer are at increased risk of adverse outcomes post-chemotherapy [17]. Recently, there has been evidence that pre-chemotherapy levels of pro-inflammatory and coagulation factors are associated with poorer physical function prior to chemotherapy initiation in patients with breast cancer [36]. Here we show that, in addition to being bio-markers of frailty in both non-cancer and cancer (pre-chemotherapy) populations, levels of IL-6, sTNFRI, and sTNFRII may predict which pa-tients with cancer will develop chemotherapy-induced frailty. Frailty is a dynamic process, and while there is a significant increase of frailty in the short-term after the completion of chemotherapy, resilient patients return to their baseline levels a year after the completion of their chemotherapy regimen [37,38]. However, understanding the subset of patients that lack this resilience, and are unable to rebound after chemotherapy is important. Markers of inflammation, including cyto-kine levels, can give us insights into how to best treat this subset of pa-tients. Since this study evaluated the short term effect of the level of pre-chemotherapy cytokines on post-chemotherapy frailty, future studies should evaluate the long-term effect of elevated cytokine level on post-chemotherapy frailty and whether these biomarkers can also predict which patients have reduced resilience after chemotherapy.
    Prior studies in patients with breast cancer have evaluated the asso-ciation of IL-6 and TNF-α with tumor aggressiveness and their negative effect on treatment outcomes and survival, with higher levels of these cytokines being associated with higher tumor burden [39–41]. Our sub-analysis of the adjuvant chemotherapy population—showing a consistent trend of increased pre-chemotherapy levels of IL-6, sTNFRI, and sTNFRII being associated with post-chemotherapy frailty—suggests that these elevated levels are likely not as a result of tumor burden, but instead that post-chemotherapy frailty might be due to increased in-flammation. Sustained vascular circulation of these molecules may re-sult in a negative effect on varying body systems, causing increased weakness and fatigue with a concomitant decrease in physical activity and walking speed, which are characteristic of frailty. Future work should evaluate the interplay between inflammation and micro-metastasis. Given that the pre-chemotherapy levels of IL-6, sTNFRI, and sTNFRII were similar in both the adjuvant and neoadjuvant sub-groups suggests that the chemotherapy-induced frailty was not due to inflammation as a result of the tumor including micro-metastases; however, this needs to be further evaluated due to the small number of patients receiving neoadjuvant chemotherapy in our analysis (Table 1).