In this secondary analysis of data from a multi-center longitudinal cohort study, we confirmed the relationships between inflammation and frailty characteristics that have been reported in community-dwelling older adults as well as older adults with cancer over the age of 65 years.(12, 14, 21) Additionally, we demonstrated an association between cellular markers of inflammation and chemotherapy-induced frailty characteristics. We showed that a greater increase in neutrophils, NLR, and total WBC from pre-chemotherapy to post-chemotherapy was positively associated with frailty characteristics at the post-chemotherapy time-point. Moreover, we demonstrated that these associations were not due to the receipt of growth factors with chemotherapy. In this cohort of patients, we found that in women with breast cancer undergoing chemotherapy, frailty increased from pre-chemotherapy to post-chemotherapy and returned to pre-chemotherapy levels by six months after the completion of chemotherapy. To our knowledge, this is the first study to investigate the predictive effect of cellular markers of inflammation using laboratory data on frailty characteristics that are associated with chemotherapy.
Chronic low grade inflammation (i.e. subclinical inflammation) is independently associated with frailty. Leukocytes are an essential component of the immune system and consist of neutrophils, eosinophils, and basophils (that comprise the granulocytic component) as well as lymphocytes and monocytes (that comprise the non-granulocytic component). Neutrophils are the most abundant granulocytic leukocyte and have traditionally been thought of as the first line of defense against infections. However, recent studies have shown that neutrophils also play a vital role in chronic inflammatory responses in immunological diseases such as cancer by interacting with other immune cells such as lymphocytes.(29) We have shown that in patients with breast cancer, the level of neutrophils in peripheral blood is independently associated with frailty characteristics prior to receiving chemotherapy.
While no significant changes were observed in the levels of neutrophils and monocytes from pre-chemotherapy to post-chemotherapy, there were significant changes in the concentration of WBC, lymphocytes, NLR, LMR, hemoglobin, hematocrit, platelets, and albumin. However, it is important to emphasize that these changes remained within the laboratory-referenced normal range. Given that these tests were completed within one month of completing chemotherapy and that the values remained within the normal ranges suggests that the hematopoietic systems of these patients recovered after chemotherapy.
Notably, even though there were subtle and non-significant changes within the normal range of neutrophil concentration from pre-chemotherapy to post-chemotherapy, we found that an increase in neutrophils from pre-chemotherapy to post-chemotherapy was associated with frailty at the post-chemotherapy time-point, after controlling for the pre-chemotherapy frailty score. These findings suggest that subclinical changes (changes within the normal range) are important to consider when making treatment decisions based on the effect of cancer treatment on frailty in patients with breast cancer.
Along with neutrophilic responses, NLR is also commonly used as a marker of subclinical inflammation. NLR can signify an imbalance between various components of the immune system, with higher neutrophils indicating an activation of the pro-inflammatory immune pathways and lower lymphocytes reflecting depressed cellular immunity.(11) In fact, in patients with breast cancer an elevated NLR has been associated with poor prognosis.(30, 31) The observed independent association of NLR with frailty suggests that low grade inflammation as well as subclinical changes in inflammation is a prognostic factor for frailty in patients with breast cancer. Unfortunately, the mechanism underlying the contribution of NLR to poor outcomes including frailty is unknown. Emerging evidence indicates that the roles of neutrophils are more complex than previously thought. In patients with cancer, neutrophils can be polarized to exhibit different phenotypes depending on which tumor-derived factors as well as other immune cells interact with them. As a result, in patients with cancer, neutrophils can have either immunostimulating or immunosuppressive properties. Immunostimulating neutrophils, also known as anti-tumorigenic neutrophils, can activate a cytotoxic CD8 + T cells (a subset of lymphocytes) to exert immunostimulating effects.(29, 32) On the other hand, in patients with cancer, neutrophils have been shown to exert immunosuppressive properties.(33, 34) More work is needed to clarify the varying roles of neutrophil subsets as well as the ratios of different leukocyte subsets as immunological biomarkers that may predict frailty and frailty trajectories in patients with breast cancer.
A recent study by Bailur et al. aimed to elucidate the association of distinct immune subsets with frailty through the use of immunoprofiling flow cytometry techniques. These authors showed that in older adults with breast cancer, patients with higher pre-chemotherapy levels of granulocytic cells but lower levels of myeloid-suppressor cells and regulatory T cells were more frail prior to initiating chemotherapy.(35) While no association was found between pre-chemotherapy immune subsets and frailty (assessed using the geriatric assessment) at three and twelve months after starting chemotherapy, these profiles were predictive of unexpected hospitalizations. Our study had complementary findings; we demonstrated that neutrophils, which make up a major component of the granulocytic immune component, were associated with frailty in patients with cancer. While Bailur et al. found no association between immune cell profiles and frailty after chemotherapy, we found that changes to the neutrophil component following chemotherapy were independently associated with post-chemotherapy frailty but not with frailty 6 months after-completing chemotherapy. These differences in findings may be multifactorial. Firstly, participants in our study were younger (mean age 53 vs 73). Secondly, there were differences in the timing of blood draws for the post-chemotherapy time-point (within 4 weeks after the last chemotherapy cycle vs on the day of the last cycle of chemotherapy). Thirdly, in the current study we examined the association between longitudinal changes in cellular markers of inflammation over the course of treatment and frailty. Nevertheless, the study by Bailur et. al indicates that chemotherapy has varying effects on different cell subsets within the immune system. Thus, when assessing the role of immune cell components on clinical outcomes of patients with cancer in the context of chemotherapy, the change of each immune subset should be carefully monitored. Together our current study along with that of Bailur et. al sheds light on the complexity of immunological biomarkers as predictors of frailty. Future studies evaluating the value of immune cell subsets as biomarkers to predict frailty should consider immunoprofiling techniques, where the individual contributions of distinct immune subsets (e.g. immunostimulating vs immunosuppressive neutrophils) are evaluated for their association with chemotherapy-induced frailty.
Interestingly, while the changes in neutrophils and NLR were associated with post-chemotherapy frailty as well as change in frailty from pre-chemotherapy to post-chemotherapy, they were not predictive of frailty six months after completing chemotherapy. This suggests that while immune cell counts might be valuable in providing information to assist oncologists in making decisions about acute frailty, these immune profiles might not be predictive of chronic chemotherapy-induced frailty in patients with breast cancer.
Although frailty is typically characterized as an age-related condition, it is important to recognize that frailty also exists in younger patients, especially in the context of cancer.(3, 36) It has been demonstrated that childhood survivors of cancer are more frail than their aged-matched non-cancer counterparts, and they exhibit features of accelerated aging.(3) Cancer contributes to biological changes across varying domains that result in an overall dysregulation of energy systems. This dysregulation has clinical manifestations such as weakness, exhaustion, low physical activity, slow walking speed, and weight loss which ultimately constitutes the frailty phenotype.(4, 37) Thus, in patients with cancer, frailty is a stronger predictor than age of negative cancer treatment outcomes such as post-operative outcomes, chemotherapy-related toxicities, unexpected hospitalizations, morbidity and mortality.(2) In our cohort, we found that patients with breast cancer with a mean age of 53 years were already exhibiting frailty characteristics prior to starting chemotherapy, with about 40% of patients having more than two frailty characteristics before the first chemotherapy cycle (Table 2). Thus, when treating patients with breast cancer, oncologists should consider the effect of chemotherapy on frailty on all patients, both those younger and older than 65 years of age.
This study had several strengths. First, even though this was a younger cohort (mean age 53 years), we were able to replicate the findings of multiple studies on the association between cellular markers of inflammation and frailty. In addition, this study used available data from a cohort study that enrolled participants from multiple community oncology sites within the United States, making our findings generalizable to patients seen in oncology clinics within community settings that traditionally treat the majority of patients with cancer. Third, this was a large (n = 581) longitudinal study with measures obtained at multiple time-points, allowing us to observe longitudinal changes in the cellular markers of inflammation as well as changes in frailty.
Our study also has limitations. We utilized a modified Fried score due to the inability to measure unintentional weight loss. However, even with the use of the modified frailty criteria we were able to corroborate previous findings of an association between inflammation and frailty. Given the complexity of the components and functions of the immune system, future work evaluating the role of cellular markers of inflammation on chronic chemotherapy-induced frailty should use immunoprofiling techniques, such as multiplex immunofluorescence, genomics, and/or proteomics.