Association of changes of pro-inflammatory markers with physical function in women with breast cancer receiving chemotherapy.
Authors: Gilmore Nikesha , Belcher Elizabeth , Lin Po-Ju , Kleckner Amber , Kadambi Sindhuja G , Loh Kah Poh , Mohamed Mostafa Refaat , Mustian Karen Michelle , Corso Steven W , Esparaz Benjamin , Giguere Jeffrey K. , Mohile Supriya Gupta , Janelsins Michelle Christine 
Published: June 2021

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Background: Chemotherapy adversely affects the immune system and physical function. Inflammation is independently associated with functional decline. Compared to the individual cytokines [e.g., interleukin-6 (IL-6)], the pro-inflammatory index, IL-6/IL-10 ratio, is a better predictor of poor outcomes and mortality in many diseases. Other markers of inflammation such as soluble tumor necrosis factor (sTNFR) I, and sTNFRII have also been shown to be predictive of poor outcomes. We have previously reported a significant increase in sTNFRI/II with chemotherapy in patients with breast cancer. However, it is not yet understood if chemotherapy-related changes to inflammatory makers is associated with physical function after treatment. In this study, we assessed the relationship between changes of pro-inflammatory markers during chemotherapy with physical function after completing chemotherapy. Methods: This was a secondary analysis of a large nationwide cohort study in women with stage I-III breast cancer (NCT01382082). Serum levels of IL6, IL10, sTNFRI, and sTNFRII were measured ≤7 days before chemotherapy (T1) and ≤1 month after chemotherapy (T2), and the IL6/IL10 ratio was calculated. Absolute changes (T2-T1) of sTNFR-I and sTNFRII (reported in pg/mL) and the IL6/IL10 ratio were calculated. Physical function was measured by the Functional Assessment of Cancer Therapy: General – physical well being (FACT-PWB) at T1 and T2 and contains 7-items, each using a 5-point rating scale ranging from 0 (Not at all) to 4 (Very much), with a total score ranging from 0-28; higher scores represent higher physical function. ANOVA was used to compare means of FACT-PWD scores and mean changes of pro-inflammatory markers. Multivariate linear regressions were used to determine if increased pro-inflammatory markers were associated with lower FACT-PWD at T2, controlling for baseline FACT-PWD, age, race, education, and marital status. Results: We included 580 patients (mean age=53 years, range 22-81). Physical function significantly and clinically declined from T1-T2 (mean=22.2, SE=0.23 vs mean=19.4, SE=0.25; p<0.001). From T1-T2, there was a significant increase in IL6/IL10 (average change = 0.32, SE=0.09; p=0.004). A greater increase in pro-inflammatory markers from T1 to T2 was associated with lower FACT-PWD score at T2; sTNFRI (β=-3.92, SE=1.4), sTNFRII (β=-14.9, SE=7.1), and IL6/IL10 (β=-0.17, SE=0.06); all p<0.05. Conclusions: Serum pro-inflammatory markers increased from pre-chemotherapy to post-chemotherapy in patients with breast cancer. Greater increases in pro-inflammatory markers are associated with lower physical function within one month of the completion of chemotherapy. Pro-inflammatory markers; sTNFRI, sTNFRII, and IL6/IL10, may serve as useful biomarkers to help identify patients at risk of reduced physical function after chemotherapy.