Inflammation-related proteins as biomarkers of treatment-related behavioral symptoms: A longitudinal study of breast cancer patients and age-matched controls.

Background: Behavioral symptoms in breast cancer (BC) survivors have been attributed to cancer treatment and resulting inflammation. However, studies linking behavioral symptoms to BC treatment have observed patients only after some treatment. Our prospective study with pre-treatment baseline investigates post-treatment changes in inflammation-related biomarkers and whether those changes correlate with changes in symptoms. Methods: Participants were postmenopausal women, newly-diagnosed with stage 0-3 BC before any treatment (n = 173 "patients"), and age-matched women without cancer (n = 77 "controls"), who were assessed on plasma markers [soluble tumor necrosis factor receptor type 2 (sTNF-RII), interleukin (IL)-6, IL-1 receptor antagonist (IL-1RA), C-reactive protein (CRP)]) and symptoms (Physical Functioning, Pain, Attention/concentration, Perceived Cognitive Problems, Fatigue, Sleep Insufficiency, Depression). Participants were assessed again 1 month, 1 year, and 2 years after completing primary treatment or similar interval in controls. Generalized linear mixed models tested 4 treatments (surgery alone or with chemotherapy, radiation, or both) for association with change per marker. Joint models tested change per marker for association with change per symptom. Models considered demographic, socioeconomic, and clinical covariates. False Discovery Rate method controlled risk of error from multiple hypotheses. Results: At one month post-completion of treatment, sTNF-RII and IL-6 were elevated by all BC treatments, as were IL-1RA and CRP after surgery alone (all, p < 0.05). By 1 year, markers' average values returned to baseline. Throughout 2-year follow-up, increase-from-baseline in sTNF-RII, IL-1RA, and IL-6 coincided with worsened Physical Functioning, and increase-from-baseline in sTNF-RII coincided with increased Pain (all, p < 0.01). These biomarker-symptom associations (excepting IL-6) were exclusive to patients. No other symptoms worsened, and baseline Fatigue and Depression improved in all participants. Conclusions: BC treatment, even surgery, is associated with transient elevation in inflammatory markers. In patients post-treatment, increase-from-baseline in sTNF-RII accompanies increased Pain and decreased Physical Functioning, suggesting that sTNF-RII merits development as a clinical biomarker in BC patients.