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Low-grade inflammation has been associated with cancer related fatigue (CRF). However, most studies focused on CRF during or shortly after treatment. Longitudinal studies are rare with inconsistent results. We assessed the association of inflammatory biomarkers with total CRF and all subdomains (physical, cognitive, affective) in long-term breast cancer survivors. Patients recruited between 2002 and 2005 provided information on CRF at first follow-up (FU1) (N = 1292) and second follow-up (FU2) (N = 1205), after a median of 6.2 years and 11.7 years, respectively. Associations of 11 inflammatory biomarkers with CRF at FU1 and at FU2 were assessed using linear regression models. Logistic regression models were used to compare patients fatigued at both time-points and those never fatigued (N = 932). C-reactive protein (CRP) was significantly associated with total CRF at FU1 (β = 1.47, 95%CI = 0.62–2.31, p = 0.0007), at FU2 (β = 1.98, 95 %CI = 0.96–2.99, p = 0.0001) and with persistent CRF (OR = 1.29, 95%CI = 1.13–1.47, p < 0.0001). IL-6 levels were associated with total CRF at FU1 (β = 1.01, 95%CI = 0.43–1.59, p = 0.0006), but not with CRF at FU2 or persistent CRF. No association remained significant after adjustment for relevant covariates. CRP and Il-6 were associated with risk of CRF in long-term breast cancer survivors, but were not independent of other known risk factors, suggesting that currently studied inflammatory markers are not suitable to identify patients at risk of long-term CRF. • Associations of inflammatory biomarkers were assessed for total CRF and all CRF subdomains (physical, cognitive, affective). • Circulating CRP and Il-6 were associated with risk of CRF in long-term breast cancer survivors. • CRP and Il-6 were not independent of other known risk factors and therefore not suitable to identify patients at risk. • No support for suspected pathways of low-grade inflammation as underlying biological mechanisms of long-term CRF. [ABSTRACT FROM AUTHOR]

Highlights • Genetic association assessed for CRF and all subdomains (physical, cognitive, affective) • Previously reported SNPs associated with total CRF were not confirmed. • TNF-α SNP rs3093662 was significantly associated with physical CRF. Abstract Background Studies to date have reported several associations between single nucleotide polymorphisms (SNPs) and cancer related fatigue (CRF), but have been limited by small sample sizes, missing adjustment for relevant covariates or multiple testing, as well as varying CRF definitions, i.e. time and method of assessment. This study aimed to validate previously reported associations using the largest independent breast cancer sample to date and to evaluate further functional cytokine variants in relation to total CRF and all relevant CRF subdomains (physical, cognitive, and affective CRF). Method 45 candidate SNPs in inflammatory pathway genes were selected based on previous reports (16 SNPs) or regulatory function (29 SNPs). Breast cancer patients recruited between 2002 and 2005 provided information on CRF at first follow-up (FU1) (N = 1389) and second follow-up (FU2) (N = 950), a median of 6.2 years and 11.7 years respectively after diagnosis. SNP associations were assessed using linear regression models on CRF scores separately for FU1 and FU2. Additionally, patients with persistent fatigue (fatigued at both time-points) were compared to those never fatigued using logistic regression models (N = 684). All analyses were adjusted for relevant covariates. Secondary analyses were conducted for CRF subdomains. Results For total CRF none of the previously reported associations were confirmed after correction for multiple testing. The p-value distribution of all SNPs was not different than the one expected by chance. Analyses of CRF subdomains yielded a significant association between TNF-α rs3093662 and persistent physical CRF (Odds Ratio (OR) = 3.23, 95% Confidence Interval (CI) = 1.71–6.10, p = 0.0003). Conclusion We were unable to confirm previously reported findings, suggesting that individual SNPs are unlikely to be of clinical utility. Further investigations in well powered studies are warranted, which consider genetic heterogeneity according to subdomains of CRF. [ABSTRACT FROM AUTHOR]