Association of genetic predisposition to low-grade systemic inflammation with cancer-related fatigue in women receiving chemotherapy for non-metastatic breast cancer in URCC07012 and URCC10055.

556 Background: Cancer-related fatigue (CRF) is reported by ~75% of patients receiving chemotherapy for breast cancer. CRF has been linked to inflammation. Chronic, low grade systemic inflammation is a polygenic trait, and a polygenic risk score for inflammation (iPRS) might be associated with risk of CRF. Methods: Using data from the UK Biobank,we developed an iPRS using the INFLA-score, a composite measure of serum C-reactive protein, white-cell count, platelet count, and neutrophil-lymphocyte ratio. The iPRS was evaluated for association with CRF among women with non-metastatic breast cancer enrolled in one of two completed multi-site clinical trials of the University of Rochester Cancer Center NCI Community Oncology Research Program (NCORP) Research Base. CRF was measured before and after standard-of-care chemotherapy using the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). Linear regression evaluated the change in MFSI-SF score from pre- to post-chemotherapy; logistic regression evaluated a binary outcome of any vs no worsening of scores. Analyses were adjusted for patient and treatment factors. Results: The NCORP cohort included 802 women who received chemotherapy (anthracycline-based = 51.8%; previous surgery = 85.0%) at a median age of 55 years (range = 22 to 81). There was an increase in MFSI in 55% of the women, with a mean increase of 8 (range=-64 to 71) from prechemotherapy (mean=8, range = -24 to 83) to post-chemotherapy (mean=15.3, range = -24 - 88), indicating an overall increase in CRF. The iPRS was associated with a significant decrease in MFSI-SF (β=-3.29; 95%CI=-6.25 to -0.34; P =0.029; covariate-adjusted β=-2.71; 95%CI=-5.50 to 0.08; P =0.057) and lower odds of worsening CRF (OR=0.66; 95%CI=0.47-0.93; P =0.016; covariate-adjusted OR=0.67; 95%CI=0.47 to 0.96; P =0.029). The negative relationship between the iPRS and change in CRF was partially explained by the finding that women with an iPRS in the highest quartile have worse pre-chemotherapy MFSI-SF scores (β=4.33; 95%CI=0.23 to 8.43; P =0.038). Conclusions: Women with genetic predisposition to low-grade systemic inflammation, indicated by a higher iPRS, have worse CRF pre-chemotherapy that does not worsen, and may improve, over the course of treatment while women with a lower iPRS have less CRF pre-chemotherapy and are at greatest risk of developing new or worsening CRF during treatment. If validated, the iPRS could identify patients in need of supportive care interventions to reduce CRF. This work was supported by the National Institutes of Health National Cancer Institute Contract No. HHSN261201500003I, Task Order No. HHSN261000039 and by UG1CA189961, URCC NCORP Research Base.