Genetic associations of fatigue and other symptoms following breast cancer treatment: A prospective study

Background: Cancer-related fatigue, mood disturbances, pain and cognitive disturbance are common after adjuvant cancer therapy, but vary considerably between individuals despite common disease features and treatment exposures. A genetic basis for this variability was explored in a prospective cohort. Methods: Physical and psychological health of women were assessed prospectively following therapy for early stage breast cancer with self-report questionnaires. Participation in a genetic association sub-study was offered. Indices for the key symptom domains of fatigue, pain, depression, anxiety, and neurocognitive difficulties were empirically derived by principal components analysis from end-treatment questionnaires, and then applied longitudinally. Genetic associations were sought with functional single nucleotide polymorphisms (SNPs) in pro- and anti-inflammatory cytokine genes - tumour necrosis factor (TNF)-α (−308 ​GG), interferon (IFN)-ɣ (+874 ​TA), interleukin (IL)-10 (1082 ​GA and −592 CA), IL-6 (−174 ​GC), IL-1β (−511 ​GA). Results: Questionnaire data was available for 210 participants, of whom 111 participated in the genetic sub-study. As expected, symptom domain scores generally improved over several months following treatment completion. Tumour and adjuvant treatment related factors were unassociated with either severity or duration of the individual symptom domains, but severity of symptoms at end-treatment was strongly associated with duration for each domain (all p ​< ​0.05). In multivariable analyses, risk genotypes were independently associated with: fatigue with IL-6 -174 ​GG/GC and IL-10 -1082 GG; depression and anxiety with IL-10 -1082 AA; neurocognitive disturbance: TNF-α −308 GG; depression IL-1β (all p ​< ​0.05). The identified SNPs also had cumulative effects in prolonging the time to recovery from the associated symptom domain. Conclusions: Genetic factors contribute to the severity and duration of common symptom domains after cancer therapy.