Impact of APOE Genotype on Neurocognition Following Conformal Whole Brain Radiotherapy for Brain Metastases: A Post hoc Analysis of Phase II Randomized Trial

Background The genetic risk of radiotherapy-induced cognitive decline (RICD) in patients undergoing whole-brain radiotherapy (WBRT) has not been clearly established. Apolipoprotein E (APOE) polymorphisms, known to influence cognitive aging and Alzheimer’s disease risk, may also modulate neurocognitive outcomes after cranial irradiation. This post-hoc analysis investigates the association between APOE genotype and RICD in patients with brain metastases (BM) treated with conformal or hippocampal-avoidant (HA) WBRT. Methods Patients with BM were randomly assigned to receive conformal or hippocampal avoidant (HA) WBRT. Patients had at least four-month follow-up and APOE genotype information were eligible for this post-hoc analysis. The association between APOE genotype and RICD measured by the Hopkins Verbal Learning Test–Revised (HVLT-R) was analyzed by the general linear model. Results Among 70 randomized patients, APOE genotyping was available for 60% of patients (ε3/ε3, n = 24; ε2/ε3, n = 11; ε4/ε3, n = 7). No differences in baseline characteristics and cognition were observed among patients with different APOE genotypes. At six-month, patients carrying the APOE ε2 allele had the best preservation in HVLT-R total recall (mean difference, ε2: +3.18 versus ε4: −3.20, p = 0.007) and delayed recall (mean difference, ε2 carrier: +0.46 versus ε4 carrier: −2.40, p = 0.049) whereas those with the ε4 allele had the worst. Only patients with the APOE ε3 homozygous alleles showed an improvement in late memory score preservation six months following HA-WBRT (mean difference, HA: +3.67 versus conformal: −3.18, p = 0.037) and beyond. Conclusions APOE genotype is associated with the RICD risk and the effect of benefit in the preservation of late verbal memory following HA-WBRT for patients with BM. Further prospective investigations are warranted to validate our proposed hypothesis. Trial Registration This trial is registered at ClinicalTrials.gov (NCT02393131).