International journal of radiation oncology, biology, physics | 2021
Impact of APOE Genotype on Neurocognitive Outcomes in Hippocampal Avoidance Whole Brain Radiotherapy for Brain Metastases: A Secondary Analysis of Phase II Blinded Randomized Trial.
Abstract
PURPOSE/OBJECTIVE(S)\nApolipoprotein E (APOE) polymorphism is a well-known risk associated with Alzheimer s disease. Its role in neurocognition decline after whole brain radiotherapy (WBRT) for brain metastases is not well-investigated. The present secondary analysis of a prospective blinded randomized controlled phase II trial aimed to evaluate the impact of APOE genotypes upon neurocognitive outcomes after WBRT with or without hippocampal avoidance.\n\n\nMATERIALS/METHODS\nAdult patients with brain metastases were stratified by prior radiosurgery and randomized to hippocampal avoidant conformal WBRT versus conformal WBRT without hippocampal avoidance to 30 Gy in 10 fractions from March 2015 to November 2018. Memantine was not used during or after WBRT. Standardized neurocognitive test battery (Hopkins Verbal Learning Test-Revised [HVLT-R], Trail Making Test), was performed at baseline, 1, 2, 4, 6, and every 3 months up to two years by trained independent health professionals. Both clinical trial participants and examiners were blinded to the treatment group assignment. APOE alleles were determined by the genome-wide genotyping. The association between APOE genotypes and neurocognitive outcomes was analyzed by general linear model. The role of APOE genotypes on the effect of hippocampal avoidance during WBRT was also evaluated. Factorial ANOVA was used to assess the independent factors associated with neurocognitive outcomes.\n\n\nRESULTS\nAmong 65 analyzable patients, APOE genotyping was available for 64.6% (n\u202f=\u202f42) of patients. The most frequent APOE allele was ε3 homozygote (ε3/ε3, n\u202f=\u202f24), followed by ε2 carrier (ε2/ε3, n\u202f=\u202f11) and ε4 carrier (ε4/ε3, n\u202f=\u202f7). No differences in baseline characteristics and cognitions between patients of different APOE genotypes. At 6-month, patients carrying APOE ε2 and ε4 allele had the best and worst preservation in HVLT-R total recall (mean difference, ε2: +3.18 versus ε4: -3.20, P\u202f=\u202f0.008), and delayed recall (mean difference, ε2 carrier: +0.46 versus ε4 carrier: -2.40, P\u202f=\u202f0.03), respectively. The effect of preservation in 6-month memory score is the strongest in the APOE ε2 carriers followed by the APOE ε3 homozygotes, and the least in the APEO ε4 carriers in order (P\u202f=\u202f0.028). Only patients of APOE ε3 homozygotes showed improved preservation in late memory score by hippocampal avoidant WBRT at 6-month (mean difference, hippocampal avoidant: +3.67 versus conformal: -3.18, P\u202f=\u202f0.037) and beyond. APOE genotyping was independent of age and hippocampal avoidance to be associated with the preservation of 6-month HVLT-R total recall (P\u202f=\u202f0.042), and HVLT-R delayed recall (P\u202f=\u202f0.032).\n\n\nCONCLUSION\nThe APOE genotype is associated with the risk of memory decline after WBRT. Specifically, APOE ε2 carriers exhibited better while ε4 carriers showed worse perpetuation in verbal memory function after WBRT. APOE ε3 homozygotes but not APOE ε2 or ε4 carriers benefit late memory preservation by hippocampal avoidant WBRT for brain metastases.