A Feasibility Study of Magnesium Supplementation for Cognitive Impairment from Adjuvant Endocrine Therapy for Breast Cancer

Abstract

A Feasibility Study of Magnesium Supplementation for Cognitive Impairment from Adjuvant Endocrine Therapy for Breast Cancer Porter D1,2, Baguley B3, Lambert A4, Huang Y5, Sharples K 6,7, Crooks C6, Barrett C1, Benge S6, Isaacs R8, Jeffery M9, Findlay M 2,6 1Auckland Regional Cancer and Blood Service 2Discipline of Oncology, University of Auckland 3Auckland Cancer Society Research Centre, University of Auckland 4School of Psychology, University of Auckland 5 Section of Epidemiology & Biostatistics, School of Population Health, University of Auckland 6Cancer Trials New Zealand, 7Department of Medicine, Dunedin School of Medicine and Department of Mathematics and Statistics, University of Otago 8MidCentral Health Regional Cancer Treatment Service 9Canterbury Regional Cancer and Haematology Service Studies indicate that patients receiving endocrine therapy with tamoxifen or an aromatase inhibitor (AI) perform more poorly than treatment free controls on objective measures of verbal learning and memory, attention, and processing speed. This cognitive impairment has generally been attributed to a direct effect mediated by oestrogen receptors in the brain. However, renal Mg++ handling by the TRPM6 transporter protein is regulated by oestrogen so that depletion of circulating oestradiol, or anti-oestrogen therapies have the potential to decrease overall reuptake of Mg++ at the proximal convoluted tubule, leading to Mg++ depletion over time. Low Mg++ stores are associated with poorer cognition in rodent models and in humans with Alzheimer’s disease or familial hypomagnesaemia. We hypothesised that oral Mg supplementation might improve cognitive function in women receiving adjuvant endocrine therapy for breast cancer. We conducted a feasibility study for a randomised controlled trial of Mg supplementation. Women aged >18 who had received a minimum of 6 months adjuvant endocrine therapy for early breast cancer were randomised to receive 400mg elemental Mg per day or matching placebo for three months. Cognition was recorded objectively at baseline and at end of study using the NHI toolkit and validated questionnaires. Mg levels were monitored monthly on treatment and selected AEs recorded. 34 women aged 39-70 were enrolled in the study between April and October 2016 in 3 New Zealand centres; 1 patient withdrew consent. 22 patients were receiving tamoxifen and 11 an AI. 15 patients had received adjuvant chemotherapy ± trastuzumab. 16 patients were randomised to receive Mg, 17 to placebo. 1 patient stopped study treatment after a small midbrain CVA thought to be unrelated to treatment. There were no other grade 3/4 toxicities. but 4 patients on active treatment experienced grade 1 diarrhoea compared with 2 in the placebo group. The increase in serum total Mg during the study was greater in the Mg group than in the placebo group (difference 0.036 mmol/l, 95% CI: 0.004 to 0.068 p=0.028). Median total time to complete all study questionnaires was 39 minutes at baseline and 36 minutes at study end. Women found the study procedures easy to complete. Feasibility and acceptability of the study design and procedures were confirmed The results indicate Mg stores can be replenished with oral Mg and no safety concerns were observed. A phase III nationwide study is planned to evaluate the efficacy and safety of Mg in improving cognitive function.