Phase II double blinded randomized placebo-controlled trial of minocycline to ameliorate chemotherapy-induced cognitive changes in breast cancer (BC) patients.
Authors: Sharpe Jessica M. , Schnell Patrick , Knopp Michael V. , Binzel Katherine , Magyer Melissa , Cherian Mathew Amprayil , Gatti-Mays Margaret Elena , Pariser Ashley , Wesolowski Robert , Sardesai Sagar D. , VanDeusen Jeffrey Bryan , Stover Daniel G. , Ramaswamy Bhuvaneswari , Williams Nicole Olivia , DeVries A. Courtney , Shinde Namrata Vilas , Orchard Tonya , Lustberg Maryam B. 
Published: June 2021

e12528

Background: Chemotherapy promotes oxidative stress and neuroinflammation through microglial activation. In preclinical models, minocycline is a potent mitigator of microglial activation. We evaluated the efficacy of co-administration of minocycline with chemotherapy and its effect on inflammatory markers, PET/CT imaging, and cognitive changes in patients with BC. Methods: Women initiating first line adjuvant or neoadjuvant chemotherapy for BC were randomized to receive 100mg twice daily minocycline or placebo during chemotherapy treatment. Depression, anxiety, and cognitive function symptoms were measured with CES-D, STAI, BRIEF-A, and MFMQ testing. Inflammatory changes were evaluated by cytokine panels and PET/CT brain imaging. PET/CT imaging was performed on a Philips Vereos with a single bed dynamic acquisition over the brain acquired continuously for 75 minutes after injection of 3mCi 18F-fluorodeoxyglucose (FDG). Linear mixed effects models were used for statistical analysis. Results: 60 BC patients were randomized (stage distribution: 18.3% IA, 30% IIA, 10% IDC, 8.3% IB, 18.3% IIB, 13.3% IIIA). Median age was 52 years (range 26 - 71). 27 patients (45%) received an anthracycline (AC)-containing regimen, while 33 (55%) received a non-AC-containing regimen. Minocycline group had 42.9% ER+/PR+, HER2- and 32.1% HER2+ disease, while placebo had 51.9% ER+/PR+, HER2- and 22.2% HER2+. Inflammatory cytokine levels increased over time with chemotherapy regardless of group (Log10 of IL-8, TNF-alpha, and TNF-RII +0.5, +0.21, +1.7 with p < 0.001). There were no statistically significant differences between minocycline and placebo groups in changes in anxiety (STAI, -7.9 vs -7.6, p = 0.93), depression (CES-D, -0.3 vs -2.1, p = 0.39), cognitive function (BRIEF-A: +5.8 vs -0.4, p = 0.20; MFMQ: -1.8 vs -5.1, p = 0.49), or cytokine levels. 20 patients underwent PET/CT at treatment onset, 15 repeated imaging at cycle 4, and 13 at 6 months post-treatment. Although not significantly related to treatment group, distinct changes in brain metabolic characteristics in key regions such as the hippocampus were identifiable and quantifiable on an individual basis, and a significantly higher rate of FDG uptake was found over 75 minutes in the left hippocampus in patients who received AC-based chemotherapy compared to non-AC chemotherapy (p = 0.0271). Conclusions: Inflammation increased during chemotherapy. Minocycline co-administration did not mitigate changes in anxiety, depression, cognitive function, cytokine levels, or FDG-uptake in PET/CT imaging. The hippocampal differences in patients receiving AC verses non-AC chemotherapy suggest that AC therapy was more pro-inflammatory. This highlights the potential of PET/CT to monitor microglial activation, providing an objective assessment of neurocognitive function in future studies. Clinical trial information: NCT02203552.