Chemotherapy Induced Cognitive Impairment

Ten critical research gaps and translational priorities in breast cancer were identified and published in 2013. One of them (#9) highlighted the need of developing interventions and support to improve the survivorship experience. It is well known that cancer treatment can cause significant long-term effects on a patient's life. Cognitive dysfunction has been recognised as one of those negative effects. The majority of breast cancer patients are living significantly beyond their breast cancer diagnosis. Most of the patients receiving chemotherapy are deemed to be at performance status '0'; fully participating in society, fully active with no restrictions on any activities prior to their cancer diagnosis. These patients are treated with curative intent. It is anticipated for them to fully integrate and return to their everyday life after their breast cancer treatment has been completed. However, for some this is not the case.

Many side effects of chemotherapy, such as fatigue or immune suppression, are well-known but it is less recognised that chemotherapy can cause long-term changes in concentration, memory and learning. This has been referred to as "chemofog". Recent studies suggest that about 15-45% of patients complain about memory and attention problems, lack of concentration, and deficits in multitasking or decision-making following chemotherapy. A number of possible explanations have been proposed for these changes, one is that many chemotherapy drugs are designed to stop cell division. An important part of normal brain function is neurogenesis, the process of creating new neurons, the building blocks of the brain. If cell division is stopped these building blocks can no longer be produced. The hippocampus and striatum are areas critically important to many brain functions. If new neurons are not made, the hippocampus shrinks which is a marker of the memory problems associated with dementia. As well as reducing neurogenesis, chemotherapeutic drugs can also change the balance of important chemicals in the brain called neurotransmitters. This can lead to decreased focus, arousal, and thinking speed. Finally, chemotherapeutic drugs can induce inflammation which can maintain these deficits for years after treatments cease.

Fifty patients will be recruited who have been diagnosed with breast cancer and are having either neoadjuvant or adjuvant chemotherapy as part of their treatment. They will attend the University of Aberdeen research MRI facility on 3 occasions: 1) within 2 weeks of diagnosis, 2) 4 weeks after the last cycle of chemotherapy, 3) 6 months following the end of chemotherapy. Patients on the most common treatment, anthracyclines with or without taxane, will be the focus of this study. A baseline scan before chemotherapy means each patient will be their own control.

During each visit the following will take place:

Brain magnetic resonance imaging: Brain MRI will be performed using a Philips Ingenia dStream 3T scanner and a 32-channel phase-array head coil. The protocol will include structural images (3D T1-weighted, 3D T2-weighted, 3D susceptibility weighted imaging (SWI), fluid attenuated inversion recovery (FLAIR), resting state fMRI (rs-fMRI) and diffusion tensor imaging (DTI). These sequences will allow us measure regional brain volumes and brain functional connectivity and also to see clinically significant features.

Cognitive and general health assessments: 5 individual components of general intelligence, cognitive fatigue, a potential confounder in cognitive testing, depression and anxiety and general health:

• Digit Symbol Coding to measure information processing speed
• Mill Hill Vocabulary test used as a measure of acquired verbal intelligence and an estimate of peak cognitive ability
• Controlled Oral Word Association task used as a measure of verbal fluency
• The Logical Memory test used to assess

• immediate declarative recall
• delayed declarative recall (30 min. apart)
• Matrix Reasoning test, assessing perceptual organisation and visuospatial logic
• Chalder Fatigue Scale
• Hospital Anxiety and Depression Scale
• General Health Questionnaire Blood sample collection: Blood samples will be collected at the time of imaging and cognitive testing to allow high sensitivity ELISA (Enzyme-Linked Immunosorbent Assay) tests for plasma levels of inflammation markers: Total body iron index (sTfR and Ferritin), IL-6, TNF-alpha, IL-1beta, Glutathione Peroxidase-3 (GPX3) activity, Colony-stimulating factor 1 (CSF-1), high-sensitivity c-reactive protein (hsCRP) and F2-isoprostane, a systemic marker of oxidative stress that reflects lipid peroxidation levels. A full blood count will be performed to screen for clinically significant levels of anaemia and immune cell counts.

Inclusion criteria

• Women and men >18 years
• Diagnosed with HER2 negative breast cancer
• Receiving EC-Taxane or Taxane only based chemotherapy
• Able to communicate in English
• Willing and able to give informed consent for participation in the study.

Exclusion criteria

• Any patient whose physical condition will preclude them from lying still for the duration of the brain scan.
• pre-excisting mental condition/disability
• Contraindication to magnetic resonance scanning such as an implantable cardiac device.