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25 March 2020

What are the biological mechanisms behind chemotherapy-associated cognitive impairment?

Despite chemotherapy-associated cognitive impairment (CACI, aka chemobrain) affecting 75% of all cancer survivors, little is understood about the mechanisms underlying the disorder. In efforts to address this research gap, Prof Alexandre Chan from the University of California, Irvine used CANTAB to conduct an evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment. Read on to find out the results.  

Can you tell us more about your research?

Chemotherapy-associated cognitive impairment (CACI, aka chemobrain) is commonly observed among cancer patients and survivors during and after treatment. Reports have shown that cognitive deficits can negatively affect patients’ social functioning and quality of life. In our previous research as well as other published literature, the prevalence of this problem ranges up to 75% of all cancer survivors.

What is the rationale behind your study?

Currently, the mechanisms underlying CACI is currently unknown. Recently, a prospective study reported cognitive decline is associated with DNA methylation of leukocytes in breast cancer patients receiving chemotherapy, providing evidence of epigenetic links to CACI. DNA methylation is catalyzed by DNA methyltransferase (DNMT) enzymes. Hence, we conducted a study to evaluate the impact of a single nucleotide polymorphism (SNP) situated within the coding of DNMT1 gene (which controls the extent of methylation in human) on CACI. We hypothesize that carriers of the A allele of the rs2162560 polymorphism have increased DNA methylation activity that protects them from CACI.

Which methods did you use?

We conducted a multicenter, prospective, longitudinal cohort study. Patients were eligible to participate in this study if they fulfilled the following inclusion criteria: (i) at least 21 years old, (ii) diagnosed with stage I-IIIA breast cancer, (iii) scheduled for four cycles of anthracycline- or taxane-based chemotherapy, (iv) no history of chemotherapy or radiotherapy, and (v) read and understand English or Mandarin. Patients who were (i) symptomatically ill, (ii) diagnosed with brain metastasis or any neuropsychiatric illness that may cause cognitive impairment, or (iii) physically or mentally incapable of giving written informed consent were excluded. We assessed patients’ cognitive functioning using a self-reported tool (FACT-Cog) and we used the Cambridge Neuropsychological Test Automated Battery (CANTAB, Cambridge Cognition Ltd., UK) to assess patients’ objective cognitive function.

What are your key findings?

In this study, 1 out of 3 patients self-reported impairment relative to baseline in one or more cognitive domains. Using CANTAB, the most commonly affected cognitive domains included processing speed (36.9%), response speed (30.3%) and attention (26.2%). The DNMT1 rs2162560 A allele was observed in 21.8% of patients and this was associated with lower odds of self-reported cognitive decline in the concentration (OR = 0.45, 95% CI: 0.25–0.82, P = 0.01) and functional interference (OR = 0.48, 95% CI: 0.24–0.95, P = 0.03) domains. Interestingly, we did not observe any significant association between DNMT1 rs2162560 and objective cognitive function using CANTAB.

What are the implications of your study?

These findings suggest that self-reported CACI in cancer patients, which is often exacerbated by behavioral symptoms, is associated with epigenetic processes. Further validation of the current findings is required.

Why did you choose CANTAB?

We chose CANTAB because we have used it in numerous studies, and it is sensitive in capturing alterations in neuropsychological performance in the cognitive domains that are recommended by the International Cancer and Cognitive Task Force (ICCTF). In this study, the CANTAB test battery contained five tests: reaction time (RTI), paired associates learning (PAL), spatial working memory (SWM), attention switching task (AST), and rapid visual information processing (RVP) that assessed response speed, learning and memory, working memory, multitasking, and sustained attention, respectively, yielding a total of nine measures. We computed the reliable change indices (RCI) to reflect cognitive changes in participants, and the RCI were obtained by adjusting for practice effects and dividing by the standard error of difference from a control population using similar testing intervals.

What are the next steps for your research?

Our research group continues to identify biomarkers that are associated with CACI. It is hoped that with an improvement understanding of the mechanisms of CACI, potential pharmacological interventions for management of this complex condition can be developed.

The full research article is available to download here: An Evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment: A Prospective, Longitudinal Study

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Prof Alexandre Chan - University of California, Irvine