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Anthracyclines might increase the risk for certain long-term memory problems and brain injury in patients with breast cancer, according to a small study published online December 3 in JAMA Oncology.
The study is the first to directly assess the neurotoxic effects of anthracyclines and nonanthracyclines in long-term survivors of breast cancer.
Cognitive problems related to cancer and its treatment are sometimes referred to as "cancer brain." These problems can persist over the long term and greatly decrease quality of life. Studies have linked chemotherapy to faster brain aging and to neurodegenerative disorders like Alzheimer's disease.
So far, the neurotoxic effects of various types of chemotherapy regimens are unclear, say researchers Shelli Kesler, PhD, from the University of Texas M.D. Anderson Cancer Center in Houston, and Douglas W. Blayney, MD, from the Stanford University School of Medicine in Palo Alto, California.
But their study indicates that regimen matters.
"Using standardized neuropsychological tests and resting state fMRI, we demonstrated significantly lower verbal memory performance and left precuneus connectivity in participants who received anthracycline regimens compared with those who received nonanthracycline regimens and to participants who did not receive chemotherapy," the pair write.
The left precuneus region is involved in memory, visuospacial processing, and consciousness. It is part of the brain's default mode network, which refers to cognitive activities carried out while the brain is at rest. Changes in connectivity in this region could lower the efficiency of information processing. Past studies have suggested that the default mode network is particularly vulnerable to the chemotherapy used to treat breast cancer. Studies have also linked changes in the default mode network to neurodegenerative disorders, Drs Kesler and Blayney report.
In their study, the researchers evaluated results from standardized cognitive tests and resting state functional MRI data for 62 survivors of primary breast cancer (mean age, 54.7 years). Patients had been off therapy for an average of 2 years. Twenty patients had received four to eight cycles of anthracycline-based chemotherapy, 19 had received four to eight cycles of nonanthracycline chemotherapy, and 23 had no history of chemotherapy. Patients were treated at Stanford University from 2008 to 2014.
There was a significant decrease in verbal memory performance in the anthracycline group, compared with the other two groups. This included a decrease in immediate recall (F = 3.73; P = .03) and delayed recall (F = 11.11; P < .001).
There was also less left precuneus connectivity in the anthracycline group than in the other two groups (F = 7.48; P = .001). And patients treated with anthracyclines had significantly less default mode network connectivity (effect size, 0.6 - 1.3; P = .001).
Patient-reported outcomes for cognitive dysfunction and psychologic distress were worse in patients treated with anthracyclines (F = 7.27; P = .002) and nonanthracyclines (F = 5.64; P = .006) than in those not treated with chemotherapy. Executive functioning and fatigue were also worse in both chemotherapy groups than in the no-chemotherapy group.
There was no association between the number of chemotherapy cycles and cognitive status (P > .50), or between the number of cycles and treatment with endocrine therapy (P > .63). Adjustment for disease stage did not significantly change the results.
The small sample size and the retrospective cross-sectional design limited the study, the researchers acknowledge.
"Larger, prospective studies are needed that include pretreatment and post-treatment assessments so that patients' individual cognitive and neurobiologic trajectories can be evaluated with respect to potential anthracycline-related neurotoxic effects," the researchers conclude. "Continued research regarding the mechanisms by which anthracyclines disrupt neurocircuitry could help identify interventions that will protect against anthracycline-associated neurotoxic effects without reducing the anticancer efficacy of these regimens."
The complexity of research in this area was highlighted in an accompanying editorial by Kelly Nudelman, PhD, Brenna McDonald, PsyD, and Andrew Saykin, PsyD, all from the Indiana University School of Medicine in Indianapolis.
Imaging studies have suggested that a wide array of brain regions are affected by cancer and chemotherapy, they write. "Connectomics," they suggest, could help create a larger picture of the way cancer and its treatment affect cognitive functioning and brain networking.
Larger studies need to include different types of cancer, evaluate genetic factors, and look at the differential role of various cancer agents in neurodegeneration and cognitive aging, they explain.
"Additional prospective studies are needed to address baseline differences and the impact of specific treatments on cognitive function, the underlying neural substrate, and specific biological pathways," the editorialists write. "Resolving the pathways leading to cognitive dysfunction will be important for development of targeted interventions."
Dr Kesler and her colleagues note that anthracyclines, such as doxorubicin, work by inducing double-stranded DNA breaks and free-radical damage in both healthy and cancerous cells. The use of these agents has been linked to neuroinflammation, oxidative stress, and cerebrovascular disease, such as microinfarcts, all of which could contribute to neurodegeneration.


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