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3367 A Mouse Model of APOE Genotype in Chemotherapy Related Cognitive Impairment
- Tamar Demby, G. William Rebeck, Christopher Albanese, Olga C. Rodriguez, Yichien Lee, Jeanne Mandelblatt
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- Journal:
- Journal of Clinical and Translational Science / Volume 3 / Issue s1 / March 2019
- Published online by Cambridge University Press:
- 26 March 2019, p. 1
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- Article
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OBJECTIVES/SPECIFIC AIMS: Chemotherapy-related cognitive impairment (CRCI) affects 15-35% of breast cancer survivors and constitutes a significant challenge for survivor quality of life. Among older breast cancer survivors who received chemotherapy treatment, carriers of at least one ɛ4 allele of the APOE gene, which encodes apolipoprotein E, are at higher risk for developing CRCI than non-carriers. APOE4 is well characterized as the strongest genetic risk factor for Alzheimer’s disease, but how it contributes to CRCI is not yet understood, and no animal models of APOE genotype and CRCI have yet been established. To better understand how APOE4 acts as a risk factor for CRCI, we used APOE targeted replacement (TR) mice to develop a model of its effects on cognition following treatment with doxorubicin, a chemotherapy drug commonly used in breast cancer treatment. METHODS/STUDY POPULATION: Twelve-to-thirteen month old APOE3 and APOE4 targeted replacement mice expressing human APOE3 or human APOE4 under control of the endogenous murine promoter were treated with 10 mg/kg doxorubicin or equivolume saline given via two IP injections spaced one week apart. One week post-treatment, mice were tested using Open Field and Elevated Zero apparatuses to assess baseline locomotive activity and anxiety and exploratory behaviors. Five weeks post-treatment, mice were assessed using the Barnes Maze over four days of training trials and one 72 hour memory probe. RESULTS/ANTICIPATED RESULTS: We found no differences in Open Field and Elevated Zero behavior, indicating limited influence of doxorubicin treatment on locomotive and anxiety behaviors in both genotypes. During Barnes Maze training, APOE4 mice treated with doxorubicin showed increased latency compared to untreated APOE4 mice as well as treated and untreated APOE3 mice, indicating deficiencies in spatial learning. In APOE3 mice, no differences in performance were seen between doxorubicin-treated and untreated mice (n = 15-16/group, p <.0001). DISCUSSION/SIGNIFICANCE OF IMPACT: These results indicate that APOE4 targeted replacement mice have specific cognitive vulnerabilities to doxorubicin treatment that can be reliably detected using the Barnes Maze assessment. Future directions include experiments to determine how other chemotherapy drugs or drug combinations impact cognition of APOE4 mice. Ultimately this model may be used to assess preventive measures or therapies for CRCI in the vulnerable APOE4 carrier population with the ability to validate cognitive impacts of these interventions.
10 - Short-term outcomes of chemoprevention, genetic susceptibility testing, and screening interventions: What are they? How are they measured? When should they be measured?
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- By Jeanne S. Mandelblatt, M.D., M.P.H., Director Georgetown University, Washington, DC, Joe V. Selby, M.D., M.P.H., Director Kaiser-Permanente Medical Care Program, Oakland, CA
- Edited by Joseph Lipscomb, National Cancer Institute, Bethesda, Maryland, Carolyn C. Gotay, Claire Snyder, National Cancer Institute, Bethesda, Maryland
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- Book:
- Outcomes Assessment in Cancer
- Published online:
- 18 December 2009
- Print publication:
- 23 December 2004, pp 216-240
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Summary
Introduction
Cancer is a frequent and serious illness with major impact on the quantity and quality of life. For several common cancers, preventive measures and periodic screening can reduce the risk for cancer incidence or, through early detection, lower morbidity and mortality from incident cancers. More recently, genetic testing has been introduced to screen for cancer susceptibility mutations. Presumably, the benefits of screening and early detection are accompanied by net improvements in the quality of life for persons in whom cancers are prevented or detected early. However, both prevention efforts and screening also have the potential to influence quality of life more subtly, either positively or negatively, for the large majority of asymptomatic individuals who would never have developed the cancer.
Faced with an increasing number of effective prevention and screening strategies and technologies, individual patients, health care systems, and policy analysts need accurate assessments of quality-of-life outcomes to inform shared decision making and to conduct relevant decision and cost-effectiveness analyses.– However, there has been little research on short-term effects on quality of life, which may be the predominant effects of chemopreventive or screening interventions.
In this chapter, short-term outcomes are defined, a framework for understanding and measuring these outcomes presented, the quality-of-life domains most relevant to cancer prevention and screening activities explored, the existing literature and tools currently employed to measure outcomes reviewed, methodological challenges highlighted, and recommendations for future studies made.