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The impact of APOE and smoking history on cognitive function in older, long-term breast cancer survivors

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Abstract

Purpose

This study aims to determine whether older breast cancer survivors score lower on neuropsychological tests compared to matched non-cancer controls and to test the hypotheses that survivors who were APOE ε4 carriers would have the lowest cognitive performance but that smoking history would decrease the negative effect of ε4 on cognition.

Methods

Female breast cancer survivors who had been diagnosed and treated at age 60 or older and were 5–15-year survivors (N = 328) and age and education matched non-cancer controls (N = 162) were assessed at enrollment and at 8-, 16-, and 24-month follow-ups with standard neuropsychological and psychological assessments. Blood for APOE genotyping was collected, and smoking history was assessed at enrollment. Participants were purposely recruited so that approximately 50% had a history of treatment with chemotherapy or no chemotherapy and approximately 50% had a smoking history.

Results

After adjusting for age, cognitive reserve, depression, and fatigue, breast cancer survivors scored significantly lower on all domains of cognitive function. A significant two-way interaction demonstrated that the negative effect of ε4 on cognitive performance was stronger among survivors. A significant three-way interaction supported the hypothesis that smoking history had a protective effect on cognitive function in ε4 carriers that was more pronounced in the controls than the survivors.

Conclusions

The results support the long-term cognitive impact of breast cancer diagnosis and treatments on older, disease-free survivors, particularly for ε4 carriers. The results also emphasize the importance of assessing smoking history when examining APOE and cognition and are an example of the complex interactions of age, genetics, health behaviors, and disease history in determining cognitive function.

Implications for Cancer Survivors

These results help explain why only a subset of breast cancer survivors appear to be vulnerable to cognitive problems.

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Data availability

Data will be made available upon reasonable request to the first author in accordance with the guidelines of the National Cancer Institute.

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Acknowledgements

We thank the study participants, professionals, and members of Love Research Army (formerly the Army of Women) and the research professionals at Memorial Sloan Kettering Cancer Center and City of Hope Comprehensive Cancer Center.

Funding

This research was supported by grants from the National Cancer Institute (TA: R01 CA172119, U54 CA137788, P30 CA008748), the American Cancer Society (SKP: RSG-17–023-01-CPPB), and the Internal MSK grants (IO: Society of MSK, Brain Tumor Center Award).

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Tim A. Ahles, Elizabeth Schofield, Yuelin Li, Elizabeth Ryan, James C. Root, Katrazyna McNeal & Alexandra Gaynor

  2. Molecular Epidemiology Laboratory, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Irene Orlow, Sergio Corrales–Guerrero & Keimya Sadeghi

  3. Departments of Population Science and Supportive Care Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Sunita K. Patel, Heidi Tan, Vani Katheria & Jessica Vazquez

  4. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Tiffany Traina

  5. Center for Cancer and Ageing, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Arti Hurria

Authors
  1. Tim A. Ahles
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  2. Irene Orlow
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  3. Elizabeth Schofield
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Contributions

Tim Ahles, Arti Hurria, Irene Orlow, Elizabeth Ryan, and James Root contributed to the study conception and design. Statistical analyses were conducted by Yuelin Li and Elizabeth Schofield. Data collection and material preparation were performed by Katrazyna McNeal, Heidi Tan, Vani Katheria, Jessica Vazquez, Sergio Corrales–Guerrero, and Keimya Sadeghi. The first draft of the manuscript was written by Tim Ahles, and all authors commented on previous versions. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Tim A. Ahles.

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Ethics approval

All methods and procedures were approved by the institutional review boards of Memorial Sloan Kettering Cancer Center and City of Hope Comprehensive Cancer Center.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors declare no competing interests.

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This paper is dedicated to the memory of Arti Hurria, MD, FASCO, who was a world leader in breast cancer and geriatric oncology.

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Ahles, T.A., Orlow, I., Schofield, E. et al. The impact of APOE and smoking history on cognitive function in older, long-term breast cancer survivors. J Cancer Surviv 18, 575–585 (2024). https://doi.org/10.1007/s11764-022-01267-z

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