Cognitive sequelae of endocrine therapy in women treated for breast cancer: a meta-analysis
Evidence suggests anti-estrogen endocrine therapy (ET) is associated with adverse cognitive effects; however, findings are based on small samples and vary in the cognitive abilities affected. We conducted a meta-analysis to quantitatively synthesize the evidence.
Electronic databases were searched in November 2016. Fourteen studies totaling 911 BC patients on aromatase inhibitors (AIs) or tamoxifen (TAM) and 911 controls (i.e., non-cancer controls and BC controls not using ET) were included. Neuropsychological tests were categorized into six domains. Effect sizes were computed to compare (1) ET patients versus controls and (2) TAM patients versus AI patients.
In cross-sectional comparisons, ET patients performed worse than control groups on verbal learning/memory, visual learning/memory, frontal executive function, and processing speed, but did not differ on psychomotor efficiency or visuospatial function. Subgroup analyses revealed that verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls. In other domains, ET patients and BC controls performed equivalently. Regarding change from pre-treatment performance, ET patients did not differ from controls on any domain. TAM and AI patients did not from one another differ overall; however, subgroup analyses indicated that TAM patients performed better than non-steroidal AI patients on several domains, but showed few performance differences relative to steroidal AI patients.
Verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls, suggesting specific adverse effects on this domain. Additional studies assessing change from pre-treatment performance and differences between steroidal and non-steroidal AIs are warranted.
KeywordsEndocrine therapy Breast cancer Cognitive functioning Neuropsychological tests
Kathy Zhang (Research Assistant, Sunnybrook Research Institute) assisted with abstract screening, full-text screening, data extraction, and manuscript formatting. We thank Dr. Carlo DeAngelis (Pharmacist and Clinician Scientist, Odette Cancer Centre, Sunnybrook Health Sciences Centre) for providing pharmacological expertise, and Dr. Gerald Lebovic (Biostatistician, Applied Health Research Centre, St. Michael’s Hospital) for his critical review of this manuscript.
This meta-analysis was funded by a Sunnybrook Alternative Funding Plan Innovation Fund. E.A.U. was supported by a Canadian Federation for University Women fellowship and an Ontario Graduate Scholarship award. M.C.T. is supported by a Clinician Scientist award from the Department of Family & Community Medicine, University of Toronto and Sunnybrook Health Sciences Centre. P.A.R holds the Retired Teachers of Ontario/ERO Chair in Geriatric Medicine. The funders were not involved in any aspect of study conception, design, data collection, analysis, manuscript preparation, or submission of this manuscript for publication.
Compliance with ethical standards
Conflicts of interest
KI.P. has served in consulting and advisory roles for, and received honoraria and travel support from, AstraZeneca, Pfizer, Roche, Amgen, Novartis, and Eisai. No other authors have conflicts of interest to report.
For this type of study (meta-analysis), formal consent is not required.
- 1.Burstein HJ, Temin S, Anderson H, Buchholz TA, Davidson NE, Gelmon KE, Giordano SH, Hudis CA, Rowden D, Solky AJ, Stearns V, Winer EP, Griggs JJ (2014) Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol 32(21):2255–2269. https://doi.org/10.1200/jco.2013.54.2258 CrossRefPubMedPubMedCentralGoogle Scholar
- 2.Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Wang YC, Dowsett M, Ingle J, Peto R (2011) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378(9793):771–784. https://doi.org/10.1016/s0140-6736(11)60993-8 CrossRefPubMedGoogle Scholar
- 3.Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials (2015). Lancet 386 (10001):1341–1352. https://doi.org/10.1016/s0140-6736(15)61074-1
- 16.Stewart SA (2005) The effects of benzodiazepines on cognition. J Clin Psychiatr 66(Suppl 2):9–13Google Scholar
- 19.Lezak MD (2004) Neuropsychological assessment. Oxford University Press, OxfordGoogle Scholar
- 20.Hedges LVO I (1985) Statistical methods for meta-analysis. Academic Press, San DiegoGoogle Scholar
- 22.Higgins J, Green S (2011) Identifying and measuring heterogeneity. Cochrane handbook for systematic reviews of interventions version 5.0, vol 1. The cochrane collaborationGoogle Scholar
- 25.Schilder CM, Eggens PC, Seynaeve C, Linn SC, Boogerd W, Gundy CM, Beex LV, Van Dam FS, Schagen SB (2009) Neuropsychological functioning in postmenopausal breast cancer patients treated with tamoxifen or exemestane after ac-chemotherapy: cross-sectional findings from the neuropsychological team-side study. Acta Oncol 48(1):76–85. https://doi.org/10.1080/02841860802314738 CrossRefPubMedGoogle Scholar
- 33.Schilder CM, Seynaeve C, Beex LV, Boogerd W, Linn SC, Gundy CM, Huizenga HM, Nortier JW, van de Velde CJ, van Dam FS, Schagen SB (2010) Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. J Clin Oncol 28(8):1294–1300CrossRefPubMedGoogle Scholar
- 37.Le Rhun E, Delbeuck X, Lefeuvre-Plesse C, Kramar A, Skrobala E, Pasquier F, Bonneterre J (2015) A phase iii randomized multicenter trial evaluating cognition in post-menopausal breast cancer patients receiving adjuvant hormonotherapy. Breast Cancer Res Treat 152(3):569–580. https://doi.org/10.1007/s10549-015-3493-1 CrossRefPubMedGoogle Scholar
- 39.Lange M, Giffard B, Noal S, Rigal O, Kurtz JE, Heutte N, Levy C, Allouache D, Rieux C, Le Fel J, Daireaux A, Clarisse B, Veyret C, Barthelemy P, Longato N, Eustache F, Joly F (2014) Baseline cognitive functions among elderly patients with localised breast cancer. Eur J Cancer 50(13):2181–2189. https://doi.org/10.1016/j.ejca.2014.05.026 CrossRefPubMedGoogle Scholar
- 40.Sherwin BB, Phillips S (1990) Estrogen and cognitive functioning in surgically menopausal women. Ann NY Acad Sci 592(1):474–475. https://doi.org/10.1111/j.1749-6632.1990.tb30379.x CrossRefGoogle Scholar
- 46.Tierney MC, Oh P, Moineddin R, Greenblatt EM, Snow WG, Fisher RH, Iazzetta J, Hyslop PS, MacLusky NJ (2009) A randomized double-blind trial of the effects of hormone therapy on delayed verbal recall in older women. Psychoneuroendocrinology 34(7):1065–1074. https://doi.org/10.1016/j.psyneuen.2009.02.009 CrossRefPubMedGoogle Scholar
- 50.Yaffe K, Barnes D, Lindquist K, Cauley J, Simonsick EM, Penninx B, Satterfield S, Harris T, Cummings SR (2007) Endogenous sex hormone levels and risk of cognitive decline in an older biracial cohort. Neurobiol Aging 28(2):171–178. https://doi.org/10.1016/j.neurobiolaging.2006.10.004 CrossRefPubMedGoogle Scholar
- 54.Ariazi EA, Leitao A, Oprea TI, Chen B, Louis T, Bertucci AM, Sharma CG, Gill SD, Kim HR, Shupp HA, Pyle JR, Madrack A, Donato AL, Cheng D, Paige JR, Jordan VC (2007) Exemestane’s 17-hydroxylated metabolite exerts biological effects as an androgen. Mol Cancer Ther 6(11):2817–2827. https://doi.org/10.1158/1535-7163.mct-07-0312 CrossRefPubMedGoogle Scholar
- 58.Ahles TA, Saykin AJ, McDonald BC, Li Y, Furstenberg CT, Hanscom BS, Mulrooney TJ, Schwartz GN, Kaufman PA (2010) Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. J Clin Oncol 28(29):4434–4440. https://doi.org/10.1200/jco.2009.27.0827 CrossRefPubMedPubMedCentralGoogle Scholar