Abstract
Purpose
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.
Methods
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.
Results
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.
Conclusions
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.
Similar content being viewed by others
References
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
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
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
Galea LAM, Frick KM, Hampson E, Sohrabji F, Choleris E (2017) Why estrogens matter for behavior and brain health. Neurosci Biobehav Rev 76:369–379. https://doi.org/10.1016/j.neubiorev.2016.03.024
Birge SJ (2007) Aromatase inhibitors: a time for reflection. Menopause 14(6):971–972. https://doi.org/10.1097/gme.0b013e318156dd2f
Lee PE, Tierney MC, Wu W, Pritchard KI, Rochon PA (2016) Endocrine treatment-associated cognitive impairment in breast cancer survivors: evidence from published studies. Breast Cancer Res Treat 158(3):407–420. https://doi.org/10.1007/s10549-016-3906-9
Zwart W, Terra H, Linn SC, Schagen SB (2015) Cognitive effects of endocrine therapy for breast cancer: keep calm and carry on? Nat Rev Clin Oncol 12(10):597–606. https://doi.org/10.1038/nrclinonc.2015.124
Blaustein JD (2017) Treatments for breast cancer that affect cognitive function in postmenopausal women. Policy Insights Behav Brain Sci 4(2):170–177. https://doi.org/10.1177/2372732217717271
DeSantis C, Ma J, Bryan L, Jemal A (2014) Breast cancer statistics, 2013. CA Cancer J Clin 64(1):52–62. https://doi.org/10.3322/caac.21203
Laird-Fick HS, Gardiner JC, Tokala H, Patel P, Wei S, Dimitrov NV (2013) Her2 status in elderly women with breast cancer. J Geriatr Oncol 4(4):362–367. https://doi.org/10.1016/j.jgo.2013.05.007
Anderson WF, Katki HA, Rosenberg PS (2011) Incidence of breast cancer in the United States: current and future trends. J Natl Cancer Inst 103(18):1397–1402. https://doi.org/10.1093/jnci/djr257
Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198
Wefel JS, Schagen SB (2012) Chemotherapy-related cognitive dysfunction. Curr Neurol Neurosci Rep 12(3):267–275
Hindmarch I (2009) Cognitive toxicity of pharmacotherapeutic agents used in social anxiety disorder. Int J Clin Pract 63(7):1085–1094. https://doi.org/10.1111/j.1742-1241.2009.02085.x
Wadsworth EJ, Moss SC, Simpson SA, Smith AP (2005) SSRIs and cognitive performance in a working sample. Hum Psychopharmacol 20(8):561–572. https://doi.org/10.1002/hup.725
Stewart SA (2005) The effects of benzodiazepines on cognition. J Clin Psychiatr 66(Suppl 2):9–13
Eden J (2016) Endocrine dilemma: managing menopausal symptoms after breast cancer. Eur J Endocrinol 174(3):R71–R77. https://doi.org/10.1530/eje-15-0814
Rojas-Fernandez CH, Cameron J-CF (2012) Is statin-associated cognitive impairment clinically relevant? A narrative review and clinical recommendations. Ann Pharmacother 46(4):549–557. https://doi.org/10.1345/aph.1Q620
Lezak MD (2004) Neuropsychological assessment. Oxford University Press, Oxford
Hedges LVO I (1985) Statistical methods for meta-analysis. Academic Press, San Diego
Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560
Higgins J, Green S (2011) Identifying and measuring heterogeneity. Cochrane handbook for systematic reviews of interventions version 5.0, vol 1. The cochrane collaboration
Borenstein M, Hedges LV, Higgins JPT, Rothstein HR (2009) Subgroup analyses. Introduction to meta-analysis. Wiley, Hoboken, pp 149–186
Berndt U, Leplow B, Schoenfeld R, Lantzsch T, Grosse R, Thomssen C (2016) Memory and spatial cognition in breast cancer patients undergoing adjuvant endocrine therapy. Breast Care 11(4):240–246. https://doi.org/10.1159/000446901
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
Breckenridge LM, Bruns GL, Todd BL, Feuerstein M (2012) Cognitive limitations associated with tamoxifen and aromatase inhibitors in employed breast cancer survivors. Psycho-Oncol 21(1):43–53
Boele FW, Schilder CM, de Roode ML, Deijen JB, Schagen SB (2015) Cognitive functioning during long-term tamoxifen treatment in postmenopausal women with breast cancer. Menopause 22(1):17–25
Chen X, Li J, Chen J, Li D, Ye R, Zhang J, Zhu C, Tian Y, Wang K (2014) Decision-making impairments in breast cancer patients treated with tamoxifen. Horm Behav 66(2):449–456
Lejbak L, Vrbancic M, Crossley M (2010) Endocrine therapy is associated with low performance on some estrogen-sensitive cognitive tasks in postmenopausal women with breast cancer. J Clin Exp Neuropsychol 32(8):836–846
Palmer JL, Trotter T, Joy AA, Carlson LE (2008) Cognitive effects of tamoxifen in pre-menopausal women with breast cancer compared to healthy controls. J Cancer Surviv 2(4):275–282. https://doi.org/10.1007/s11764-008-0070-1
Collins B, Mackenzie J, Stewart A, Bielajew C, Verma S (2009) Cognitive effects of hormonal therapy in early stage breast cancer patients: a prospective study. Psycho-Oncol 18(8):811–821
Ganz PA, Petersen L, Castellon SA, Bower JE, Silverman DH, Cole SW, Irwin MR, Belin TR (2014) Cognitive function after the initiation of adjuvant endocrine therapy in early-stage breast cancer: an observational cohort study. J Clin Oncol 32(31):3559–3567
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):1294–1300
Debess J, Riis JO, Engebjerg MC, Ewertz M (2010) Cognitive function after adjuvant treatment for early breast cancer: a population-based longitudinal study. Breast Cancer Res Treat 121(1):91–100
Hedayati E, Alinaghizadeh H, Schedin A, Nyman H, Albertsson M (2012) Effects of adjuvant treatment on cognitive function in women with early breast cancer. Eur J Oncol Nurs 16(3):315–322
Jenkins V, Shilling V, Fallowfield L, Howell A, Hutton S (2004) Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psycho-Oncol 13(1):61–66. https://doi.org/10.1002/pon.709
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
Ahles TA, Root JC, Ryan EL (2012) Cancer- and cancer treatment-associated cognitive change: an update on the state of the science. J Clin Oncol 30(30):3675–3686
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
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
Phillips SM, Sherwin BB (1992) Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 17(5):485–495. https://doi.org/10.1016/0306-4530(92)90007-T
Maki PM (2015) Verbal memory and menopause. Maturitas 82(3):288–290. https://doi.org/10.1016/j.maturitas.2015.07.023
Epperson CN, Sammel MD, Freeman EW (2013) Menopause effects on verbal memory: findings from a longitudinal community cohort. J Clin Endocrinol Metab 98(9):3829–3838. https://doi.org/10.1210/jc.2013-1808
Kampen DL, Sherwin BB (1994) Estrogen use and verbal memory in healthy postmenopausal women. Obstet Gynecol 83(6):979–983
Maki PM, Zonderman AB, Resnick SM (2001) Enhanced verbal memory in nondemented elderly women receiving hormone-replacement therapy. Am J Psychiatr 158(2):227–233. https://doi.org/10.1176/appi.ajp.158.2.227
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
Hogervorst E, De Jager C, Budge M, Smith AD (2004) Serum levels of estradiol and testosterone and performance in different cognitive domains in healthy elderly men and women. Psychoneuroendocrinology 29(3):405–421
Wolf OT, Kirschbaum C (2002) Endogenous estradiol and testosterone levels are associated with cognitive performance in older women and men. Horm Behav 41(3):259–266. https://doi.org/10.1006/hbeh.2002.1770
Drake EB, Henderson VW, Stanczyk FZ, McCleary CA, Brown WS, Smith CA, Rizzo AA, Murdock GA, Buckwalter JG (2000) Associations between circulating sex steroid hormones and cognition in normal elderly women. Neurology 54(3):599–603
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
Tierney MC, Ryan J, Ancelin ML, Moineddin R, Rankin S, Yao C, MacLusky NJ (2013) Lifelong estrogen exposure and memory in older postmenopausal women. J Alzheimers Dis 34(3):601–608. https://doi.org/10.3233/jad-122062
Calamia M, Markon K, Tranel D (2012) Scoring higher the second time around: meta-analyses of practice effects in neuropsychological assessment. Clin Neuropsychol 26(4):543–570. https://doi.org/10.1080/13854046.2012.680913
Schagen SB, van Dam FS (2006) Does cognitive impairment after chemotherapy for breast cancer improve over time or does practice make perfect? J Clin Oncol 24(32):5170–5171. https://doi.org/10.1200/jco.2006.07.8303 author reply 5171–5172
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
Wefel JS, Vardy J, Ahles T, Schagen SB (2011) International Cognition and CancerTask Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol 12(7):703–708. https://doi.org/10.1016/s1470-2045(10)70294-1
Lange M, Rigal O, Clarisse B, Giffard B, Sevin E, Barillet M, Eustache F, Joly F (2014) Cognitive dysfunctions in elderly cancer patients: a new challenge for oncologists. Cancer Treat Rev 40(6):810–817
Mandelblatt JS, Jacobsen PB, Ahles T (2014) Cognitive effects of cancer systemic therapy: implications for the care of older patients and survivors. J Clin Oncol 32(24):2617–2626. https://doi.org/10.1200/jco.2014.55.1259
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
Tierney MC, Szalai JP, Snow WG, Fisher RH, Nores A, Nadon G, Dunn E, St.George-Hyslop PH (1996) Prediction of probable Alzheimer’s disease in memory-impaired patients: a prospective longitudinal study. Neurology 46(3):661–665
Artero S, Tierney MC, Touchon J, Ritchie K (2003) Prediction of transition from cognitive impairment to senile dementia: a prospective, longitudinal study. Acta Psychiatr Scand 107(5):390–393
Tierney MC, Yao C, Kiss A, McDowell I (2005) Neuropsychological tests accurately predict incident Alzheimer’s disease after 5 and 10 years. Neurology 64:1853–1859
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ (2007) Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment. Neurology 68(19):1588–1595
Acknowledgements
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.
Funding
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Ethical approval
For this type of study (meta-analysis), formal consent is not required.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Underwood, E.A., Rochon, P.A., Moineddin, R. et al. Cognitive sequelae of endocrine therapy in women treated for breast cancer: a meta-analysis. Breast Cancer Res Treat 168, 299–310 (2018). https://doi.org/10.1007/s10549-017-4627-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-017-4627-4