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Very Late Treatment-Related Alterations in Brain Function of Breast Cancer Survivors

  • Myrle M. Stouten-Kemperman (a1) (a2), Michiel B. de Ruiter (a1) (a2), Willem Boogerd (a3), Dick J. Veltman (a4), Liesbeth Reneman (a2) and Sanne B. Schagen (a1)...


Although adjuvant chemotherapy (CT) for breast cancer (BC) is associated with very late side-effects on cognition and brain function, studies on adverse effects of specific treatment regimens are scarce. Here, neurotoxicity profiles after different treatment strategies were compared in BC survivors randomized to high-dose (HI) or conventional-dose (CON-) CT, in women treated with radiotherapy (RT) -only and a healthy control (HC) group. We administered a neurocognitive test battery, a planning fMRI task (Tower of London) and episodic memory fMRI task (Paired Associates paradigm) in BC survivors who received CON-CT (n=24) and HC (n=27). Data were compared to BC survivors who received HI-CT (n=17) and RT-only (n=15) and who were previously assessed. Testing took place ±11.5 years post-CT. Furthermore, neurocognitive data were compared to neurocognitive data acquired ≤2 years post-treatment. Cognitive assessment revealed sustained cognitive decline in 10.5% of HI-CT, 8.3% of CON-CT, 6.7% of RT-only patients and 0% in the HC. Hypoactivation was found in task-related prefrontal and parietal areas for both CT-groups versus RT-only, with HI-CT showing more pronounced hypoactivation than CON-CT, combined with worse task performance. RT-only survivors performed at a similar level to HC while showing hyperactivation in task-related brain areas. Long after treatment, CT is associated with cognitive problems and task-related hypoactivation that depend on the specific cytotoxic regimen. This worse performance in patients who received CT could be explained by impaired brain functioning that is more severe with more intense CT. (JINS, 2015, 21, 50–61)


Corresponding author

Correspondence and reprint requests to: Sanne B. Schagen, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail:


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Aaronson, N.K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N.J., & de Haes, J.C. (1993). The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. Journal of the National Cancer Institute, 85(5), 365376. Retrieved from
Ahles, T.A., Root, J.C., & Ryan, E.L. (2012). Cancer- and cancer treatment-associated cognitive change: An update on the state of the science. Journal of Clinical Oncology, 30(30), 36753686. doi:10.1200/JCO.2012.43.0116
Ahles, T.A., Saykin, A.J., McDonald, B.C., Li, Y., Furstenberg, C.T., Hanscom, B.S., & Kaufman, P.A. (2010). Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: Impact of age and cognitive reserve. Journal of Clinical Oncology, 28(29), 44344440. doi:10.1200/JCO.2009.27.0827
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. Psychooncology, 18(8), 811821. doi:10.1002/pon.1453
Collins, B., Mackenzie, J., Tasca, G.A., Scherling, C., & Smith, A. (2013). Cognitive effects of chemotherapy in breast cancer patients: A dose-response study. Psychooncology, 22(7), 15171527. doi:10.1002/pon.3163
Conroy, S.K., McDonald, B.C., Smith, D.J., Moser, L.R., West, J.D., Kamendulis, L.M., & Saykin, A.J. (2013). Alterations in brain structure and function in breast cancer survivors: Effect of post-chemotherapy interval and relation to oxidative DNA damage. Breast Cancer Research and Treatment, 137(2), 493502. doi:10.1007/s10549-012-2385-x
De Ruiter, M.B., Reneman, L., Boogerd, W., Veltman, D.J., Caan, M., Douaud, G., & Schagen, S.B. (2012). Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: Converging results from multimodal magnetic resonance imaging. Human Brain Mapping, 33(12), 29712983. doi:10.1002/hbm.21422
De Ruiter, M.B., Reneman, L., Boogerd, W., Veltman, D.J., van Dam, F.S., Nederveen, A.J., & Schagen, S.B. (2011). Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Human Brain Mapping, 32(8), 12061219. doi:10.1002/hbm.21102
De Ruiter, M.B., & Schagen, S.B. (2013). Functional MRI studies in non-CNS cancers. Brain Imaging and Behavior, 7(4), 388408. doi:10.1007/s11682-013-9249-9
Dietrich, J., Monje, M., Wefel, J., & Meyers, C. (2008). Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. The Oncologist, 13(12), 12851295. doi:10.1634/theoncologist.2008-0130
Dumas, J.A., Kutz, A.M., McDonald, B.C., Naylor, M.R., Pfaff, A.C., Saykin, A.J., & Newhouse, P.A. (2013). Increased working memory-related brain activity in middle-aged women with cognitive complaints. Neurobiology of Aging, 34(4), 11451147. doi:10.1016/j.neurobiolaging.2012.08.013
Eberling, J.L., Wu, C., Tong-Turnbeaugh, R., & Jagust, W.J. (2004). Estrogen- and tamoxifen-associated effects on brain structure and function. Neuroimage, 21(1), 364371. doi:10.1016/j.neuroimage.2003.08.037
Hesbacher, P.T., Rickels, K., Morris, R.J., Newman, H., & Rosenfeld, H. (1980). Psychiatric illness in family practice. The Journal of Clinical Psychiatry, 41(1), 610. Retrieved from
Husain, K., Whitworth, C., Hazelrigg, S., & Rybak, L. (2003). Carboplatin-induced oxidative injury in rat inferior colliculus. International Journal of Toxicology, 22(5), 335342. doi:10.1177/109158180302200502
Jansen, C.E., Cooper, B.A., Dodd, M.J., & Miaskowski, C.A. (2011). A prospective longitudinal study of chemotherapy-induced cognitive changes in breast cancer patients. Supportive Care in Cancer, 19(10), 16471656. doi:10.1007/s00520-010-0997-4
Jenkins, V., Shilling, V., Deutsch, G., Bloomfield, D., Morris, R., Allan, S., & Winstanley, J. (2006). A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. British Journal of Cancer, 94(6), 828834. doi:10.1038/sj.bjc.6603029
Kesler, S.R., Bennett, F.C., Mahaffey, M.L., & Spiegel, D. (2009). Regional brain activation during verbal declarative memory in metastatic breast cancer. Clinical Cancer Research, 15(21), 66656673. doi:10.1158/1078-0432.CCR-09-1227
Kesler, S.R., Kent, J.S., & O’Hara, R. (2011). Prefrontal cortex and executive function impairments in primary breast cancer. Archives of Neurology, 68(11), 14471453. doi:10.1001/archneurol.2011.245
Koppelmans, V., Breteler, M.M.B., Boogerd, W., Seynaeve, C., Gundy, C., & Schagen, S.B. (2012). Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. Journal of Clinical Oncology, 30(10), 10801086. doi:10.1200/JCO.2011.37.0189
Koppelmans, V., de Ruiter, M.B., van der Lijn, F., Boogerd, W., Seynaeve, C., van der Lugt, A., & Schagen, S.B. (2012). Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy. Breast Cancer Research and Treatment, 132(3), 10991106. doi:10.1007/s10549-011-1888-1
Manoach, D.S. (2003). Prefrontal cortex dysfunction during working memory performance in schizophrenia: Reconciling discrepant findings. Schizophrenia Research, 60(2–3), 285298. doi:10.1016/S0920-9964(02)00294-3
McDonald, B.C., Conroy, S.K., Ahles, T.A., West, J.D., & Saykin, A.J. (2012). Alterations in brain activation during working memory processing associated with breast cancer and treatment: A prospective functional magnetic resonance imaging study. Journal of Clinical Oncology, 30(20), 25002508. doi:10.1200/JCO.2011.38.5674
Mignone, R.G., & Weber, E.T. (2006). Potent inhibition of cell proliferation in the hippocampal dentate gyrus of mice by the chemotherapeutic drug thioTEPA. Brain Research, 1111(1), 2629. doi:10.1016/j.brainres.2006.06.093
Nguyen, C.M., Yamada, T.H., Beglinger, L.J., Cavanaugh, J.E., Denburg, N.L., & Schultz, S.K. (2013). Cognitive features 10 or more years after successful breast cancer survival: Comparisons across types of cancer interventions. Psychooncology, 22(4), 862868. doi:10.1002/pon.3086
Phillips, K.M., Jim, H.S., Small, B.J., Laronga, C., Andrykowski, M.A., & Jacobsen, P.B. (2012). Cognitive functioning after cancer treatment: A 3-year longitudinal comparison of breast cancer survivors treated with chemotherapy or radiation and noncancer controls. Cancer, 118(7), 19251932. doi:10.1002/cncr.26432
Poppelreuter, M., Weis, J., Külz, A.K., Tucha, O., Lange, K.W., & Bartsch, H.H. (2004). Cognitive dysfunction and subjective complaints of cancer patients. European Journal of Cancer, 40(1), 4349. doi:10.1016/j.ejca.2003.08.001
Pullens, M.J.J., De Vries, J., & Roukema, J.A. (2010). Subjective cognitive dysfunction in breast cancer patients: A systematic review. Psychooncology, 19(11), 11271138. doi:10.1002/pon.1673
Rodenhuis, S., Bontenbal, M., Beex, L.V., Wagstaff, J., Richel, D.J., Nooij, M.A., & de Vries, E.G. (2003). High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. The New England Journal of Medicine, 349(1), 716. doi:10.1056/NEJMoa022794
Root, J.C., Ryan, E., Barnett, G., Andreotti, C., Bolutayo, K., & Ahles, T. (2014). Learning and memory performance in a cohort of clinically referred breast cancer survivors: The role of attention versus forgetting in patient-reported memory complaints. Psychooncology doi:10.1002/pon.3615
Schagen, S.B., Muller, M.J., Boogerd, W., Mellenbergh, G.J., & van Dam, F.S. (2006). Change in cognitive function after chemotherapy: A prospective longitudinal study in breast cancer patients. Journal of the National Cancer Institute, 98(23), 17421745. doi:10.1093/jnci/djj470
Schilder, C.M., Eggens, P.C., Seynaeve, C., Linn, S.C., Boogerd, W., Gundy, C.M., & Schagen, S.B. (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 Oncologica (Stockholm, Sweden), 48(1), 7685. doi:10.1080/02841860802314738
Schilder, C.M., Seynaeve, C., Beex, L.V., Boogerd, W., Linn, S.C., Gundy, C.M., & Schagen, S.B. (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. Journal of Clinical Oncology, 28(8), 12941300. doi:10.1200/JCO.2008.21.3553
Seigers, R., Schagen, S.B., Van Tellingen, O., & Dietrich, J. (2013). Chemotherapy-related cognitive dysfunction: Current animal studies and future directions. Brain Imaging and Behavior, 7(4), 453459. doi:10.1007/s11682-013-9250-3
Stouten-Kemperman, M.M., de Ruiter, M.B., Koppelmans, V., Boogerd, W., Reneman, L., & Schagen, S.B. (2014). Neurotoxicity in breast cancer survivors ≥10 years post-treatment is dependent on treatment type. Brain Imaging and Behavior doi:10.1007/s11682-014-9305-0
Van den Heuvel, O.A., Groenewegen, H.J., Barkhof, F., Lazeron, R.H.C., van Dyck, R., & Veltman, D.J. (2003). Frontostriatal system in planning complexity: A parametric functional magnetic resonance version of Tower of London task. Neuroimage, 18(2), 367374. Retrieved from
Vearncombe, K.J., Rolfe, M., Wright, M., Pachana, N.A., Andrew, B., & Beadle, G. (2009). Predictors of cognitive decline after chemotherapy in breast cancer patients. Journal of the International Neuropsychological Society, 15(6), 951962. doi:10.1017/S1355617709990567
Wagner, G., Sinsel, E., Sobanski, T., Köhler, S., Marinou, V., Mentzel, H.-J., & Schlösser, R.G.M. (2006). Cortical inefficiency in patients with unipolar depression: An event-related FMRI study with the Stroop task. Biological Psychiatry, 59(10), 958965. doi:10.1016/j.biopsych.2005.10.025
Wefel, J.S., Saleeba, A.K., Buzdar, A.U., & Meyers, C.A. (2010). Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer, 116(14), 33483356. doi:10.1002/cncr.25098
Wefel, J.S., & Schagen, S.B. (2012). Chemotherapy-related cognitive dysfunction. Current Neurology and Neuroscience Reports, 12(3), 267275. doi:10.1007/s11910-012-0264-9
Yamada, T.H., Denburg, N.L., Beglinger, L.J., & Schultz, S.K. (2010). Neuropsychological outcomes of older breast cancer survivors: Cognitive features ten or more years after chemotherapy. The Journal of Neuropsychiatry and Clinical Neurosciences, 22(1), 4854. doi:10.1176/appi.neuropsych.22.1.48


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