Skip to main content

Focal white matter microstructural alteration after anthracycline-based systemic treatment in long-term breast cancer survivors: a structural magnetic resonance imaging study

Abstract

Understanding the neural correlates of cognitive problems in patients with breast cancer (BC) after systemic treatment have been a topic of increasing investigation. The heterogeneity of the systemic treatment regimens may undermine our ability to identify brain microstructural alterations resulting from any given regimen. We investigated the detrimental effects of the anthracycline-based systemic treatment (AST) regimen (epirubicin and cyclophosphamide + docetaxel + tamoxifen) on brain gray matter (GM) and white matter (WM) microstructural alteration in long-term BC survivors. We performed a battery of neuropsychological tests and structural magnetic resonance imaging (MRI) to 31 long-term BC survivors who had received the AST regimen (AST group) and 43 healthy controls (HC group). Voxel-based morphometry evaluated the whole-brain voxel-wise GM volume, while diffusion tensor imaging technique with tract‐based spatial statistics analysis evaluated whole-brain WM microstructural alteration. Partial least squares regression (PLSR) was used to evaluate the relationship between cognitive impairment and brain microstructural alteration in BC survivors. Compared with the HC group, the AST group exhibited a significantly poorer performance in attention, as well as a marginal significantly poorer performance in verbal working memory and executive function. Significantly lower fractional anisotropy (FA), higher radial diffusivity (RD), and lower axial diffusivity (AD) in multiple brain WM regions were showed in AST group compared with the HC group. Overlap of lower FA and higher RD was found in the body of corpus callosum (CC) and bilateral superior corona radiata (SCR), whereas overlap of lower FA and AD was found in the body of CC and right SCR. The PLSR results showed that the WM regions with overlap of lower FA and AD were significantly associated with executive and verbal working memory decline. No significant difference was observed in the GM volume between groups. Our results suggest that microstructural abnormalities of certain vulnerable WM regions in the AST regimen-exposed brain may provide neuroimaging evidence for the identification of brain injury and cognitive impairment induced by specific chemotherapy regimens.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. 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), 3675–3686. https://doi.org/10.1200/JCO.2012.43.0116

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Ahles, T. A., & Saykin, A. J. (2007). Candidate mechanisms for chemotherapy-induced cognitive changes. Nature Reviews Cancer, 7(3), 192–201. https://doi.org/10.1038/nrc2073

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 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. J Clin Oncol, 28(29), 4434-4440. https://doi.org/10.1200/JCO.2009.27.0827

  4. Alexander, A. L., Lee, J. E., Lazar, M., & Field, A. S. (2007). Diffusion tensor imaging of the brain. Neurotherapeutics, 4(3), 316–329. https://doi.org/10.1016/j.nurt.2007.05.011

    Article  PubMed  PubMed Central  Google Scholar 

  5. Andica, C., Kamagata, K., Hatano, T., Saito, A., Uchida, W., Ogawa, T., . . . Aoki, S. (2019). Free-Water Imaging in White and Gray Matter in Parkinson's Disease. Cells, 8(8). https://doi.org/10.3390/cells8080839

  6. Arbuthnott, K., & Frank, J. (2000). Trail making test, part B as a measure of executive control: Validation using a set-switching paradigm. Journal of Clinical and Experimental Neuropsychology, 22(4), 518–528. https://doi.org/10.1076/1380-3395(200008)22:4;1-0;FT518

    CAS  Article  PubMed  Google Scholar 

  7. Barton, M. K. (2013). Cognitive deficits are usually mild in patients with breast cancer after chemotherapy. CA: A Cancer Journal for Clinicians, 63(1), 3–4. https://doi.org/10.3322/caac.21164

    Article  Google Scholar 

  8. Billiet, T., Emsell, L., Vandenbulcke, M., Peeters, R., Christiaens, D., Leemans, A., . . . Deprez, S. (2018). Recovery from chemotherapy-induced white matter changes in young breast cancer survivors? Brain Imaging Behav, 12(1), 64-77. https://doi.org/10.1007/s11682-016-9665-8

  9. Bourisly, A. K., Gejo, G., Hayat, A. A., Alsarraf, L., Dashti, F. M., & Di Paola, M. (2017). White Matter Sexual Dimorphism of the Adult Human Brain. Translational Neuroscience, 8, 49–53. https://doi.org/10.1515/tnsci-2017-0009

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chen, B. T., Ye, N., Wong, C. W., Patel, S. K., Jin, T., Sun, C. L., . . . Dale, W. (2020). Effects of chemotherapy on aging white matter microstructure: A longitudinal diffusion tensor imaging study. J Geriatr Oncol, 11(2), 290-296. https://doi.org/10.1016/j.jgo.2019.09.016

  11. Chen, H. L., Huang, C. C., Lin, H. C., Lu, C. H., Chen, P. C., Chou, K. H., . . . Lin, W. C. (2020). White matter alteration and autonomic impairment in obstructive sleep apnea. J Clin Sleep Med, 16(2), 293-302. https://doi.org/10.5664/jcsm.8186

  12. Chen, X., Li, J., Zhang, J., He, X., Zhu, C., Zhang, L., . . . Wang, K. (2017). Impairment of the executive attention network in premenopausal women with hormone receptor-positive breast cancer treated with tamoxifen. Psychoneuroendocrinology, 75, 116-123. https://doi.org/10.1016/j.psyneuen.2016.10.020

  13. Correa, D. D., Root, J. C., Kryza-Lacombe, M., Mehta, M., Karimi, S., Hensley, M. L., & Relkin, N. (2017). Brain structure and function in patients with ovarian cancer treated with first-line chemotherapy: A pilot study. Brain Imaging and Behavior, 11(6), 1652–1663. https://doi.org/10.1007/s11682-016-9608-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. de Blank, P. M., Berman, J. I., & Fisher, M. J. (2016). Systemic Chemotherapy and White Matter Integrity in Tracts Associated with Cognition Among Children With Neurofibromatosis Type 1. Pediatric Blood & Cancer, 63(5), 818–824. https://doi.org/10.1002/pbc.25896

    Article  Google Scholar 

  15. 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. Hum Brain Mapp, 33(12), 2971-2983. https://doi.org/10.1002/hbm.21422

  16. Deprez, S., Amant, F., Smeets, A., Peeters, R., Leemans, A., Van Hecke, W., . . . Sunaert, S. (2012). Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol, 30(3), 274-281. https://doi.org/10.1200/JCO.2011.36.8571

  17. Deprez, S., Amant, F., Yigit, R., Porke, K., Verhoeven, J., Van den Stock, J., . . . Sunaert, S. (2011). Chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning in breast cancer patients. Hum Brain Mapp, 32(3), 480-493. https://doi.org/10.1002/hbm.21033

  18. Dietrich, J., Han, R., Yang, Y., Mayer-Proschel, M., & Noble, M. (2006). CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. Journal of Biology, 5(7), 22. https://doi.org/10.1186/jbiol50

    Article  PubMed  PubMed Central  Google Scholar 

  19. Feng, Y., Zhang, X. D., Zheng, G., & Zhang, L. J. (2019). Chemotherapy-induced brain changes in breast cancer survivors: evaluation with multimodality magnetic resonance imaging. Brain Imaging Behav, 13(6), 1799-1814. https://doi.org/10.1007/s11682-019-00074-y

  20. Foubert-Samier, A., Catheline, G., Amieva, H., Dilharreguy, B., Helmer, C., Allard, M., & Dartigues, J. F. (2012). Education, occupation, leisure activities, and brain reserve: a population-based study. Neurobiol Aging, 33(2), 423 e415-425. https://doi.org/10.1016/j.neurobiolaging.2010.09.023

    Article  Google Scholar 

  21. Ganz, P. A., Petersen, L., Castellon, S. A., Bower, J. E., Silverman, D. H., Cole, S. W., . . . Belin, T. R. (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. https://doi.org/10.1200/JCO.2014.56.1662

  22. Han, R., Yang, Y. M., Dietrich, J., Luebke, A., Mayer-Proschel, M., & Noble, M. (2008). Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. Journal of Biology, 7(4), 12. https://doi.org/10.1186/jbiol69

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Inagaki, M., Yoshikawa, E., Matsuoka, Y., Sugawara, Y., Nakano, T., Akechi, T., . . . Uchitomi, Y. (2007). Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer, 109(1), 146-156. https://doi.org/10.1002/cncr.22368

  24. Janelsins, M. C., Heckler, C. E., Peppone, L. J., Kamen, C., Mustian, K. M., Mohile, S. G., . . . Morrow, G. R. (2017). Cognitive Complaints in Survivors of Breast Cancer After Chemotherapy Compared With Age-Matched Controls: An Analysis From a Nationwide, Multicenter, Prospective Longitudinal Study. J Clin Oncol, 35(5), 506-514. https://doi.org/10.1200/JCO.2016.68.5826

  25. Janelsins, M. C., Kesler, S. R., Ahles, T. A., & Morrow, G. R. (2014). Prevalence, mechanisms, and management of cancer-related cognitive impairment. International Review of Psychiatry, 26(1), 102–113. https://doi.org/10.3109/09540261.2013.864260

    Article  PubMed  Google Scholar 

  26. Janelsins, M. C., Mustian, K. M., Palesh, O. G., Mohile, S. G., Peppone, L. J., Sprod, L. K., . . . Morrow, G. R. (2012). Differential expression of cytokines in breast cancer patients receiving different chemotherapies: implications for cognitive impairment research. Support Care Cancer, 20(4), 831-839. https://doi.org/10.1007/s00520-011-1158-0

  27. Jim, H. S., Phillips, K. M., Chait, S., Faul, L. A., Popa, M. A., Lee, Y. H., . . . Small, B. J. (2012). Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol, 30(29), 3578-3587. https://doi.org/10.1200/JCO.2011.39.5640

  28. Kesler, S. R., & Blayney, D. W. (2016). Neurotoxic Effects of Anthracycline- vs Nonanthracycline-Based Chemotherapy on Cognition in Breast Cancer Survivors. JAMA Oncology, 2(2), 185–192. https://doi.org/10.1001/jamaoncol.2015.4333

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kesler, S. R., Watson, C. L., & Blayney, D. W. (2015). Brain network alterations and vulnerability to simulated neurodegeneration in breast cancer. Neurobiology of Aging, 36(8), 2429–2442. https://doi.org/10.1016/j.neurobiolaging.2015.04.015

    Article  PubMed  PubMed Central  Google Scholar 

  30. Koppelmans, V., Breteler, M. M., Boogerd, W., Seynaeve, C., Gundy, C., & Schagen, S. B. (2012a). Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. Journal of Clinical Oncology, 30(10), 1080–1086. https://doi.org/10.1200/JCO.2011.37.0189

    Article  PubMed  Google Scholar 

  31. 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 Res Treat, 132(3), 1099-1106. https://doi.org/10.1007/s10549-011-1888-1

  32. Krishnan, A., Williams, L. J., McIntosh, A. R., & Abdi, H. (2011). Partial Least Squares (PLS) methods for neuroimaging: A tutorial and review. NeuroImage, 56(2), 455–475. https://doi.org/10.1016/j.neuroimage.2010.07.034

    Article  PubMed  Google Scholar 

  33. Lee, P. E., Tierney, M. C., Wu, W., Pritchard, K. I., & Rochon, P. A. (2016). Endocrine treatment-associated cognitive impairment in breast cancer survivors: Evidence from published studies. Breast Cancer Research and Treatment, 158(3), 407–420. https://doi.org/10.1007/s10549-016-3906-9

    CAS  Article  PubMed  Google Scholar 

  34. Lepage, C., Smith, A. M., Moreau, J., Barlow-Krelina, E., Wallis, N., Collins, B., . . . Scherling, C. (2014). A prospective study of grey matter and cognitive function alterations in chemotherapy-treated breast cancer patients. Springerplus, 3, 444. https://doi.org/10.1186/2193-1801-3-444

  35. Linke, J. O., Stavish, C., Adleman, N. E., Sarlls, J., Towbin, K. E., Leibenluft, E., & Brotman, M. A. (2020). White matter microstructure in youth with and at risk for bipolar disorder. Bipolar Disorders, 22(2), 163–173. https://doi.org/10.1111/bdi.12885

    Article  PubMed  PubMed Central  Google Scholar 

  36. McDonald, B. C., Conroy, S. K., Ahles, T. A., West, J. D., & Saykin, A. J. (2010). Gray matter reduction associated with systemic chemotherapy for breast cancer: A prospective MRI study. Breast Cancer Research and Treatment, 123(3), 819–828. https://doi.org/10.1007/s10549-010-1088-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. McDonald, B. C., Conroy, S. K., Smith, D. J., West, J. D., & Saykin, A. J. (2013). Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: A replication and extension study. Brain, Behavior, and Immunity, 30(Suppl), S117-125. https://doi.org/10.1016/j.bbi.2012.05.007

    Article  PubMed  Google Scholar 

  38. Menning, S., de Ruiter, M. B., Veltman, D. J., Boogerd, W., Oldenburg, H. S. A., Reneman, L., & Schagen, S. B. (2018). Changes in brain white matter integrity after systemic treatment for breast cancer: A prospective longitudinal study. Brain Imaging and Behavior, 12(2), 324–334. https://doi.org/10.1007/s11682-017-9695-x

    Article  PubMed  Google Scholar 

  39. Nasreddine, Z. S., Phillips, N. A., Bedirian, V., Charbonneau, S., Whitehead, V., Collin, I., . . . Chertkow, H. (2005). The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc, 53(4), 695-699. https://doi.org/10.1111/j.1532-5415.2005.53221.x

  40. Pasternak, O., Westin, C. F., Dahlben, B., Bouix, S., & Kubicki, M. (2015). The extent of diffusion MRI markers of neuroinflammation and white matter deterioration in chronic schizophrenia. Schizophrenia Research, 161(1), 113–118. https://doi.org/10.1016/j.schres.2014.07.031

    Article  PubMed  Google Scholar 

  41. Pell, G. S., Briellmann, R. S., Chan, C. H., Pardoe, H., Abbott, D. F., & Jackson, G. D. (2008). Selection of the control group for VBM analysis: Influence of covariates, matching and sample size. NeuroImage, 41(4), 1324–1335. https://doi.org/10.1016/j.neuroimage.2008.02.050

    Article  PubMed  Google Scholar 

  42. Roland, J. L., Snyder, A. Z., Hacker, C. D., Mitra, A., Shimony, J. S., Limbrick, D. D., . . . Leuthardt, E. C. (2017). On the role of the corpus callosum in interhemispheric functional connectivity in humans. Proc Natl Acad Sci U S A, 114(50), 13278-13283. https://doi.org/10.1073/pnas.1707050114

  43. Singh, N., Fletcher, P. T., Preston, J. S., King, R. D., Marron, J. S., Weiner, M. W., . . . Alzheimer's Disease Neuroimaging, I. (2014). Quantifying anatomical shape variations in neurological disorders. Med Image Anal, 18(3), 616-633. https://doi.org/10.1016/j.media.2014.01.001

  44. Smith, S. M. (2002). Fast robust automated brain extraction. Human Brain Mapping, 17(3), 143–155. https://doi.org/10.1002/hbm.10062

    Article  PubMed  PubMed Central  Google Scholar 

  45. Smith, S. M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T. E., Mackay, C. E., . . . Behrens, T. E. (2006). Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage, 31(4), 1487-1505. https://doi.org/10.1016/j.neuroimage.2006.02.024

  46. Smith, S. M., Jenkinson, M., Woolrich, M. W., Beckmann, C. F., Behrens, T. E., Johansen-Berg, H., . . . Matthews, P. M. (2004). Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage, 23 Suppl 1, S208-219. https://doi.org/10.1016/j.neuroimage.2004.07.051

  47. Stouten-Kemperman, M. M., de Ruiter, M. B., Koppelmans, V., Boogerd, W., Reneman, L., & Schagen, S. B. (2015). Neurotoxicity in breast cancer survivors >/=10 years post-treatment is dependent on treatment type. Brain Imaging and Behavior, 9(2), 275–284. https://doi.org/10.1007/s11682-014-9305-0

    Article  PubMed  Google Scholar 

  48. Tchen, N., Juffs, H. G., Downie, F. P., Yi, Q. L., Hu, H., Chemerynsky, I., . . . Tannock, I. F. (2003). Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. J Clin Oncol, 21(22), 4175-4183. https://doi.org/10.1200/JCO.2003.01.119

  49. Turner, N., Biganzoli, L., & Di Leo, A. (2015). Continued value of adjuvant anthracyclines as treatment for early breast cancer. The Lancet Oncology, 16(7), e362-369. https://doi.org/10.1016/S1470-2045(15)00079-0

    Article  PubMed  Google Scholar 

  50. Underwood, E. A., Jerzak, K. J., Lebovic, G., Rochon, P. A., Elser, C., Pritchard, K. I., & Tierney, M. C. (2019). Cognitive effects of adjuvant endocrine therapy in older women treated for early-stage breast cancer: A 1-year longitudinal study. Supportive Care in Cancer, 27(8), 3035–3043. https://doi.org/10.1007/s00520-018-4603-5

    CAS  Article  PubMed  Google Scholar 

  51. Underwood, E. A., Rochon, P. A., Moineddin, R., Lee, P. E., Wu, W., Pritchard, K. I., & Tierney, M. C. (2018). Cognitive sequelae of endocrine therapy in women treated for breast cancer: A meta-analysis. Breast Cancer Research and Treatment, 168(2), 299–310. https://doi.org/10.1007/s10549-017-4627-4

    CAS  Article  PubMed  Google Scholar 

  52. Van Dyk, K., Petersen, L., & Ganz, P. A. (2016). Comparison of Neurocognitive Function After Anthracycline-Based Chemotherapy vs Nonanthracycline-Based Chemotherapy. JAMA Oncology, 2(7), 964–965. https://doi.org/10.1001/jamaoncol.2016.0350

    Article  PubMed  PubMed Central  Google Scholar 

  53. Vitaliano, P. P., Ustundag, O., & Borson, S. (2017). Objective and Subjective Cognitive Problems among Caregivers and Matched Non-caregivers. The Gerontologist, 57(4), 637–647. https://doi.org/10.1093/geront/gnv690

    Article  PubMed  Google Scholar 

  54. Wefel, J. S., Kesler, S. R., Noll, K. R., & Schagen, S. B. (2015). Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults. CA: A Cancer Journal for Clinicians, 65(2), 123–138. https://doi.org/10.3322/caac.21258

    Article  Google Scholar 

  55. Wilhelm, O., Hildebrandt, A., & Oberauer, K. (2013). What is working memory capacity, and how can we measure it? Frontiers in Psychology, 4, 433. https://doi.org/10.3389/fpsyg.2013.00433

    Article  PubMed  PubMed Central  Google Scholar 

  56. Zhao, Q., Guo, Q., Liang, X., Chen, M., Zhou, Y., Ding, D., & Hong, Z. (2015). Auditory Verbal Learning Test is Superior to Rey-Osterrieth Complex Figure Memory for Predicting Mild Cognitive Impairment to Alzheimer’s Disease. Current Alzheimer Research, 12(6), 520–526. https://doi.org/10.2174/1567205012666150530202729

    CAS  Article  PubMed  Google Scholar 

  57. Zheng, Y., Luo, J., Bao, P., Cai, H., Hong, Z., Ding, D., . . . Dai, Q. (2014). Long-term cognitive function change among breast cancer survivors. Breast Cancer Res Treat, 146(3), 599-609. https://doi.org/10.1007/s10549-014-3044-1

Download references

Funding

This study was funded by the National Natural Science Foundation of China (Grant No. 81901821 and 82071879), the Science and Technology Plan of Shaanxi Province (Grant 2019SF-209), and the Fundamental Research Funds for the Central Universities (Grant Nos. JB211203 and XJS201207).

Author information

Affiliations

Authors

Contributions

Huawen Zhang and Peng Li made a substantial contribution to the design and draft of the article. Tonghui Liu processed the MR data and performed the subsequent statistical analysis. Peng Li revised the article and interpreted the data. Xueyuan Wang, Wei Feng, Rui Chen, Hengyang Wei, and Long Ning performed demographic data collection of all participants. Ming Zhang and Yuchen Zhang provided intellectual content of critical importance to the work described.

Corresponding authors

Correspondence to Ming Zhang or Yuchen Zhang.

Ethics declarations

Ethical approval

All procedures carried out in studies involving human participants were consistent with the ethical standards of institutions and/or national research councils, as well as with the 1964 Helsinki Declaration and its subsequent amendments or comparable ethical standards.

Consent to participant

Informed consent was obtained from all patients included in the study.

Consent to publish

All authors approved the version to be published in the study.

Competing interests

The author(s) declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, H., Li, P., Liu, T. et al. Focal white matter microstructural alteration after anthracycline-based systemic treatment in long-term breast cancer survivors: a structural magnetic resonance imaging study. Brain Imaging and Behavior (2021). https://doi.org/10.1007/s11682-021-00551-3

Download citation

Keywords

  • Breast cancer
  • Chemotherapy
  • Cognitive impairment
  • Anthracycline-based systemic treatment
  • Tract-based spatial statistics
  • Partial least squares regression