Skip to main content

Impact of chemotherapy on cognitive functioning in older patients with HER2-positive breast cancer: a sub-study in the RESPECT trial



To investigate whether postoperative adjuvant trastuzumab plus chemotherapy negatively affected cognitive functioning during the post-chemotherapy period compared with trastuzumab monotherapy in older patients with HER2-positive breast cancer.


In the randomized RESPECT trial, women aged between 70 and 80 years with HER2-positive, stage I to IIIA invasive breast cancer who underwent curative operation were randomly assigned to receive either 1-year trastuzumab monotherapy or 1-year trastuzumab plus chemotherapy. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) test at enrollment and 1 and 3 years after initiation of the protocol treatment. The primary outcome was change in the MMSE total score from baseline. Secondary outcomes included prevalence of suspected mild cognitive impairment (MMSE total score < 28) and suspected dementia (MMSE total score < 24).


The analytical population consisted of 29 and 26 patients in the trastuzumab monotherapy and trastuzumab plus chemotherapy groups, respectively. The group differences in mean changes of the MMSE total score were 0.6 (95% confidence interval [CI] − 0.3 to 1.6) at 1 year and 0.9 (95% CI − 1.0 to 2.8) at 3 years (P = 0.136 for the group difference pooling the two visits). The prevalence of suspected mild cognitive impairment at 3 years was 41.7% in the trastuzumab monotherapy group and 28.6% in the trastuzumab plus chemotherapy group (P = 0.548).


This randomized sub-study did not show worse cognitive functioning during the post-chemotherapy period with trastuzumab plus chemotherapy than with trastuzumab monotherapy in older patients with HER2-positive breast cancer.

Trial registration number

NCT01104935 (first posted April 16, 2010).

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

Fig. 1
Fig. 2
Fig. 3

Data availability

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

Code availability

The codes used to analyze the datasets during the current study are available from the corresponding author on reasonable request.


  1. 1.

    Silberfarb PM (1983) Chemotherapy and cognitive defects in cancer patients. Annu Rev Med 34:35–46

    CAS  Article  Google Scholar 

  2. 2.

    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 30:3675–3686

    CAS  Article  Google Scholar 

  3. 3.

    Ono M, Ogilvie JM, Wilson JS et al (2015) A meta-analysis of cognitive impairment and decline associated with adjuvant chemotherapy in women with breast cancer. Front Oncol 5:59

    Article  Google Scholar 

  4. 4.

    Jenkins V, Shilling V, Deutsch G et al (2006) A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. Br J Cancer 94:828–834

    CAS  Article  Google Scholar 

  5. 5.

    Hutchinson AD, Hosking JR, Kichenadasse G et al (2012) Objective and subjective cognitive impairment following chemotherapy for cancer: a systematic review. Cancer Treat Rev 38:926–934

    Article  Google Scholar 

  6. 6.

    Ahles TA, Saykin AJ, Noll WW et al (2003) The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psychooncology 12:612–619

    Article  Google Scholar 

  7. 7.

    Mandelblatt JS, Small BJ, Luta G et al (2018) Cancer-related cognitive outcomes among older breast cancer survivors in the thinking and living with cancer study. J Clin Oncol 36:3211–3222

    CAS  Article  Google Scholar 

  8. 8.

    Jim HSL, Phillips KM, Chait S et al (2012) Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol 30:3578–3587

    CAS  Article  Google Scholar 

  9. 9.

    Smith BD, Smith GL, Hurria A et al (2009) Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 27:2758–2765

    Article  Google Scholar 

  10. 10.

    Ahles TA, Saykin AJ, McDonald BC et al (2010) Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. J Clin Oncol 28:4434–4440

    Article  Google Scholar 

  11. 11.

    Hurria A, Rosen C, Hudis C et al (2006) Cognitive function of older patients receiving adjuvant chemotherapy for breast cancer: a pilot prospective longitudinal study. J Am Geriatr Soc 54:925–931

    Article  Google Scholar 

  12. 12.

    Loh KP, Janelsins MC, Mohile SG et al (2016) Chemotherapy-related cognitive impairment in older patients with cancer. J Geriatr Oncol 7:270–280

    Article  Google Scholar 

  13. 13.

    Shepard MA (2002) Treatment preferences of seriously ill patients. N Engl J Med 347:533–535

    PubMed  Google Scholar 

  14. 14.

    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 32:2617–2626

    Article  Google Scholar 

  15. 15.

    Sawaki M, Tokudome N, Mizuno T et al (2011) Evaluation of trastuzumab without chemotherapy as a post-operative adjuvant therapy in HER2-positive elderly breast cancer patients: randomized controlled trial [RESPECT (N-SAS BC07)]. Jpn J Clin Oncol 41:709–712

    Article  Google Scholar 

  16. 16.

    Sawaki M, Taira N, Uemura Y et al (2020) Randomized controlled trial of trastuzumab with or without chemotherapy for HER2-positive early breast cancer in older patients. J Clin Oncol 38:3743–3752

    CAS  Article  Google Scholar 

  17. 17.

    Folstein MF, Folstein SE, McHugh PR (1975) “Mini-Mental State” A practical method for grading the cognitive state of paients for the clinician. J Psychiatr Res 12:189–198

    CAS  Article  Google Scholar 

  18. 18.

    Kaufer DI, Williams CS, Braaten AJ et al (2008) Cognitive screening for dementia and mild cognitive impairment in assisted living: comparison of 3 tests. J Am Med Dir Assoc 9:586–593

    Article  Google Scholar 

  19. 19.

    Saxton J, Morrow L, Eschman A et al (2009) Computer assessment of mild cognitive impairment. Postgrad Med 121:177–185

    Article  Google Scholar 

  20. 20.

    Tariq SH, Tumosa N, Chibnall JT et al (2006) Comparison of the Saint Louis University Mental Status examination and the Mini-Mental State Examination for detecting dementia and mild neurocognitive disorder - a pilot study. Am J Geriatr Psychiatry 14:900–910

    Article  Google Scholar 

  21. 21.

    Tsoi KKF, Chan JYC, Hirai HW et al (2015) Cognitive tests to detect dementia a systematic review and meta-analysis. JAMA Intern Med 175:1450–1458

    Article  Google Scholar 

  22. 22.

    Wefel JS, Vardy J, Ahles T, Schagen SB (2011) International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer. Lancet Oncol 12:703–708

    Article  Google Scholar 

  23. 23.

    Wildiers H, Kenis C (2012) Comprehensive geriatric assessment (CGA) in older oncological patients: why and how? J Geriatr Oncol 3:174–176

    Article  Google Scholar 

  24. 24.

    Rambeau A, Beauplet B, Laviec H et al (2019) Prospective comparison of the Montreal Cognitive Assessment (MoCA) and the Mini Mental State Examination (MMSE) in geriatric oncology. J Geriatr Oncol 10:235–240

    Article  Google Scholar 

  25. 25.

    Mandelblatt JS, Stern RA, Luta G et al (2014) Cognitive impairment in older patients with breast cancer before systemic therapy: is there an interaction between cancer and comorbidity? J Clin Oncol 32:1909–1918

    Article  Google Scholar 

  26. 26.

    Extermann M, Hurria A (2007) Comprehensive geriatric assessment for older patients with cancer. J Clin Oncol 25:1824–1831

    Article  Google Scholar 

  27. 27.

    Schilder CM, Seynaeve C, Beex LV et al (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 28:1294–1300

    CAS  Article  Google Scholar 

  28. 28.

    Yamada TH, Denburg NL, Beglinger LJ, Schultz SK (2014) Neuropsychological outcomes of older breast cancer survivors: cognitive features ten or more years after chemotherapy. J Neuropsychiatry Clin Neurosci 22:48–54

    Article  Google Scholar 

  29. 29.

    Crum RM, Anthony JC, Bassett SS, Folstein MF (1993) Population-based norms for the Mini-Mental State Examination by age and educational level. JAMA 269:2386–2391

    CAS  Article  Google Scholar 

Download references


The RESPECT trial was funded by the Comprehensive Support Project for Oncology Research (CSPOR) of the Public Health Research Foundation. We thank all patients who participated in the RESPECT trial and investigators, medical staff, and data managers who were dedicated to this trial. We are grateful for support from the Comprehensive Support Project for Health Outcomes Research (CSP-HOR).


The RESPECT trial was funded by the Comprehensive Support Project for Oncology Research (CSPOR) of the Public Health Research Foundation.

Author information




Study concept and design: MS, KS, YO, and NT. Administrative support: HM and NT. Provision of study material or patients: MS, YO, MT, SB, HM, and NT. Collection and assembly of data: MS, MT, TS, SB, KK, HM, and NT. Data analysis and interpretation: YH, MS, YU, TK, YO, MT, SB, HM, and NT. Statistical analysis: YH, YU, TK, and YO. Manuscript preparation: YH, MS, and NT. Manuscript editing: YH. Manuscript review: All authors.

Corresponding author

Correspondence to Yasuhiro Hagiwara.

Ethics declarations

Conflict of interest

YU reports honoraria from Chugai Pharma and Teijin Pharma; consulting and advisory role for Pfizer, Ono Pharmaceutical, Zeria Pharmaceutical, and Daiichi Sankyo; speakers' bureaus for Pfizer; and travel support from Pfizer and Chugai Pharma. YO reports compensated leadership for Statcom; stock ownership of Statcom; honoraria from Chugai Pharma, Daiichi Sankyo, Sanofi, Eisai, and Shionogi; and grants from Medical Member System. MT reports honoraria from AstraZeneca, Eli Lilly, Eisai, and Pfizer; and grants paid to the institution from Eisai, Kyowa Kirin, and Taiho Pharmaceutical. HM reports honoraria from Pfizer, Daiichi Sankyo, Taiho Pharmaceutical, and Takeda; and grants paid to the institution from Daiichi Sankyo. All remaining authors have declared no conflicts of interest.

Ethical approval

The RESPECT trial protocol, including the cognitive functioning sub-study, was approved by the institutional review boards of all participating institutions.

Informed consent

All patients provided written informed consent.

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

Hagiwara, Y., Sawaki, M., Uemura, Y. et al. Impact of chemotherapy on cognitive functioning in older patients with HER2-positive breast cancer: a sub-study in the RESPECT trial. Breast Cancer Res Treat 188, 675–683 (2021).

Download citation


  • Adjuvant chemotherapy
  • Adjuvant trastuzumab
  • Cognitive functioning
  • HER2-positive breast cancer
  • Older patients