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Cognitive Impairment in Women Treated for Early Breast Cancer: Chemoendocrine Adjuvant Therapy vs Endocrine Therapy Alone


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Women with early-stage breast cancer who received adjuvant chemoendocrine therapy reported greater cognitive impairment at 3 and 6 months than women receiving adjuvant endocrine therapy alone, according to the results from a subgroup of women participating in the TAILORx trial.1 By 12 months, the decline in cognitive impairment had leveled off among the women receiving chemoendocrine therapy, and there were no significant differences in cognitive impairment between the two treatment groups.


Chemotherapy produces early, but not sustained, cognitive impairment relative to endocrine therapy alone.
— Lynne I. Wagner, PhD

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“These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to endocrine therapy alone,” the authors concluded, “providing reassurance to patients in whom adjuvant chemotherapy is indicated to reduce recurrence risk and to their clinicians.”

That reassurance is tempered by another key finding of the study—women’s cognitive function did not return to pretreatment levels, regardless of whether they received chemoendocrine therapy or endocrine therapy alone. Both adjuvant treatments “were associated with lingering impairment,” the researchers noted, “underscoring the need for ongoing attention to cancer-related cognitive impairment, which appears to stabilize at 12 months and beyond.”

“Our results showing the impairments were lingering is concerning,” the study’s lead author Lynne I. Wagner, PhD, told The ASCO Post. “Concerns related to cognitive impairment need to be assessed not only shortly after initiating endocrine therapy, but even 1 to 2 years into treatment; for some women, the increase in impairment was gradual. As a clinician, you don’t want to assume that if there are no problems within the first 3 months or so, it is not going to be an issue.” Dr. Wagner is a Professor of Social Sciences and Health Policy at Wake Forest School of Medicine and Director of Research and Clinical Integration, Cancer Prevention and Control, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina.

Key Findings From TAILORx

TAILORx randomly assigned women with early breast cancer and a mid-range 21-gene recurrence score of 11 to 25 to chemotherapy followed by endocrine therapy or endocrine therapy alone. The trial “found no benefit from chemotherapy for 70% of women with hormone receptor–positive, HER2-negative, axillary lymph node-negative,” according to the ECOG-ACRIN Cancer Research Group,2 which coordinated the trial. The first results in 2018, published in TheNew England Journal of Medicine,3 provided clinicians with “high-quality data to inform personalized treatment recommendations for women.”

“Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy–Cognitive Function questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months,” the researchers reported. The questionnaire included the 20-item Perceived Cognitive Impairment (PCI) scale, completed on paper by study participants. The PCI scale score was the primary endpoint, with higher scores indicating less cognitive impairment.

Concerns related to cognitive impairment need to be assessed not only shortly after initiating treatment, but even 1 to 2 years into treatment.
— Lynne I. Wagner, PhD

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The mean age of study participant was 55 years in the chemoendocrine group and 56 years in the endocrine-alone group. Most women were postmenopausal (64% in the chemoendocrine group and 69% in the endocrine therapy–alone group), and 82% of women in both groups were white.

An aromatase inhibitor was the initial prescribed endocrine therapy for 58% of the substudy participants, and 37% received tamoxifen. The most common chemotherapy regimens were docetaxel and cyclophosphamide, prescribed for 70% in the chemoendocrine group, and anthracycline-based therapy, prescribed for 20%.

Increased Impairment

Women randomly assigned to either treatment group had significantly lower PCI scores (meaning increased impairment) at 3, 6, 12, and 24 months compared with baseline PCI scores. The researchers calculated a minimum change score to determine what is likely to be a clinically significant level of change. The magnitude of PCI change scores was greater at 3 and 6 months for women receiving chemotherapy plus endocrine therapy but not at 12, 24, and 36 months.

“We also calculated proportions, because we know from prior research, there are subgroups,” Dr. Wagner added, and “sometimes just simply looking at a mean score change alone can obscure the subgroup differences.” The researchers calculated the prevalence of a clinically meaningful change in PCI; they found the proportion of women who had worse cognitive impairment at 12 months was nearly the same for both treatment groups—35.3% with
endocrine therapy alone and 37.7% with chemoendocrine therapy.

In addition, the study found a “nonsignificant interaction between menopausal status and treatment arm,” challenging suggestions that cancer-related cognitive impairment could be due to chemotherapy-induced menopause. “That has been hypothesized for a number of years as one of the causes,” Dr. Wagner noted. “However, since more studies have documented changes also among postmenopausal women, that theory has been challenged. This is another study to question that this is solely the cause.”

Unanticipated Results

“We anticipated the chemotherapy group would return to pretreatment levels of patient-reported cognitive impairment and would then be comparable again to the endocrine group,” Dr. Wagner remarked. “However, we found the groups converged at 12 months, not because of improvement, but because the chemotherapy group had an early and abrupt increase in cognitive impairment, and the hormone-therapy group had a more gradual increase in cognitive impairment.”

A small subset had reported improvement in cognitive function from baseline to 12 months—14% in the group receiving hormone therapy alone and 8% in the group receiving chemotherapy plus hormone therapy. “We were surprised by that,” Dr. Wagner commented.

“I don’t think it is entirely implausible if, at the time of diagnosis, you have a lot of other factors in play,” Dr. Wagner continued. “Such factors include recent surgery; the effects of anesthesia from surgery; and the mental load from being diagnosed with cancer and planning treatment, arranging time away from work for some women, and managing family responsibilities. It is possible some women may have had a lot of these factors confounding their impairment at the time of initial assessment. Then, at 12 months, the treatment is behind them or underway. They are getting life back on track to some extent.”

However, Dr. Wagner reminded, these thoughts are hypotheses, and the study did not collect data on these issues. “It does make sense that a small proportion of women reported less
cognitive impairment at follow-up than they did at the time of randomization,” she added.

Retiring ‘Chemobrain’ Terminology

With comparable long-term cognitive impairments between groups being confirmed, Dr. Wagner noted it may be time to retire the term “chemobrain.” Dr. Wagner told The ASCO Post: “Chemobrain is inaccurate because it implies the cognitive changes are solely due to chemotherapy, and it is clearly much more complicated than that. Many more factors are contributors, including the burden of having a tumor.”

Dr. Wagner continued: “We have moved away from the term chemobrain, because we have more studies demonstrating that after surgery for breast cancer, one-third of women met criteria for cognitive impairment prior to beginning chemotherapy. It could be that the subgroup of women who are more vulnerable and who demonstrate impairment even before chemotherapy have some other inflammatory responses or are more sensitive to changes in inflammatory cytokines.” A further push away from this term is provided by the current study, showing adjuvant treatment with endocrine therapy—but without chemotherapy—is also associated with changes in cognitive impairment.

Understanding Mechanisms Underlying Cognitive Impairment

Dr. Wagner calls for ongoing attention to cancer-related cognitive impairment. “We are referring both to clinical management and also to more research to better understand the mechanisms that underlie cognitive impairment associated with hormonal therapy,” she explained. “We are assessing patient-reported cognitive impairment on a few other ECOG-ACRIN Cancer Research Group trials,” including in men receiving androgen-deprivation therapy for prostate cancer. The ongoing Remember trial (ClinicalTrials.gov identifier NCT02822573), sponsored by Wake Forest, she added, “is an exciting trial examining the possible role of the Alzheimer’s drug donepezil in preserving cognitive function and reducing cognitive impairment” after chemotherapy for breast cancer.

The assumption that chemotherapy was the sole culprit of cognitive impairment among women receiving adjuvant treatment for breast cancer may have obscured other research into its causes, according to Dr. Wagner. “Too few studies have examined cognitive changes associated with hormonal therapy,” she commented. “I do think we need more research into possible interventions to preserve quality of life” for women receiving chemoendocrine therapy as well as endocrine therapy alone.

Fatigue Data to Come

By presenting an opportunity to look at differences in treatment outcomes among women with similar demographics and clinical characteristics but who were randomly assigned to receive or not receive chemotherapy, the TAILORx design filled a “major research gap,” Dr. Wagner remarked. “We are working on a second paper now to present our fatigue and endocrine symptom data, showing more differences by menopausal status than we did with cognitive impairment. When we looked at the change in cognitive impairment and entered fatigue into the model, we found increased fatigue was correlated with increased cognitive impairment, although it does not completely explain the cognitive impairment changes. We found there is some overlap, but cognitive impairment is a distinct symptom.” 

DISCLOSURE: Dr. Wagner has an immediate family member who holds stock or other ownership interests in Eli Lilly, Gilead Sciences, and Johnson & Johnson; has served as a consultant or advisor to Celgene; and has been reimbursed for travel, accommodations, or other expenses by Celgene.

REFERENCES

1. Wagner LI, Gray RJ, Sparano JA, et al: Patient-reported cognitive impairment among women with early breast cancer randomly assigned to endocrine therapy alone vs chemoendocrine therapy: Results from TAILORx. J Clin Oncol. April 9, 2020 (early release online).

2. ECOG-ACRIN Cancer Research Group: TAILORx dispels chemo-brain notion: Women on hormone therapy also report cognitive decline. Press release, April 9, 2020. Available at https://ecog-acrin.org/news-and-info/press-releases/tailorx-dispels-chemo-brain-notion-as-women-on-hormone-therapy-also-report-cognitive-decline. Accessed May 18, 2020.

3. Sparano JA, Gray RJ, Makower DF, et al: Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 379:111-121, 2018.


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