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October 15, 2021

Cancer-Related Cognitive Impairment in Patients

With a History of Breast Cancer
Kathleen Van Dyk, PhD1; Patricia A. Ganz, MD2

 Author Affiliations | Article Information

JAMA. 2021;326(17):1736-1737. doi:10.1001/jama.2021.13309

C linical reports of cognitive difficulties in patients with breast cancer began to appear in the litera-
ture in the 1990s, coincident with the increasing use of postoperative adjuvant chemotherapy.1
Symptoms were more frequently reported in women who received very high-dose chemotherapy, rais-
ing concerns that cognitive impairment might become a dose-limiting treatment toxicity. However, this
has not occurred, in that over the past 2 decades there has been a deescalation of both the intensity
and generalized use of adjuvant chemotherapy in patients with breast cancer. Because of the initial as-
sociation of cognitive symptoms with chemotherapy treatment, early research focused on what was re-
ferred to as chemobrain or chemofog, finding preliminary evidence of measurable neurocognitive effects
among patients with breast cancer who were exposed to chemotherapy. Subsequent studies have docu-
mented cognitive changes before any cancer-directed therapies, as well as in association with other
common breast cancer treatments (eg, radiation, endocrine therapy).

The evolving body of research on this subject led to a renaming of the condition as cancer-related cog-
nitive impairment (CRCI). Although they are most commonly reported in close proximity to initial breast
cancer treatments, for some patients, symptoms of CRCI can persist for years after treatment
completion.2 Importantly, although breast cancer has been the most studied tumor type with CRCI,
there is a growing literature on this condition in persons with other types of cancer, including lym-
phoma, head and neck cancers, and brain tumors, and patients who have received stem cell transplants.

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Incidence and Nature of the Problem

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CRCI reported by patients with breast cancer is common, although the frequency and nature can vary
subject to the population sampled. According to one survey, 885 of 1147 patients (77%) with a history
of breast cancer who received chemotherapy with and without endocrine therapy and 371 of 822 (45%)
who received only endocrine therapy reported cognitive symptoms during or soon after treatment.3 A
community-based prospective longitudinal cohort study of 503 patients with breast cancer, compared
with 334 control participants without cancer, found statistically significant differences after adjuvant
treatment in both self-reported clinically meaningful cognitive decline (36.5% vs 13.6% of
participants)4 and neurocognitive decline (effect size 0.2 on the primary outcome as assessed by
Janelsins et al).5 A meta-analysis of neuropsychological outcomes in patients with breast cancer
treated with chemotherapy (n = 2939), compared with healthy control participants (n = 3420), revealed
the largest effect sizes in the domains of processing speed and language (Cohen d = −0.39), executive
function (Cohen d = −0.34), and memory (Cohen d = −0.30), but no differences compared with patients
with breast cancer who were not treated with chemotherapy (n = 1538).6

In the current era of more selective chemotherapy use, cognitive symptoms continue to emerge in
other contexts, including before any cancer-directed treatments, in association with endocrine therapy,
and with radiotherapy and surgery.7 Patients who develop cognitive difficulties during the acute phase
of breast cancer treatment may require several months to a year for recovery and, for some individuals,
cognition never fully returns to “baseline,” supported by reports of neuroimaging abnormalities.7
Although cognitive symptoms rarely reach the level of severe impairment (ie, dementia), symptoms
frequently disrupt functioning, work, and quality of life.7

Contributing Factors and Mechanisms

Several candidate mechanisms for CRCI have been hypothesized based on clinical and preclinical stud-
ies. Increased systemic inflammation occurs in response to cancer, as well as to chemotherapy, radio-
therapy, and surgery.7 Chronically elevated inflammation can lead to neuroinflammation that could re-
sult in neurotoxicity and increased oxidative damage. Evidence has also implicated mitochondrial dys-
function in neurons as well as disrupted neurogenesis and neuroplasticity.7 The potential cognitive ef-
fects of immunotherapy, an emerging breast cancer therapy, will be important to monitor in light of pa-
tient reports and earlier studies.7

Endocrine therapy is used in the majority of patients with breast cancer and is another important poten-
tial risk factor for CRCI.8 Estrogen has an important role in women’s brain health, and the downregula-
tion of natural estrogen production or blocking of its activity through endocrine therapy is associated
with effects on cognition. Although research is still evolving in this area, a 2020 report from a random-
ized clinical trial involving 552 patients reported clinically meaningful patient-reported cognitive de-
cline 12 months after starting endocrine therapy, with (37.7%) or without (35.3%) chemotherapy, and
these difficulties were present in both premenopausal and postmenopausal women.9

Patient and context-related vulnerabilities for CRCI may include aging and preexisting medical condi-
tions with known cognitive risk (eg, diabetes, heart disease). Genetic risk for CRCI is an ongoing area of
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study, with some evidence suggesting particular vulnerability among APOE*E4 carriers, the best-known
genetic risk for Alzheimer disease. Preexisting and concurrent psychosocial risks for CRCI include mood
symptoms (eg, depression) and trauma symptoms, fatigue, and sleep disturbance. In terms of protec-
tive factors, higher cognitive reserve may buffer against the neurotoxicity associated with cancer and its
treatment.7

The leading model of CRCI suggests the possibility that it represents accelerated aging, given the over-
lap in mechanisms and vulnerabilities with cognitive aging. Some neuroimaging studies have described
brain changes comparable to aging, such as compensatory hyperactivation during cognitive tasks and
reduction in gray matter, as well as a link between markers of biological aging and cognition in patients
with a history of cancer.7

Assessment and Treatment of CRCI

The National Comprehensive Cancer Network guidelines for the assessment and management of CRCI
suggest that increased patient education regarding CRCI is important. Many patients with breast cancer
are unaware of the possibility that they may have cognitive decline after treatment. Screening tools for
dementia are insufficient for CRCI evaluation. Screening for mood disturbance and survivorship con-
cerns can identify cognitive symptoms. Careful assessment of cognitive difficulties using validated
questionnaires for CRCI can be used to track impairment if clinically suspected. When patients sponta-
neously report these symptoms to clinicians, they should not be ignored. Acknowledging the patient’s
symptoms and undertaking a thorough evaluation is important. An initial first step should be examining
and addressing potentially manageable associated conditions, such as depression, sleep disturbance,
and fatigue, which are all common and frequently co-occurring in this patient population. If CRCI symp-
toms do not improve, a referral for neuropsychological evaluation should follow, because this can help
characterize specific cognitive symptoms and supply targeted recommendations and may provide reas-
surance and information for patients who may be concerned that they are developing dementia.

There is no established standard care for neuroprotection against CRCI or for managing CRCI in the set-
ting of breast cancer, and more evidence is needed. Cognitive rehabilitation and behavioral therapies
are among the most promising interventions for CRCI to date.10 Physical exercise is a promising inter-
vention but has not been adequately evaluated.7 Some pharmacologic agents have been studied (eg,
psychostimulants, dementia medications) without conclusive efficacy, and more research is needed.

Summary
CRCI is an important clinical issue that can impair daily function, work productivity, childcare, and other
responsibilities in patients with a history of breast cancer. Risk for CRCI includes cancer and cancer
treatment, as well as patient-related vulnerabilities. Management recommendations include attending
to patient-reported symptoms with a thorough symptom-targeted evaluation. Cognitive and behavioral
treatments are the primary recommended intervention. More research is needed to establish a solid ev-
idence base for CRCI that evolves alongside modern cancer treatment practices.
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Submissions: The Women's Health editors welcome proposals for features in the section. Submit yours
to [email protected].

Article Information Back to top

Corresponding Author: Patricia A. Ganz, MD, UCLA Jonsson Comprehensive Cancer Center, 650 Charles
Young Dr S, Room A2-125 CHS, Los Angeles, CA 90095-6900 ([email protected]).

Published Online: October 15, 2021. doi:10.1001/jama.2021.13309

Conflict of Interest Disclosures: Dr Van Dyk reported receiving grants from the National Institutes of
Health/National Cancer Institute outside the submitted work. Dr Ganz reported receiving grants from
the Breast Cancer Research Foundation and grants from the National Cancer Institute and grants and
personal fees from Blue Note Therapeutics outside the submitted work and being a member of a scien-
tific advisory board of the Breast Cancer Research Foundation.

References

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Comment

1 Comment for this article EXPAND ALL

October 15, 2021

Causes and Prevention

Dilipsinh Solanki, MD | Private Practice

We have been discussing “chemo-brain" for at least a decade.

What is the cause, why just focus on breast cancer? There are others with other cancers who also need
to function. Dr. Gans' focus on breast cancer is wonderful but this may not be just a breast cancer prob-
lem, and may not even have much to do with chemotherapy.

Some years ago there were preclinical data showing a CNS protective effect of rEPO (1). Our group ac-
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tually did a randomized study in women undergoing adjuvant chemotherapy; there was protection
against short term memory impairment but no long ...

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