Abstract
Background:
Cancer-related cognitive impairment (CRCI) is frequently reported by women with breast cancer after chemotherapy. Yet, the acute effects of a single infusion on perceived cognition remain understudied, especially across different age groups.
Aims:
This study assessed acute changes in perceived cognition following the first chemotherapy infusion in young (< 40 years), middle-aged (40–64 years), and older adults (≥ 65 years) with breast cancer and identified baseline risk factors associated with worsened CRCI in these age groups.
Methods:
Chemotherapy-naïve women with breast cancer scheduled for intravenous chemotherapy completed PROMIS Cognitive Abilities 4a and Cognitive Function 8a assessments before and 5 days post-infusion. Clinically significant CRCI was defined as T-scores ≤ 45. Paired t-tests, chi-square tests, and residualized regression models (univariate and multivariable) were used to evaluate changes in cognition and associated risk factors.
Results:
Among all participants (N = 528; 85 young, 329 middle-aged, 114 older), perceived cognitive performance significantly declined, and the prevalence of CRCI increased across all three age groups (FDR adjusted p-values < 0.05). Among middle-aged patients, the White race (p = 0.011) and a college degree (p = 0.001) were associated with worsened cognitive function, while a college degree (p = 0.009) and sleep disturbance (p = 0.012) were linked to worsened cognitive ability. In older adults, depressive symptoms were associated with worsened cognitive function (p = 0.017) and cognitive ability (p = 0.011).
Conclusions:
Cognitive impairment develops acutely after the first chemotherapy infusion across all age groups, with risk factors varying by age. Age-specific interventions are needed to address early cognitive decline in breast cancer patients.
Keywords: breast neoplasms, cancer-related cognitive impairment, chemotherapy, perceived cognitive performance, risk factors
1 |. Background
Cancer-related cognitive impairment (CRCI) is among the most prevalent and distressing side effects reported by women with breast cancer undergoing chemotherapy [1–4]. CRCI is reported by 11%–37% of women during chemotherapy [5, 6], 10%–83% at the end of chemotherapy [7–10], and 15%–94% in the months or years following [5, 8, 11, 12]. Women who were at least 1 year post-chemotherapy reported that CRCI negatively impacted their social relationships, work performance, daily functioning [1, 2], and overall quality of life [2]. Despite a growing body of evidence documenting the high prevalence of perceived CRCI among women with breast cancer treated with chemotherapy, the timeline for when they first notice CRCI remains unclear. This current study aimed to evaluate patient-reported CRCI before and 5 days after the first infusion of chemotherapy among women with breast cancer receiving a chemo regimen.
To our knowledge, no prior studies have specifically focused on perceived CRCI immediately after the first infusion of chemotherapy among women with breast cancer. Existing studies that examined CRCI after the first chemotherapy infusion included diverse cancer patient populations, employed different timelines to measure changes in CRCI, and reported inconsistent results [13, 14]. For example, one study focusing on patients with ovarian cancer reported worsening cognition after their first chemotherapy infusion [14]. In contrast, studies that explored changes in health-related quality of life (HRQoL) parameters, including cognitive function, after the first chemotherapy cycle among patients with colorectal cancer (with a small subset of female patients) found no significant change in cognitive function [13]. These findings highlight the heterogeneity in CRCI across cancer types and underscore the need for more focused investigations in breast cancer patients, particularly during the early stages of chemotherapy.
Various factors may influence the extent of perceived CRCI. Age is a critical factor, as cognitive demands and physiological resilience vary across age groups. Over the past 2 decades, the incidence of breast cancer diagnoses among women under the age of 40 has increased [15]. For young adults, CRCI may be particularly distressing due to heightened cognitive demands and responsibilities associated with education, employment, and family obligations [16, 17]. However, they may also demonstrate greater cognitive resilience, potentially resulting in less perceived CRCI than older adults [18]. Additionally, age-related differences in outcomes of chemotherapy exposure could affect the degree of perceived CRCI. Therefore, by incorporating age-specific analysis, this study aims to provide a more nuanced understanding of perceived CRCI and inform tailored supportive care and interventions.
In addition to age, other factors such as depressive symptomatology, fatigue, and sleep disturbance have been associated with perceived CRCI in women with breast cancer after chemotherapy [4, 11, 19]. However, studies examining additional potential risk factors for perceived CRCI, such as education level [4, 20] and social support [21], have yielded inconclusive results, underscoring the need for further research in this area. Given the variation in putative risk factors experienced across different age groups, it is plausible to hypothesize that these factors influence perceived CRCI differently throughout the lifespan. Thus, investigating the roles of these potential risk factors in perceived CRCI among women with breast cancer of varying ages following chemotherapy initiation is essential.
The goals of this study were to examine acute changes in perceived cognitive performance (i.e., cognitive function and cognitive ability) from pre-infusion to 5 days after the first chemotherapy infusion among young (i.e., < 40 years), middle-aged (i.e., 40–64 years), and older adults (i.e., ≥ 65 years) with breast cancer, and to separately examine differences in potential baseline risk factors among these three age groups. We hypothesized that patients in all three groups would report worsening cognition and increased incidence of perceived CRCI from before to 5 days after the first infusion. Further, we hypothesized that baseline risk factors, including demographic and clinical characteristics, social support, and patient-reported symptoms (i.e., fatigue, sleep disturbance, depressive symptomatology), would be associated with worsening cognition among these age groups.
2 |. Methods
2.1 |. Participants and Procedure
As part of a larger study of chemotherapy-related nausea and vomiting, participants were recruited between March 2019 and March 2023 from five academic medical centers in the United States: City of Hope, Moffitt Cancer Center, the Ohio State University, Rutgers University, and the University of Colorado Cancer Center. Eligible participants were: (1) at least 18 years of age, (2) diagnosed with breast cancer, (3) scheduled to begin moderately or highly emetogenic intravenous standard-dose chemotherapy, (4) not previously treated with chemotherapy, (5) without psychiatric or neurological disorders that could interfere with study participation, (6) able to speak and read English or Spanish, and (7) able to provide informed consent.
In collaboration with treating physicians, the research team identified potential participants via scheduled appointments and received permission from clinical providers to approach patients to introduce the study. Then, the study team contacted potential participants via phone or in-person visits to determine initial eligibility and interest in the study. Eligible and interested patients provided written or electronic informed consent to participate. Participants completed a baseline assessment before chemotherapy and a follow-up survey 5 days after the first chemotherapy infusion. The current study was performed in concordance with the principles outlined in the Declaration of Helsinki and approved by the Western Institutional Review Board (Identifier: 20180593). Informed consent was obtained from all participants before data collection and participants were provided a copy of their informed consent. Participants were not paid for survey completion.
2.2 |. Measures
2.2.1 |. Demographic and Clinical Information
Patients completed a self-reported questionnaire at baseline assessing demographic characteristics, including date of birth, race (White vs. non-White), ethnicity (Hispanic vs. non-Hispanic), educational attainment (having a college degree vs. not having a college degree), and household composition (living alone vs. living with others). Clinical characteristics, including the cancer stage at diagnosis (stages IV vs. I-III), were obtained through medical chart abstraction by research personnel within 1 month after study enrollment.
2.2.2 |. Perceived Cognition
Self-reported cognition was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function—Short Form 8a and PROMIS Cognitive Abilities—Short Form 4a measures at both time points [22]. The PROMIS Cognitive Function 8a consists of eight items assessing patients’ cognitive task deficits (e.g., “In the past 7 days…my thinking has been slow”) [22]. Items are evaluated on a five-point Likert scale (1 = very, 2 = often, 3 = sometimes, 4 = rarely, 5 = never). Item scores were summed (range 8–40) and converted to PROMIS T-scores (range 0–100, mean = 50, SD = 10) standardized to the U.S. general population, with higher scores indicating better cognitive functioning [22]. A T-score of 50 represents the mean of the relevant reference population, and 10 is the standard deviation of that population [23–25]. The PROMIS Cognitive Abilities 4a consists of four items to assess individuals’ perceived functional abilities regarding cognitive tasks (e.g., “In the past 7 days…my mind has been as sharp as usual.”) [22]. Items are evaluated on a five-point Likert scale (1 = not at all, 2 = a little bit, 3 = somewhat, 4 = quite a bit, 5 = very much) [22]. The sum of the four items produces a total raw score ranging from 5 to 20; raw scores were converted to T-scores standardized to the U.S. general population, with higher scores indicating better subjective cognitive abilities [22]. The PROMIS Cognitive Function 8a has been used to measure cognitive function in breast cancer survivors and demonstrated good convergent validity and internal reliability [26]. In this study, PROMIS T-scores ≤ 45 were used to identify clinically significant (i.e., mild to severe) cognitive impairment [22].
2.2.3 |. Social Support
Social support was assessed at recruitment using the Medical Outcomes Study–Social Support Survey (MOS-SSS) [27]. In previous studies of cancer patients, the 19-item MOS-SSS has demonstrated good internal consistency and convergent validity [28]. In this study, we focused on emotional/informational support (i.e., having someone to confide in, listen to you, and provide advice and information) and tangible support (i.e., having someone to help with daily chores, prepare meals, or drive you if needed) subscales, which encompasses a total of 12 items on a five-point Likert scale (1 = none of the time, 2 = a little of the time, 3 = some of the time, 4 = most of the time, 5 = all of the time). The total score of these 12 items reflects the overall level of social support. The range of social support scales was 0–100, with higher scores indicating higher levels of social support.
2.2.4 |. Self-Reported Symptomatology
Patient-reported symptomatology was assessed prior to the first chemotherapy infusion with the following PROMIS scales: Fatigue Short Form 7a [23], Sleep Disturbance Short Form 8a, Sleep Related Impairment 8a [24], Depression Short Form 4a [25], and Anxiety Short Form 4a [29]. Participants rated their symptomatology on a scale from 1 to 5. Responses for each subscale are summed to produce a total score, and the raw scores were subsequently converted to PROMIS T-scores (mean = 50, SD = 10). For these symptom measures, higher T-scores indicate worse symptomatology. T-scores < 55 were considered in the normal range, and 55 or greater indicated clinically significant (i.e., mild to severe) symptomatology [30]. These PROMIS scales have been used in cancer patients and have demonstrated robust psychometric properties, including reliability and validity [29].
2.3 |. Statistical Analysis
Female breast cancer patients were included in analyses if they completed the cognitive measures at both time points (i.e., pre-infusion and 5 days after infusion) and had complete data on sociodemographic characteristics, clinical characteristics, and baseline risk factors. All analyses were stratified by age group (≤ 40, 40–64, ≥ 65 years). Descriptive statistics (means, standard deviations, frequencies, percentages) were used to characterize sociodemographic and clinical characteristics of the sample, perceived cognition (i.e., cognitive function, cognitive ability), and putative baseline risk factors (i.e., social support, fatigue, sleep disturbance, sleep-related impairment, depressive symptomatology, and anxiety). ANOVA, paired t-tests, and effect sizes were used to examine changes in perceived cognition over time. McNemar’s tests were utilized to compare rates of perceived CRCI at each time point. Based on prior research, we specified candidate covariates in the analysis: demographics (including race, ethnicity, educational attainment, and household composition), cancer stage at diagnosis, and putative baseline risk factors (including social support, fatigue, sleep-related symptoms, depression, and anxiety) associated with worsening perceived cognitive performance. Associates with each cognitive outcome were examined using univariate residualized change linear regression models. To address the multiple comparison issue, Benjamini–Hochberg (BH) False Discovery Rate (FDR)-adjusted p-values were calculated for each cognitive measure across risk factors [31]. Factors identified in univariate regression models with an FDR-adjusted p-value < 0.2 were subsequently included as potential predictors in multivariable residualized change linear models to address potential confounding, with adjustment for baseline cognitive performance. This approach refined the selection of predictors by screening for individual associations before adjusting for covariates. Analyses were conducted using SAS Version 9.4 (SAS Institute Inc., Cary, NC, USA). To examine selection bias, a series of sensitivity analyses, including paired t-tests and Fisher’s exact tests with FDR adjustment, were conducted to examine if attrition (those missing at least one cognitive assessment) and missing data (those missing risk factors) were related to differences in baseline characteristics. All tests were two-sided and significant if p < 0.05 or FDR < 0.2.
3 |. Results
3.1 |. Participant Characteristics
Initially, the parent study included 611 female breast cancer patients. Of these, 64 were excluded due to missing at least one cognitive performance assessment, and an additional 19 were excluded for missing at least one risk factor, resulting in a final sample of 528 participants. Sociodemographic characteristics, clinical characteristics, and baseline risk factors did not differ between patients who completed cognitive assessment before and 5 days after the first infusion (n = 547) and those who missed at least one assessment (n = 64) (FDRs > 0.2) except that those who completed both assessments had worse sleep impairment (FDR = 0.05). Further, baseline cognitive function and cognitive ability did not differ between patients who reported data for all risk factors (n = 528) and those who were missing data for at least one risk factor (n = 19) (FDRs > 0.2).
Participant characteristics are summarized in Table 1. Among the 528 participants, 85 (16%) were young adults, 329 (62%) were middle-aged, and 114 (22%) were older adults. Across groups, the majority of participants were White, non-Hispanic, college graduates, living with others, and diagnosed with Stage I-III breast cancer. Young adults were more likely to be college graduates than middle-aged (χ2 = 8.89, FDR = 0.029) or older adults (χ2 = 6.90, FDR = 0.047). Middle-aged adults were more likely to be Hispanic (χ2 = 7.65, FDR = 0.042), have clinically significant fatigue (χ2 = 9.00, FDR = 0.027), sleep disturbance (χ2 = 6.15, FDR = 0.067), and anxiety (χ2 = 3.69, FDR = 0.190) than older adults. Compared to older adults, young (χ2 = 11.30, FDR = 0.022) and middle-aged adults (χ2 = 11.07, FDR = 0.022) were more likely to have clinically significant depression. Older adults were more likely to live alone than young (χ2 = 6.03, FDR = 0.067) and middle-aged adults (χ2 = 4.11, FDR = 0.155). In general, at both baseline and day 5, older patients have higher and better perceived cognitive function and cognitive abilities than young and middle-aged adults (FDRs < 0.060) (Supporting Information S1: Table 1).
TABLE 1 |.
Participant characteristics (N = 528).
| Characteristic | Overall (N = 528) |
Young (n = 85) |
Middle-aged (n = 329) |
Older (n = 114) |
Statistic | p |
|---|---|---|---|---|---|---|
| Age: M (SD) | 53 (13) | 35 (4) | 52 (7) | 71 (5) | — | — |
| White: n (%) | 445 (84%) | 72 (85%) | 273 (83%) | 100 (88%) | 1.45 | 0.484 |
| Hispanic: n (%) | 60 (11%) | 9 (11%) | 46 (14%) | 5 (4%) | 7.80 | 0.020 |
| College graduate: n (%) | 286 (54%) | 59 (69%) | 169 (51%) | 58 (51%) | 9.49 | 0.009 |
| Living alone: n (%) | 59 (11%) | 5 (6%) | 34 (10%) | 20 (18%) | 7.29 | 0.026 |
| Cancer stage IV: n (%) | 18 (3%) | 4 (5%) | 12 (4%) | 2 (2%) | 1.44 | 0.487 |
| Overall social support: M (SD) | 89 (16) | 91 (14) | 88 (17) | 90 (15) | 2.12 | 0.121 |
| Tangible support: M (SD) | 86 (20) | 88 (17) | 85 (21) | 89 (19) | 1.74 | 0.177 |
| Emotional/Informational support: M (SD) | 90 (16) | 92 (14) | 89 (17) | 91 (14) | 2.03 | 0.132 |
| Fatigue | ||||||
| PROMIS T-score: M (SD) | 47 (8) | 48 (8) | 48 (9) | 46 (7) | 4.08 | 0.017 |
| Clinically significant: n (%) | 100 (19%) | 15 (18) | 74 (22) | 11 (10) | 9.21 | 0.010 |
| Sleep disturbance | ||||||
| PROMIS T-score: M (SD) | 51 (10) | 51 (10) | 52 (10) | 49 (8) | 5.58 | 0.004 |
| Clinically significant: n (%) | 187 (35%) | 32 (38) | 126 (38) | 29 (25) | 6.34 | 0.042 |
| Sleep-related impairment | ||||||
| PROMIS T-score: M (SD) | 63 (11) | 61 (11) | 63 (10) | 65 (11) | 3.77 | 0.024 |
| Clinically significant: n (%) | 441 (84%) | 67 (79) | 275 (84) | 99 (87) | 2.28 | 0.320 |
| Depression | ||||||
| PROMIS T-score: M (SD) | 49 (8) | 51 (8) | 49 (8) | 46 (6) | 8.98 | < 0.001 |
| Clinically significant: n (%) | 132 (25%) | 27 (32) | 91 (28) | 14 (12) | 13.15 | 0.001 |
| Anxiety | ||||||
| PROMIS T-score: M (SD) | 55 (9) | 56 (10) | 56 (9) | 53 (9) | 3.50 | 0.031 |
| Clinically significant: n (%) | 293 (55%) | 49 (58) | 190 (58) | 54 (47) | 3.88 | 0.143 |
Note: Statistics were from ANOVA and chi-square tests. Fatigue, sleep disturbance, sleep-related impairment, and depression were considered clinically significant (mild, moderate, or severe) if PROMIS T-scores ≥ 55. P = p-value.
3.2 |. Changes in Perceived Cognition
Perceived cognition from pre-infusion to Day 5 post-infusion across age groups is shown in Table 2. Both perceived cognitive function and ability significantly worsened after the first chemotherapy infusion (FDRs < 0.001) across all three age groups. Rates of clinically significant cognitive impairment at both time points are presented in Table 3 and Supporting Information S1: Table 2. The proportion of participants reporting clinically significant impairment in cognitive functioning increased from 28% to 53% (FDR < 0.001) among young adults, from 34% to 51% among middle-aged adults, and from 19% to 37% (FDRs < 0.001) among older adults. Similarly, the proportion of participants reporting clinically significant impairment in cognitive ability increased from 34% to 49% (FDR = 0.016) among young adults, from 38% to 53% (FDR < 0.001) among middle-aged adults, and from 22% to 47% (FDR < 0.001) among older adults. Most patients either did not experience impairment at both time points or experienced impairment at baseline. However, 31% of young adults, 25% of middle-aged adults, and 22% of older adults have an onset of cognitive function impairment (i.e., they have not experienced impairment at baseline and started to experience impairment in cognitive function at day 5 follow-up) after the first infusion. The rates of cognitive ability impairment onset at 5 days after the first infusion were 25%, 21%, and 30%, respectively, for these three age groups. Based on post-hoc chi-square tests for cognitive function (χ2 = 4.393, p = 0.111) and for cognitive abilities (χ2 = 0.537, p = 0.764), the proportions of impairment onset at 5 days were not significantly different across the three age groups.
TABLE 2 |.
Perceived cognition before and 5 days after the first chemotherapy infusion (N = 528).
| Baseline | Day 5 | ||||||
|---|---|---|---|---|---|---|---|
| Mean | SD | Mean | SD | d ‡ | p | FDR | |
| Young adults (n = 85) | |||||||
| Cognitive function | 51.44 | 10.21 | 44.82 | 9.62 | 0.51 | < 0.001 | < 0.001 |
| Cognitive ability | 51.00 | 9.33 | 46.36 | 8.66 | 0.47 | < 0.001 | 0.001 |
| Middle-aged adults (n = 329) | |||||||
| Cognitive function | 50.57 | 9.76 | 45.70 | 10.43 | 0.51 | < 0.001 | < 0.001 |
| Cognitive ability | 50.12 | 9.35 | 46.40 | 8.77 | 0.44 | < 0.001 | < 0.001 |
| Older adults (n = 114) | |||||||
| Cognitive function | 54.57 | 8.56 | 47.81 | 11.08 | 0.72 | < 0.001 | < 0.001 |
| Cognitive ability | 53.92 | 7.98 | 48.65 | 9.70 | 0.59 | < 0.001 | < 0.001 |
Abbreviations: d = Cohen’s d indicates the effect size of differences; FDR = False Discovery Rate adjusted p-value; p = p-value from the t-test of the differences.
TABLE 3 |.
Rates of CRCI before and 5 days after the first chemotherapy infusion (N = 528).
| Baseline n (%) | Day 5 n (%) | χ2 | h | p | FDR | |
|---|---|---|---|---|---|---|
| Young adults (n = 85) | ||||||
| Cognitive function | 24 (28%) | 45 (53%) | 14.22 | 0.51 | < 0.001 | < 0.001 |
| Cognitive ability | 29 (34%) | 42 (49%) | 5.83 | 0.49 | 0.016 | 0.016 |
| Middle-aged adults (n = 329) | ||||||
| Cognitive function | 111 (34%) | 167 (51%) | 29.58 | 0.51 | < 0.001 | < 0.001 |
| Cognitive ability | 128 (38%) | 173 (53%) | 26.38 | 0.53 | < 0.001 | < 0.001 |
| Older adults (n = 114) | ||||||
| Cognitive function | 22 (19%) | 42 (37%) | 13.33 | 0.37 | < 0.001 | < 0.001 |
| Cognitive ability | 25 (22%) | 54 (47%) | 21.56 | 0.53 | < 0.001 | < 0.001 |
Note: PROMIS T-score cutoff points of ≤ 45 were used to identify patients experiencing perceived CRCI at each time point.
Abbreviations: CRCI = cancer-related cognitive impairment; FDR = False Discovery Rate adjusted p-value; h = Cohen’s h indicates the effect size for the difference between two proportions; p = p-value calculated using McNemar’s Test.
3.3 |. Risk Factors for Perceived Worsened Cognition
Before fitting multivariate models, we examined univariate residualized change linear regression models to examine the bivariate associations between baseline variables and cognitive performance variables for each age group (Tables 4 and 5). Results of multivariate residualized change linear regression analyses are presented in Tables 6 and 7. Among young adults, no putative baseline risk factors met the criteria for statistical significance with worsened cognitive functioning (p values ≥ 0.05), whereas greater baseline tangible social support (p = 0.022) was associated with worsened cognitive ability. Among middle-aged adults, the White race (p = 0.011) and having a college degree (p = 0.001) were significantly associated with worsened cognitive function; additionally, having a college degree (p = 0.009) and greater baseline sleep disturbance (p = 0.012) were associated with worsened perceived cognitive ability. Regarding the older adult group, greater baseline depressive symptomatology was associated with both worsened perceived cognitive function (p = 0.017) and worsened cognitive ability (p = 0.011).
TABLE 4 |.
Univariate residualized change models of day-5 perceived Cognitive Function by age group.
| Young (n = 85) | Middle-aged (n = 329) | Older (n = 114) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| β (95% CI) | p | FDR | β (95% CI) | p | FDR | β (95% CI) | p | FDR | |
| White versus. non-White | −0.31 (−0.84, 0.22) |
0.244 | 0.882 | −0.33 (−0.57, −0.09) |
0.007 | 0.032 | −0.20 (−0.67, 0.27) |
0.410 | 0.592 |
| Hispanic versus non-Hispanic | 0.05 (−0.58, 0.67) |
0.886 | 0.897 | 0.05 (−0.21, 0.31) |
0.718 | 0.778 | −0.24 (−1.00, 0.52) |
0.530 | 0.689 |
| College graduate versus not | −0.08 (−0.49, 0.34) |
0.713 | 0.897 | −0.27 (−0.45, −0.09) |
0.003 | 0.032 | −0.39 (−0.70, −0.09) |
0.013 | 0.055 |
| Living along versus with others | 0.31 (−0.50, 1.13) |
0.445 | 0.897 | 0.22 (−0.07, 0.52) |
0.139 | 0.302 | −0.05 (−0.46, 0.36) |
0.809 | 0.818 |
| Cancer stage IV versus I-III | 0.50 (−0.40, 1.41) |
0.271 | 0.882 | −0.09 (−0.58, 0.39) |
0.707 | 0.778 | 0.65 (−0.52, 1.83) |
0.273 | 0.443 |
| Overall social support | −0.01 (−0.21, 0.18) |
0.897 | 0.897 | 0.02 (−0.07, 0.11) |
0.696 | 0.778 | 0.16 (0.00, 0.32) |
0.047 | 0.154 |
| Tangible support | −0.08 (−0.27, 0.11) |
0.413 | 0.897 | −0.01 (−0.10, 0.09) |
0.872 | 0.872 | 0.15 (−0.01, 0.31) |
0.061 | 0.159 |
| Emotional/Informational support | 0.03 (−0.17, 0.23) |
0.766 | 0.897 | 0.03 (−0.06, 0.12) |
0.502 | 0.726 | 0.15 (−0.02, 0.31) |
0.075 | 0.163 |
| Fatigue | −0.04 (−0.27, 0.20) |
0.765 | 0.897 | −0.12 (−0.24, −0.01) |
0.041 | 0.127 | −0.14 (−0.33, 0.04) |
0.124 | 0.230 |
| Sleep disturbance | −0.18 (−0.39, 0.02) |
0.076 | 0.493 | −0.14 (−0.24, −0.04) |
0.005 | 0.032 | −0.02 (−0.19, 0.14) |
0.774 | 0.818 |
| Sleep impairment | 0.03 (−0.16, 0.22) |
0.748 | 0.897 | −0.06 (−0.15, 0.04) |
0.232 | 0.377 | 0.02 (−0.14, 0.17) |
0.818 | 0.818 |
| Depression | −0.04 (−0.25, 0.17) |
0.690 | 0.897 | −0.06 (−0.16, 0.04) |
0.209 | 0.377 | −0.32 (−0.47, −0.17) |
< 0.001 | 0.001 |
| Anxiety | −0.18 (−0.38, 0.01) |
0.066 | 0.493 | −0.10 (−0.20, −0.00) |
0.049 | 0.127 | −0.25 (−0.40, −0.10) |
0.001 | 0.009 |
TABLE 5 |.
Univariate residualized change model of day-5 perceived Cognitive Ability by age group.
| Young (n = 85) | Middle-aged (n = 329) | Older (n = 114) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| β (95% CI) | p | FDR | β (95% CI) | p | FDR | β (95% CI) | p | FDR | |
| White versus. non-White | −0.44 (−0.99, 0.11) |
0.112 | 0.244 | −0.27 (−0.50, −0.03) |
0.028 | 0.120 | 0.28 (−0.21, 0.77) |
0.254 | 0.331 |
| Hispanic versus non-Hispanic | 0.23 (−0.42, 0.87) |
0.482 | 0.574 | −0.08 (−0.34, 0.18) |
0.539 | 0.637 | 0.28 (−0.51, 1.07) |
0.478 | 0.518 |
| College graduate versus not | −0.38 (−0.81, 0.04) |
0.077 | 0.244 | −0.22 (−0.40, −0.05) |
0.014 | 0.091 | −0.22 (−0.55, 0.11) |
0.185 | 0.308 |
| Living along versus with others | 0.36 (−0.48, 1.21) |
0.394 | 0.569 | 0.18 (−0.12, 0.47) |
0.238 | 0.516 | −0.27 (−0.69, 0.15) |
0.211 | 0.308 |
| Cancer stage IV versus I-III | −0.42 (−1.36, 0.52) |
0.377 | 0.569 | −0.18 (−0.66, 0.29) |
0.450 | 0.600 | 0.19 (−1.05, 1.42) |
0.767 | 0.767 |
| Overall social support | −0.27 (−0.46, −0.07) |
0.009 | 0.055 | −0.02 (−0.11, 0.07) |
0.682 | 0.739 | 0.15 (−0.01, 0.32) |
0.072 | 0.186 |
| Tangible support | −0.33 (−0.52, −0.14) |
< 0.001 | 0.010 | −0.03 (−0.13, 0.06) |
0.462 | 0.600 | 0.10 (−0.06, 0.27) |
0.213 | 0.308 |
| Emotional/Informational support | −0.20 (−0.40, 0.00) |
0.052 | 0.227 | −0.01 (−0.10, 0.08) |
0.842 | 0.842 | 0.17 (−0.00, 0.34) |
0.053 | 0.172 |
| Fatigue | −0.14 (−0.39, 0.12) |
0.279 | 0.518 | −0.12 (−0.23, −0.00) |
0.044 | 0.142 | −0.21 (−0.39, −0.03) |
0.026 | 0.127 |
| Sleep disturbance | −0.08 (−0.30, 0.15) |
0.486 | 0.574 | −0.16 (−0.26, −0.07) |
0.001 | 0.015 | −0.08 (−0.25, 0.10) |
0.373 | 0.441 |
| Sleep impairment | 0.03 (−0.18, 0.23) |
0.801 | 0.801 | −0.04 (−0.13, 0.05) |
0.387 | 0.600 | −0.12 (−0.28, 0.04) |
0.146 | 0.308 |
| Depression | 0.05 (−0.17, 0.27) |
0.664 | 0.720 | −0.05 (−0.15, 0.05) |
0.312 | 0.579 | −0.30 (−0.46, −0.14) |
< 0.001 | 0.003 |
| Anxiety | −0.17 (−0.38, 0.03) |
0.097 | 0.244 | −0.08 (−0.17, 0.02) |
0.105 | 0.274 | −0.18 (−0.34, −0.02) |
0.029 | 0.127 |
Note: Each univariate residualized change model controls for baseline perceived cognitive ability. For dichotomous predictors (e.g., White vs. non-White), β represents the standardized mean difference in the outcome between the two groups. For continuous predictors, β represents the change in the outcome (in standard deviation units) associated with a one standard deviation increase in the predictor. Values of approximately 0.10, 0.30, and 0.50 correspond to small, medium, and large effects, respectively.
Abbreviations: CI = confidence interval; FDR = False Discovery Rate adjusted p-value; p = p-value; β = standardized regression coefficient.
TABLE 6 |.
Multivariate residualized change model of day-5 perceived Cognitive Function by age group (N = 528).
| Young (n = 85) | Middle-aged (n = 329) | Older (n = 114) | ||||
|---|---|---|---|---|---|---|
| β (95% CI) | p | β (95% CI) | p | β (95% CI) | p | |
| Baseline cognitive function | 0.48 (0.29, 0.67) | < 0.001 | 0.44 (0.32, 0.56) | < 0.001 | 0.48 (0.32, 0.64) | < 0.001 |
| White versus. non-White | — | — | −0.31 (−0.54, −0.07) | 0.011 | — | — |
| College graduate versus not | — | — | −0.29 (−0.47, −0.12) | 0.001 | −0.23 (−0.54, 0.09) | 0.155 |
| Overall social support | — | — | — | — | 0.09 (−0.23, 0.41) | 0.563 |
| Tangible support | — | — | — | — | −0.05 (−0.36, 0.27) | 0.770 |
| Fatigue | — | — | −0.08 (−0.20, 0.04) | 0.165 | — | — |
| Sleep disturbance | — | — | −0.10 (−0.20, 0.01) | 0.068 | — | — |
| Depression | — | — | — | — | −0.23 (−0.41, −0.04) | 0.017 |
| Anxiety | — | — | −0.04 (−0.14, 0.05) | 0.381 | −0.10 (−0.28, 0.07) | 0.258 |
TABLE 7 |.
Multivariate residualized change models of day-5 perceived Cognitive Ability by age group (N = 528).
| Young (n = 85) | Middle-aged (n = 329) | Older (n = 114) | ||||
|---|---|---|---|---|---|---|
| β (95% CI) | p | β (95% CI) | p | β (95% CI) | p | |
| Baseline cognitive ability | 0.41 (0.21, 0.61) | < 0.001 | 0.48 (0.37, 0.59) | < 0.001 | 0.34 (0.16, 0.52) | < 0.001 |
| White versus. non-White | — | — | −0.23 (−0.47, 0.00) | 0.050 | — | — |
| College graduate versus not | — | — | −0.23 (−0.41, −0.06) | 0.009 | — | — |
| Overall social support | 0.20 (−0.24, 0.64) | 0.369 | — | — | −0.22 (−0.71, 0.28) | 0.384 |
| Tangible support | −0.51 (−0.94, −0.07) | 0.022 | — | — | — | — |
| Emotional/Informational support | — | — | — | — | 0.28 (−0.20, 0.77) | 0.252 |
| Fatigue | — | — | −0.07 (−0.18, 0.05) | 0.248 | −0.15 (−0.33, 0.03) | 0.094 |
| Sleep disturbance | — | — | −0.13 (−0.23, −0.03) | 0.012 | — | — |
| Depression | — | — | — | — | −0.25 (−0.44, −0.06) | 0.011 |
| Anxiety | — | — | — | — | −0.03 (−0.21, 0.15) | 0.741 |
Note: For dichotomous predictors (e.g., White vs. non-White), β represents the standardized mean difference in the outcome between the two groups. For continuous predictors, β represents the change in the outcome (in standard deviation units) associated with a one standard deviation increase in the predictor. Values of approximately 0.10, 0.30, and 0.50 correspond to small, medium, and large effects, respectively.
Abbreviations: β = standardized regression coefficient; CI = confidence interval.
4 |. Discussion
This study is one of the first to our knowledge to examine acute change in perceived cognitive performance and CRCI among women with breast cancer from before to shortly after their first chemotherapy infusion across different age groups. Given the increasing numbers of younger (age 40 or below) patients and the fact that age may be a risk factor for CRCI, we stratified analyses by younger (≤ 40 years), middle-aged (41–64 years), and older (≥ 65 years) adults. As hypothesized, women across all three groups reported significantly worsened cognition and increased rates of CRCI from before to after the first infusion. Furthermore, several potential baseline items were associated with perceived worsened cognition, including greater tangible social support among young adults; White race, college education, and worse sleep disturbance among middle-aged adults; and greater depressive symptomatology among older adults.
Despite the fact that older age has been repeatedly identified as a risk factor for objective CRCI, in the current study, older adults reported better perceived cognitive functioning and cognitive ability than middle-aged adults both before and 5 days after the first chemo infusion. Similarly, a larger number of older adults did not perceive CRCI at either time point relative to middle-aged and younger adults. Combined with objective findings from other studies, these data suggest that older patients may have less insight into CRCI or may be more likely to overestimate their cognitive performance than younger patients [32], potentially making them more vulnerable to undetected cognitive impairment. It is also interesting that younger adults reported perceived cognition and rates of CRCI that were broadly similar to those of middle-aged adults. These findings suggest that, at least early in the breast cancer treatment trajectory, younger age is neither protective nor a risk factor for perceived CRCI. Although in our study the onset of CRCI shortly after chemotherapy was not different across the three age groups, further research is needed to determine whether the cumulative impact of multiple chemotherapy infusions affects women differently by age.
Greater tangible social support (e.g., assistance with daily activities, transportation, problem-solving) was associated with perceived worsened cognitive ability after the first chemotherapy infusion in young adult patients. This association may reflect the presence of a larger social network that is more attentive to signs of impaired cognitive performance. The greater tangible social support prior to infusion may also reflect a greater reliance on external support to manage daily responsibilities during treatment. Young adults often face high cognitive demands in academic, professional, and caregiving roles [16], and impaired cognitive performance could negatively impact their productivity, income, and well-being [33]. Moreover, young adults with a robust support system may have higher demands for tangible social support and increased awareness of CRCI symptoms as they balance treatment with ongoing responsibilities.
Among middle-aged patients, worse sleep disturbance was associated with worsened perceived cognition. This finding is consistent with previous research in breast cancer survivors aged ≥ 40 years, wherein worse sleep quality was strongly associated with perceived cognitive decline post-chemotherapy treatment [11]. Proactive management of sleep disturbance early in the trajectory of cancer diagnosis and treatment may help mitigate worsened perceived cognition. In contrast to previous research suggesting that lower educational attainment is a risk factor for both objective and perceived CRCI [34], in our sample, more educated patients were more likely to report worsened cognition, even after controlling for other demographic and clinical variables. This finding may reflect that individuals with higher education levels have greater cognitive demands or expectations regarding their cognitive performance, making subtle declines more noticeable to them. Additionally, highly educated patients may be more attuned to or concerned about cognitive changes, particularly when facing the challenges of cancer diagnosis and treatment.
Consistent with the previous cross-sectional literature focusing on older breast cancer survivors [34], our results indicate that worse depression symptoms at baseline were associated with worse perceived cognitive performance among older adults. Meta-analysis data assessing the global prevalence of depression among women with breast cancer revealed a rate of 32.2% [35]. Among older patients specifically, clinically significant depressive symptoms were reported at a rate of 11.8% post-surgery but prior to initiating systemic therapy [36]. Patients with current depression are more likely to hold negative appraisals of cognitive functioning [37], emphasizing the importance of early detection and management of depressive symptomatology in older breast cancer patients before receiving chemotherapy. A comprehensive geriatric assessment when planning chemotherapy may allow oncologists to proactively intervene to help reduce these adverse effects [38].
Notably, 20%–39% of patients reported CRCI even before their first chemotherapy infusion, aligning with other studies documenting CRCI prior to chemotherapy treatment. Mouse models suggest that the presence of cancer itself may influence cognitive function and potentially contribute to CRCI [39]. Additionally, a significant proportion of patients reported cognitive decline or onset of cognitive impairment as early as 5 days after their first infusion. Cognitive changes in cancer patients may vary based on clinical characteristics, such as individual responses to cancer and treatment, as well as treatment-related toxicity. Further research is needed to explore how cancer- and treatment-related factors impact the onset and severity of CRCI.
4.1 |. Limitations
This study has several limitations that should be considered when interpreting the findings. First, the sample was relatively homogenous, with most participants identifying as White, non-Hispanic, and possessing higher education levels across all three age groups. This may limit generalizability to populations with more diverse racial, ethnic, and socioeconomic backgrounds. Additionally, our method may have excluded predictors with borderline significance, potentially overlooking critical contributors like anxiety and fatigue in middle-aged and older patients, which could meaningfully contribute in a multivariable context [40]. Moreover, the clinical data in our analysis were also limited, with missing information on factors such as surgical status and inflammatory responses, both of which are known to influence cognitive function. Finally, this study focused exclusively on perceived CRCI without assessing objective CRCI. While perceived cognitive decline is often more clinically relevant to patients, the lack of objective measures leaves uncertainty about the extent to which the reported changes reflect neurocognitive impairment.
4.2 |. Clinical Implications
This study underscores the importance of early counseling and support for breast cancer patients, particularly regarding the risk of perceived CRCI after the first chemotherapy infusion. Clinicians should proactively discuss potential cognitive challenges with patients and their families before initiating chemotherapy. Integrating cognitive assessments into routine care may help identify individuals at higher risk for cognitive decline and inform the development of timely and targeted interventions. Tailored resources, such as interventions to improve sleep quality among middle-aged adults and programs to address depression among older patients, may promote cognitive well-being during treatment and enhance overall health outcomes. Moreover, given that young adults may experience heightened distress from the cognitive demands of their life stage, they should receive focused attention. Group support may be particularly beneficial, helping young cancer patients adapt to new realities while sharing tangible management strategies with their peers. Lastly, our analyses of risk factors were exploratory. Future studies should adopt theory-driven, a priori covariate specifications aligned with the causal question.
5 |. Conclusions
Using comprehensive subjective measures of cognitive performance and a longitudinal study design, this study examined the acute effects of the first chemotherapy infusion on perceived cognition and the potential risk factors associated with worsened cognitive performance among three age groups. Findings revealed that women with breast cancer face an increased risk for perceived CRCI following their first chemotherapy infusion, characterized by deficits and challenges in daily cognitive tasks. Notably, the determinants of perceived CRCI vary across age groups. These results emphasize the need for early intervention and targeted supportive care for patients undergoing chemotherapy to address cognitive concerns proactively. Future research should focus on larger, more diverse samples and examine additional clinical variables to better understand the risk factors influencing perceived CRCI. Extended follow-up studies are also critical to understanding the timeline of perceived cognitive change and identifying effective strategies to preserve cognitive function during and after treatment.
Supplementary Material
Supporting Information
Additional supporting information can be found online in the Supporting Information section.
Supporting Information S1: pon70288-sup-0001-suppl-data.docx.
Acknowledgments
This study was supported by a grant from the National Cancer Institute (R01CA219389) to Dr. Jim and the Fulbright scholarship program (Doctoral Dissertation Research Award) to Hui-Ying Yang. Dr. Lee’s time was supported by the National Cancer Institute of the National Institutes of Health under award number K08CA279076. The Participant Research, Interventions, and Measurements Core Facility has also partly supported it at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center (P30-CA076292).
Conflicts of Interest
Heather Jim has been a consultant for SBR Bioscience and received grant funding from Kite Pharma. Martine Extermann received honoraria from OncLive.
Footnotes
Ethics Statement
The current study was performed in concordance with the principles outlined in the Declaration of Helsinki and approved by the Western Institutional Review Board (Identifier: 20180593).
Consent
Informed consent was obtained from all participants before data collection and participants were provided a copy of their informed consent.
Data Availability Statement
To protect the privacy of individuals who participate in this study, individual-level data underlying this article, including protected health information, will not be available in the public repository. Summary-level data may be requested by contacting the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
To protect the privacy of individuals who participate in this study, individual-level data underlying this article, including protected health information, will not be available in the public repository. Summary-level data may be requested by contacting the corresponding author.