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Cognitive function following breast cancer treatment and

associations with concurrent symptoms
Kathleen Van Dyk1,2, Julienne E. Bower2,3, Catherine M. Crespi2,4, Laura Petersen2 and Patricia A. Ganz 2,5,6

Cognitive changes after breast cancer treatment are often attributed to chemotherapy, without considering other important factors
such as other treatments (e.g., surgery, radiation, endocrine therapy (ET)). We compared neuropsychological functioning in the
domains of learning, memory, attention, visuospatial, executive function, and processing speed according to primary breast cancer
treatment exposures in early survivorship, before the initiation of ET (n = 189). We were also interested in the association of
neuropsychological functioning with select clinical, psychological, and behavioral factors. Compared to those who only underwent
surgery (n = 28), all neuropsychological domain scores were comparable in a sample of breast cancer survivors with different
treatment exposures, i.e., radiation therapy (n = 64), chemotherapy (n = 20), or both (n = 77), p’s < 0.05, adjusted for age, IQ,
depression, and time since treatment completion. Physical fatigue, pain, and sleep correlated with several cognitive domains
regardless of treatment exposure. There are minimal treatment-related neuropsychological differences on neuropsychological
measures in early breast cancer survivorship, but the influence of other co-occurring symptoms warrants attention.
npj Breast Cancer (2018)4:25 ; doi:10.1038/s41523-018-0076-4

INTRODUCTION Depression Inventory, 2nd edition (BDI-II) did not correlate with
Cognitive dysfunction following breast cancer treatment is an any domain, and was included as an additional control. In
important survivorship concern.1 Studies predominantly focus on additional exploratory analyses (data not presented) we examined
chemotherapy treatment as the primary risk, although other linear regression models of domains that included treatment
treatments such as endocrine therapy (ET) and co-occurring group and interactions between treatment group and each
factors likely also play a role.2 The mind body study (MBS) was a clinical/psychosocial factor, none of which emerged as signifi-
prospective, longitudinal, cohort study of early-stage breast cancer cantly related to cognitive domains.
survivors (BCS) designed to assess the impact of ET on
neurocognitive function; baseline analyses of this sample allows
us to examine the effects of primary cancer treatments without
the confound of concomitant ET. In prior baseline analyses, we DISCUSSION
found that higher subjective cognitive complaints were linked to Neuropsychological performance did not significantly vary based
combined chemotherapy and radiation therapy exposure.3 The on primary breast cancer treatment exposure in this early
current baseline study extends those findings by comparing survivorship period. Strengths of our study are assessment prior
neuropsychological functioning across treatment exposures; we to ET exposure and the surgery-only comparison group. The
further explored relationships with modifiable clinical, psycholo- current null findings are in contrast with our prior report of
gical, and behavioral factors. subjective cognition.3 Such inconsistency is not uncommon in
survivorship studies, which compellingly portray the cognitive
effects of cancer and its treatment by self-report, raising the
RESULTS possibility that neuropsychological methods may not be the most
Table 1 displays sample characteristics and cognitive outcomes by sensitive to these subtle effects.4
treatment exposure. We found comparable rates of impairment Neurocognitive function did correlate with physical fatigue,
across treatment groups, and also failed to find any differences on sleep quality, and pain, regardless of treatment. Fatigue is a known
neuropsychological domain scores between No Adjuvant and any correlate of self-reported cognition in BCS, but pain and sleep
adjuvant treatment group; effect sizes were small to negligible disturbance are surprisingly understudied risks despite their
(see Supplementary Information for model details). Select clinical prevalence in survivorship and known risk in other popula-
and psychosocial factors were correlated with several domains, tions.5–7 Coefficients are small but portray a consistent pattern.
notably the Pittsburgh Sleep Quality Index (PSQI), the Multi- Cognitive function is complex and multi-determined; it is
dimensional Fatigue Symptom Inventory–Short Form (MFSI) important to exhaust all risks and opportunities for improvement,
Physical, and the Breast Cancer Prevention Trial Symptom reflected in existing recommendations for multi-modal
Checklist (BCPT) Musculoskeletal Pain, see Table 2. Beck approaches to intervention.8

1
UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA; 2UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA; 3Departments of
Psychology and Psychiatry/Biobehavioral Sciences, University of California-Los Angeles, Los Angeles, CA, USA; 4Department of Biostatistics, UCLA Fielding School of Public Health,
Los Angeles, CA, USA; 5UCLA David Geffen School of Medicine, Los Angeles, CA, USA and 6UCLA Fielding School of Public Health, Los Angeles, CA, USA
Correspondence: Patricia A. Ganz ([email protected])

Received: 1 May 2018 Revised: 11 July 2018 Accepted: 13 July 2018

Published in partnership with the Breast Cancer Research Foundation

 Cognitive function following breast cancer treatment and
K Van Dyk et al.
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Table 1. Sample characteristics and cognitive performance by treatment group
Treatment groups

Whole sample (A) No Adjuvant (B) Rad Only (C) Chemo Only (D) Chemo + Rad (n = 77) p across groups
(n = 189) (n = 28) (n = 64) (n = 20)

Age mean (SD) 51.35 (8.34) 51.57 (6.08) 53.88 (7.95) 46.95 (8.06) 50.31 (8.88) 0.001
Education, n (%)
Less than college 34 (18%) 2 (7%) 14 (22%) 3 (15%) 15 (19%) 0.55
College degree 56 (30%) 8 (29%) 16 (25%) 8 (40%) 24 (31%)
More than college 99 (52%) 18 (64%) 34 (53%) 9 (45%) 38 (49%)
Marital status, n (%) married 124 (66%) 11 (39%) 24 (38%) 6 (30%) 24 (31%) 0.78
Race, n (%) White 151 (80%) 23 (82%) 53 (83%) 16 (80%) 59 (77%) 0.82
Annual income, n (%; n = 186)
>$100,000 112 (60%) 18 (64%) 40 (65%) 11 (55%) 43 (57%) 0.72
<$100,000 74 (40%) 10 (36%) 22 (35%) 9 (45%) 33 (43%)
Employment status, n (%) employed FT or PT 122 (66%) 20 (71%) 44 (69%) 10 (50%) 48 (63%) 0.38
Post-menopausal, n (%) 100 (53%) 15 (54%) 40 (62%) 5 (25%) 40 (52%) 0.03
Surgery
Lumpectomy 125 4 63 0 58 < 0.01
Mastectomy 64 24 1 20 19
Months since treatment completion, mean (SD) 1.197 (1.038) 2.48 (0.731) 0.960 (0.951) 1.282 (0.92) 0.908 (0.879) <0.01
Anthracycline treatment, n (%) 24 (25%) NA NA 3 (15%) 21 (27%) 0.385
Stage at diagnosis, n (% of group)
0 25 (13%) 14 (50%) 11 (17%) 0 (0%) 0 (0%) <0.01
1 87 (46%) 13 (46%) 44 (69%) 7 (35%) 23 (30%)
1234567890():,;

2 59 (31%) 1 (4%) 9 (14%) 12 (60%) 37 (48%)

3 18 (10%) 0 (0%) 0 (0%) 1 (5%) 17 (22%)
Endocrine therapy planned, n (%; n = 181) 129 (71%) 13 (48%) 50 (81%) 15 (75%) 51 (71%) 0.03
PSQI, mean (SD) (n = 186) 8.28 (3.46) 7.61 (3.79) 6.59 (3.36) 8.35 (4.03) 8.26 (3.31) 0.034
BDI-II, mean (SD) 8.85 (6.87) 7.36 (6.92) 6.86 (6.76) 12.75 (8.48) 10.04 (5.85) <0.01
State anxiety inventory, mean (SD) 35.51 (8.75) 35.14 (8.24) 35.11 (9.38) 37.42 (9.95) 35.48 (8.16) 0.77
IQ WTAR, mean (SD) (n = 188) 114.28 (9.09) 116.61 (8.18) 114.37 (8.77) 111.10 (9.33) 114.18 (9.50) 0.23
MFSI total, mean (SD) 11.46 (19.34) 6.43 (19.02) 6.71 (19.12) 18.20 (20.16) 15.48 (18.32) <0.01
MFSI mental, mean (SD) 5.51 (4.66) 3.61 (3.45) 4.11 (4.10) 7.30 (5.09) 6.91 (4.81) <0.01
MFSI physical, mean (SD) 4.15 (4.29) 4.43 (4.83) 2.75 (3.54) 6.35 (3.50) 4.64 (4.52) <0.01
BCPT scale, musculoskeletal pain mean (SD) 1.26 (0.95) 1.25 (0.88) 0.96 (0.75) 1.32 (0.75) 1.50 (1.10) <0.01
# of impaired neuropsychological measures (z < −1.5) 1.40 (1.73) 1.46 (1.71) 1.17 (1.60) 1.15 (1.59) 1.64 (1.86) 0.39
# of impaired neuropsychological measures (z < −2) 0.075 (1.31) 0.64 (1.10) 0.66 (1.18) 0.65 (1.04) 0.88 (1.55) 0.71
Impaired by ICCTF guidelines n (% group) 89 (47%) 13 (46%) 27 (42%) 9 (45%) 40 (52%) 0.71
Neuropsychological domains Standardized coefficients
(95% CI) for A vs. B, A vs. C,
and A vs. Da
Learning, mean (SD)b 0.39 (0.70) 0.47 (0.80) 0.43 (0.75) 0.38 (0.64) 0.32 (0.65) 0.03, 0.04, −0.02
Memory, mean (SD)b 0.21 (0.62) 0.19 (0.68) 0.29 (0.63) 0.16 (0.65) 0.17 (0.58) 0.07, 0.06, 0.14
Attention, mean (SD)b 0.46 (0.65) 0.66 (0.61) 0.49 (0.62) 0.31 (0.42) 0.40 (0.73) −0.03, −0.08, −0.10
Visuospatial, mean (SD)b −0.35 (0.74) −0.24 (0.69) −0.28 (0.77) −0.54 (0.79) −0.40 (0.72) −0.06, −0.08, −0.11
Executive function, mean (SD)b 0.23 (0.76) 0.42 (0.86) 0.28 (0.73) 0.06 (0.64) 0.16 (0.76) −.07, −0.09, −0.15
Processing speed, mean (SD)b −0.06 (0.67) 0.08 (0.55) −0.01 (0.71) −0.12 (0.65) −0.15 (0.68) 0.11, −0.05, 0.02

BDI-II Beck Depression Inventory, 2nd edition, MFSI Multidimensional Fatigue Symptom Inventory, BCPT Breast Cancer Prevention Trial Symptom Checklist, PSQI
Pittsburgh Sleep Quality Index, ICCTF International Cognition and Cancer Task Force13
a
Coefficients in linear models adjusted for age, IQ, BDI-II, and time since treatment completion; all p’s > 0.1
b
Unadjusted scores

Study limitations include the predominantly white and highly health in BCS. Our future work will extend this baseline report to
educated sample aged 65 or younger. Additional work should characterize the cognitive effects of ET and other risks over time.
examine the roles of socioeconomic factors, education, age, and
comorbidity. The smaller sizes of the Chemo Only and No
Adjuvant groups likely reduced power and we did not control for METHODS
multiple comparisons, but effect sizes were nonetheless mostly As previously described, three recruitment took place from
negligible. Importantly, we did not have pre-treatment assess- 2007–2011 through clinical oncology practices and rapid case
ments, which would permit more precise inferences about ascertainment using the Los Angeles County Surveillance,
treatment-related differences. Epidemiology, and End Results Program registry with collaborat-
To conclude, we failed to find differences on neuropsycholo- ing physicians and hospitals. This is a report of baseline data only;
gical test performance based on primary breast cancer treatment. participants were age 21–65 years, had a recent early-stage breast
The commonly reported symptoms of physical fatigue, pain, and cancer diagnosis, had completed primary treatment within the last
sleep disturbance are promising targets for supporting cognitive 3 months but did not yet start ET. We excluded women with active

npj Breast Cancer (2018) 25 Published in partnership with the Breast Cancer Research Foundation
 Cognitive function following breast cancer treatment and
K Van Dyk et al.
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Table 2. Correlations between cognitive domains and other symptoms

MFSI total MFSI physical MFSI mental PSQI global BCPT musculoskeletal pain

Learning
Correlation 0.02 −0.08 −0.07 −0.18 −0.15
p 0.84 0.28 0.36 0.02 0.04
df 180 180 180 177 180
Memory
Correlation −0.01 −0.14 −0.04 −0.22 −0.16
p 0.92 0.06 0.59 <0.01 0.04
df 179 179 179 177 179
Attention
Correlation −0.13 −0.25 −0.09 −0.29 −0.13
p 0.09 <0.01 0.24 <0.01 0.08
df 179 179 179 177 179
Visuospatial
Correlation 0.09 −0.08 0.04 −0.15 −0.12
p 0.24 0.30 0.64 0.05 0.11
df 179 179 179 177 179
Executive function
Correlation −0.15 −0.25 −0.12 −0.17 −0.21
p 0.04 <0.01 0.10 0.02 <0.01
df 181 181 181 178 181
Processing speed
Correlation −0.10 −0.20 −0.08 −0.14 −0.08
p 0.16 <0.01 0.30 0.06 0.29
df 181 181 181 178 181
Controls: Age, IQ, Time since TX, BDI-II
BDI-II Beck Depression Inventory, 2nd edition, MFSI Multidimensional Fatigue Symptom Inventory, BCPT Breast Cancer Prevention Trial Symptom Checklist, PSQI
Pittsburgh Sleep Quality Index. Bold values indicate p< .05

psychotic or major depressive disorders, or any history of Data availability

treatments or conditions with known effects on cognition or On reasonable request, the data analyzed in this study are
inflammation. The UCLA institutional review board approved the available from the corresponding author in accordance with
study and all participants provided written informed consent. institutional policies.
We obtained demographic and clinical information from
medical records and self-report questionnaires. The following
measures were used: BCPT,9 PSQI,10 MFSI,11 and BDI-II.12 We ACKNOWLEDGEMENTS
administered a neuropsychological battery composed of standar- We would also like to thank Steven Castellon, PhD, for his role in developing and
collecting neuropsychological assessments. This research was supported by funding
dized clinical neuropsychological tests (see Supplementary
from the National Cancer Institute R01CA109650, P30 CA16042, the Breast Cancer
Information); z-scores based on published normative data were Research Foundation (to PAG), and the AmericanCancer Society (to KVD).
averaged into domain scores.
All participants received surgery; those with no adjuvant
treatment (No Adjuvant) were considered the no-treatment AUTHOR CONTRIBUTIONS
comparison group, and the rest were grouped by specific adjuvant K.V.D. conducted the data analysis, interpretation, and drafted the manuscript. J.B.
therapy—those who received only chemotherapy (Chemo Only), contributed to the overall study design, data collection, interpretation and
only radiation therapy (Rad Only), or both chemotherapy and manuscript text. C.C. guided the statistical approach, interpretation of findings, and
manuscript text. L.P. contributed to the data management and processing,
radiation (Chemo + Rad). We compared demographic, clinical, and
interpretation of findings and manuscript text. P.G. is the PI and guarantor—she
impairment variables13 using two-sided analysis of variance contributed to the overall design of the study, the data collection, statistical
(ANOVA) and chi-square tests. Multivariable linear regression approach, interpretation of findings, and manuscript text. This research was
models of neuropsychological domain scores controlled for age, supported by funding from the National Cancer Institute R01 CA109650, P30
intelligence quotient (IQ), time since treatment completion, and CA16042, the Breast Cancer Research Foundation (to P.A.G.), and the American
BDI-II, with treatment group dummy coded making No Adjuvant Cancer Society (to K.V.D.).

the reference group. We obtained partial correlations between

cognitive domain scores and clinical and behavioral measures ADDITIONAL INFORMATION
controlling for age, IQ, time since treatment completion and BDI-II. Supplementary information accompanies the paper on the npj Breast Cancer
We used SPSS software (IBM SPSS Statistics for Windows, V.24.0. website (https://doi.org/10.1038/s41523-018-0076-4).
Armonk, NY: IBM Corp) and set statistical significance at p < 0.05.

Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2018) 25
 Cognitive function following breast cancer treatment and
K Van Dyk et al.
4
Competing interests: Dr. Ganz discloses that she is a member of the Scientific 9. Stanton, A. L., Bernaards, C. A. & Ganz, P. A. The BCPT Symptom Scales: A measure
Advisory Board of the Breast Cancer Research Foundation. The other authors declare of physical symptoms for women diagnosed with or at risk for breast cancer. JNCI
no competing interests. J. Natl Cancer Inst. 97, 448–456 (2005).
10. Buysse, D. J., Reynolds, C. F., Monk, T. H., Berman, S. R. & Kupfer, D. J. The
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and
in published maps and institutional affiliations. research. Psychiatry Res. 28, 193–213 (1989).
11. Stein, K. D., Martin, S. C., Hann, D. M. & Jacobsen, P. B. A multidimensional
measure of fatigue for use with cancer patients. Cancer Pr. 6, 143–152 (1998).
12. Beck, A. T., Steer, R. A. & Brown, G. K. Beck Depression Inventory-II. (Psychological
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