Abstract
Objective:
Hormones have been implicated as modulators of cognitive functioning. For instance, results of our previous work in women with breast cancer showed that cognitive impairment was more severe and involved more memory domains in those who received adjuvant tamoxifen therapy compared with women who received chemotherapy alone or no adjuvant therapy. Recently aromatase inhibitors such as anastrozole have been used in lieu of tamoxifen for the adjuvant treatment of postmenopausal women with hormone receptor–positive, early-stage breast cancer. Plasma estrogen levels are significantly lower in women who receive anastrozole compared with those who receive tamoxifen. We hypothesized, therefore, that anastrozole would have a more profound effect on cognitive function than tamoxifen, a mixed estrogen agonist/antagonist.
Design:
To test this hypothesis we compared cognitive function in women with early-stage breast cancer who received tamoxifen with those who received anastrozole therapy in a cross-sectional study. We evaluated cognitive function, depression, anxiety, and fatigue in 31 postmenopausal women with early-stage breast cancer who were between the ages of 21 and 65 years and treated with tamoxifen or anastrozole for a minimum of 3 months.
Results:
The results showed that women who received anastrozole had poorer verbal and visual learning and memory than women who received tamoxifen.
Conclusions:
Additional, prospective studies are needed to validate and confirm the changes in cognitive function associated with hormone therapy for breast cancer.
Keywords: Memory, Cognitive function, Anastrozole, Tamoxifen, Breast cancer, Chemotherapy
Adjuvant therapy regimens for breast cancer that modify hormone action have significantly improved the cure rate for women with early-stage disease, but their use is associated with several negative sequelae, including cognitive impairment.1,2 Results of our work suggest that cognitive impairment is more severe and affects more memory domains in women who receive tamoxifen as part of their therapy regimen compared with women with breast cancer who receive chemotherapy alone or no adjuvant therapy.3 Tamoxifen is a mixed estrogen agonist/antagonist that alters hormone action by binding to estrogen receptors and blocking endogenous estrogen action. The impact of this partial blocking may contribute to cognitive impairment. Agents such as the aromatase inhibitor anastrozole are replacing tamoxifen for the treatment of postmenopausal women with hormone receptor–positive, early-stage breast cancer.4-6 Plasma estrogen levels are significantly lower in women with early-stage disease who receive anastrozole compared with those who receive tamoxifen.7 Because estrogen action has been implicated as a modulator of cognitive function,8 we hypothesized that anastrozole may have a more profound effect on cognitive function than tamoxifen. To test this hypothesis we conducted a pilot study to compare cognitive function in women with early-stage breast cancer who receive tamoxifen with cognitive function in those who receive anastrozole.
METHODS
This study was approved by the University of Pittsburgh Institutional Review Board. We used a cross-sectional design and evaluated cognitive function, depression, anxiety, and fatigue after participants had been treated with tamoxifen (20 mg/d) or anastrozole (1 mg/d) for a minimum of 3 months. The convenience sample consisted of postmenopausal women (amenorrhea persisting for an entire year; oophorectomy; or hysterectomy and age greater than 51 years), between the ages of 21 and 65 years, who had early-stage breast cancer. Women who had clinical evidence of metastasis, a previous cancer diagnosis, history of neurologic disease, or self-reported hospitalization for psychiatric illness within the past 2 years were excluded.
Cognitive function was assessed with a battery of reliable, validated measures that have been described in detail elsewhere.9 We evaluated attention with the Digit Vigilance Test,10 the Trail Making Test A,11 and the Digit Span Forward and Backward12; learning and memory with the Rey Auditory Verbal Learning Test (RAVLT),13 the Rey Osterrieth Complex Figure Recall (ROCF),14 the Rivermead Behavioral Memory Test (RBMT) Story Recall,15 and the Four Word Short Term Memory Test16; psychomotor speed with the Grooved Pegboard Test10 and the Digit Symbol Substitution Test12; mental flexibility with the Trail Making Test B11; visuospatial ability with the Rey Osterrieth Complex Figure Copy14; and estimated general intelligence with the National Adult Reading Test–Revised.17 Depression was assessed with the Beck Depression Inventory II,18 anxiety with the Profile of Mood States (POMS) Tension/Anxiety scale, and fatigue with the POMS fatigue/inertia scale.19 The study battery was administered and scored by one nurse trained by a neuropsychologist.
Analysis
Initially measures of central tendency (mean, median) and dispersion (SD, range) were computed for continuous variables, and frequency counts and percentages were computed for categorical variables. t tests were computed to explore differences between groups on cognitive function measures. Hierarchical linear regression was later performed to compare cognitive function between groups, controlling for age, years of education, time on hormone therapy, depression, anxiety, and fatigue in the first block and the cancer treatment variables anastrozole use (yes/no) and chemotherapy use (yes/no) in the second block. Change in R2 was computed to assess improvement in the model with respect to explained variability in the cognitive function end points of interest with the addition of anastrozole and chemotherapy use. The percentage of unique variance explained by a particular cancer treatment was estimated and residual analysis was conducted to identify sources of model misspecification, outliers, and possible influential observations.
RESULTS
Thirty-one women with early-stage breast cancer participated in this study; 15 (48%) were receiving anastrozole and 16 (52%) were receiving tamoxifen. χ2 tests showed no differences between study groups in means for marital status, number of children, number of years of education, or breast cancer stage. The mean age of the overall sample was 52.68 y; the SD was 6.69. Women receiving anastrozole (mean age, 57.4 y) were significantly older (P < 0.01) than the women receiving tamoxifen (mean age, 48.2 y). Conversely, women in the tamoxifen group had been receiving that hormonal agent for a significantly longer period of time (P = 0.05; mean, 23.8 mo) than women in the anastrozole group (mean, 14.3 mo). There were no group differences in the number of women who had received chemotherapy before hormone therapy.
There were no differences in Beck Depression Inventory II scores between groups. Mean (SD) Beck Depression Inventory II scores were 6.20 (3.36) for the tamoxifen group and 6.88 (4.95) for the anastrozole group. Similarly, women were not anxious or fatigued (POMS tension/anxiety and fatigue/inertia scales, respectively), and there were no differences between groups on these measures. The mean scores and standard deviations on the POMS tension/anxiety scale were 5.64 (1.46) for the tamoxifen group and 3.53 (1.45) for the anastrozole group. The mean scores and standard deviations on the POMS fatigue/inertia scale were 7.38 (6.53) for the tamoxifen group and 6.53 (2.92) for the anastrozole group.
Women receiving anastrozole had significantly poorer performances on learning and memory measures than women receiving tamoxifen (Table 1).10-12,17,20 Significant differences in scores were not found between groups on measures of any of the remaining cognitive domains. After controlling for covariates, women receiving anastrozole had significantly more visual and verbal learning and memory impairments than women receiving tamoxifen (Table 2). Scores on most learning and memory measures consistently were significantly poorer in women receiving anastrozole than women receiving tamoxifen, and these differences ranged from an average of −3.5 (P < 0.01) to 10.9 (P < 0.001). The performance of women receiving anastrozole on the RAVLT, a measure of verbal learning and memory, was significantly worse than that of women receiving tamoxifen in both the total score (P < 0.001) and delayed recall condition (P = 0.008). The R2 change for the addition of chemotherapy and anastrozole to the model was 0.4 for the total RAVLT score and 0.3 for the delayed recall condition. The percentage of unique variance explained by anastrozole was 35% for the total RAVLT score and 29% for the delayed recall condition.
TABLE 1.
Differences in scores on cognitive function measures between women who received anastrozole (n = 15) and women who received tamoxifen (n = 16)
| Cognitive domain/measure | Anastrozole, mean (SD) | Tamoxifen, mean (SD) | t (df = 29) | P |
|---|---|---|---|---|
| Attention | ||||
| Digit Span (Forward) | 8.6 (1.8) | 9.2 (2.4) | −0.77 | 0.45 |
| Digit Span (Backward) | 7.7 (2.3) | 8.4 (2.7) | −0.78 | 0.44 |
| Trail Making Test–A | 29.7 (8.8) | 34.2 (27.0) | −0.62 | 0.54 |
| Digit Vigilance Test | 322.4 (45.7) | 341.5 (74.8) | −0.85 | 0.40 |
| Learning and memory | ||||
| RAVLT (total) | 54.9 (6.9) | 60.1 (3.61) | −2.66 | 0.01 |
| RAVLT (delayed recall) | 11.3 (2.5) | 12.8 (1.29) | −2.10 | 0.04 |
| RBMT (immediate recall) | 7.0 (2.8) | 10.0 (3.8) | −2.45 | 0.02 |
| ROCF (immediate recall) | 13.1 (4.9) | 6.36 (1.6) | −3.73 | 0.001 |
| ROCF (delayed recall) | 12.9 (4.8) | 6.04 (1.5) | −3.36 | 0.002 |
| Psychomotor efficiency | ||||
| Grooved Pegboard (dominant) | 77.5 (25.3) | 72.8 (14.0) | 0.65 | 0.52 |
| Grooved Pegboard (nondominant) | 83.3 (29.6) | 84.6 (28.3) | −0.12 | 0.90 |
| Mental flexibility | ||||
| Trail Making Test–B | 71.1 (14.1) | 72.1 (27.4) | −0.12 | 0.91 |
| Visuospatial ability | ||||
| Rey Complex Figure Test (Copy) | 32.3 (3.9) | 32.6 (2.8) | −0.21 | 0.83 |
| General intelligence | ||||
| National Adult Reading Test–Revised | 113.9 (5.5) | 113.0 (6.7) | 0.38 | 0.70 |
RAVLT, Rey Auditory Verbal Learning Test; RBMT, Rivermead Behavioral Memory Test; ROCF, Rey Osterrieth Complex Figure.
TABLE 2.
Significant results of the hierarchical linear regression for learning and memory measures related to anastrozole and chemotherapy use, controlling for identified covariates (age, education, time on therapy, depression, fatigue, and anxiety)
| RAVLT (Total) | RAVLT (Delayed Recall) |
RBMT Story (Immediate Recall) |
ROCF (Immediate Recall) |
ROCF (Delayed Recall) |
|
|---|---|---|---|---|---|
| Predictors | |||||
| Age | 0.6a,e (0.2)b | 0.2d (0.1) | 0.2 (0.1) | 0.3 (0.2) | 0.2 (0.2) |
| Education | 0.7 (0.4) | 0.4d (0.2) | 0.6d (0.3) | 0.9 (0.5) | 0.8 (0.5) |
| Time on therapy | −0.0 (0.1) | −0.2 (0.0) | 0.0 (0.0) | −0.0 (0.1) | −0.1 (0.1) |
| BDI-II | −0.3 (0.3) | −0.1 (0.1) | −0.2 (0.2) | 0.2 (0.4) | 0.3 (0.4) |
| POMS fatigue | 0.4 (0.2) | 0.1 (0.1) | 0.1 (0.1) | −0.1 (0.3) | −0.1 (0.3) |
| POMS anxiety | −0.7e (0.2) | −0.1 (0.1) | −0.1 (0.1) | 0.0 (0.2) | 0.0 (0.2) |
| Anastrozole | −10.9f (2.4) | −3.5e (1.0) | −3.9d (1.8) | −9.8e (3.2) | −8.4d (3.0) |
| Chemotherapy | −0.5 (1.8) | 0.4 (0.8) | −1.5 (1.4) | 3.6 (2.5) | 3.7 (2.3) |
| R2 change | |||||
| Variable block 1c | 0.23 | 0.15 | 0.23 | 0.26 | 0.27 |
| Variable block 2d | 0.40 | 0.30 | 0.20 | 0.23 | 0.20 |
| Total R2 | 0.63 | 0.45 | 0.43 | 0.49 | 0.47 |
| % Explained unique variance | |||||
| Anastrozole | 35.0 | 29.0 | 12.2 | 21.7 | 18.6 |
| Chemotherapy | 0.1 | 0.6 | 3.0 | 4.9 | 6.0 |
RAVLT, Rey Auditory Verbal Learning Test; ROCF, Rey Osterrieth Complex Figure; RBMT, Rivermead Behavioral Memory Test; BDI-II, Beck Depression Inventory II; POMS, Profile of Mood States.
Unstandardized regression coefficients.
SEs of the coefficients.
Variable block 1 includes age, education, time on therapy, depression, fatigue and anxiety.
Variable block 2 includes age, education, time on therapy, depression, fatigue and anxiety, chemotherapy and anastrozole.
0.01 ≤ P > 0.05.
0.001 ≤ P > 0.01.
P > 0.001.
The performance of women receiving anastrozole was also significantly poorer (P = 0.03) than that of women receiving tamoxifen on the immediate recall of the RBMT story recall 15, another measure of verbal learning and memory. Similarly, women receiving anastrozole performed marginally significantly more poorly (P = 0.069) than women receiving tamoxifen on the delayed recall of the RBMT story recall. The R2 change for the addition of chemotherapy and anastrozole to the model was 0.2 for the RBMT story immediate recall. The percentage of unique variance explained by anastrozole was 12.2%.
Finally, the performance of women receiving anastrozole on the ROCF,14 a measure of visual memory, was significantly poorer than that of women receiving tamoxifen in both the immediate (P = 0.006) and delayed (P = 0.011) recall conditions. The R2 change for the addition of chemotherapy and anastrozole to the model was 0.2 for both the immediate and delayed recall of the ROCF. The percentage of unique variance explained by anastrozole was 21.7% for the immediate recall and 18.6% for the delayed recall of the ROCF.
DISCUSSION
We found that women with breast cancer who received anastrozole therapy experienced poorer verbal and visual learning and memory than women with breast cancer who received tamoxifen. These findings may be related to the changes in estrogen levels experienced by women receiving this therapy. The effects of abrupt and complete loss of estrogen on the brain may be analogous to the effects of the abrupt loss of estrogen at the time of menopause, particularly surgical menopause, which seems to be associated with an increase in Alzheimer's disease and other neurodegenerative diseases such as Parkinson's disease.21
Jenkins et al2 found evidence of impairments in verbal memory and psychomotor speed in women with breast cancer receiving anastrozole as compared with healthy women. They did not detect impairment in visual memory as measured by the Faces Recognition Test 12, but our measure of visual memory (ROCF) may have been more challenging.14 Conversely, we did not detect impairment in psychomotor speed. This may be explained by the fact that women in the study by Jenkins et al had been receiving anastrozole for a longer duration (mean, 36 mo) than women in our study (mean, 14.3 mo).
We cannot exclude age as a variable contributing to the poorer cognitive performance in the women receiving anastrozole. Advancing age22,23 has been associated with cognitive impairment in patients with cancer. Conversely, women who received tamoxifen had a significantly longer treatment duration, and this too has been associated with cognitive impairment in patients with cancer.24 We controlled for age and therapy duration as well as years of education, depression, anxiety, and fatigue in our analysis, and the women who received anastrozole still had poorer cognitive functioning than those who received tamoxifen. Future studies should control for these variables to make our results more directly comparable.
The results of this study must be interpreted with caution because of the small sample size and use of a cross-sectional design. However, significant effects were detected. Because we lacked pretreatment evaluations, we cannot be sure that our results represent a change from pretreatment performance. Longitudinal designs that incorporate pretreatment evaluations will permit assessment of change in cognitive function over time and ultimately whether cognitive function returns to pretreatment levels after therapy.
CONCLUSION
It is important to clearly define the cognitive impairments associated with this and other cancer therapies. Cognitive impairments have significant implications for the quality of life of patients with cancer. They can affect occupational achievement, psychological well-being, and patients' adherence to medical regimens. Additional prospective studies are needed that include pretreatment evaluations to validate and confirm the changes in cognitive function associated with hormone therapy for breast cancer and lead to the development and testing of interventions to help women compensate for the cognitive changes they experience with this therapy.
Acknowledgments
Funding/support: Original work supported by the Center for Research in Chronic Disorders Pilot Feasibility Funding.
Footnotes
Financial disclosure: None reported.
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