Breast Cancer
Conditions
Keywords
Alteration, Cognitive Function, Exercise
Brief summary
This randomized control trial will examine whether a well-controlled and monitored exercise intervention improves cognitive function in postmenopausal women with early-stage breast cancer and will explore whether neuroimaging metrics of brain health, pro-inflammatory biomarkers and symptoms (fatigue, sleep problems, depression, anxiety) mediate the effects of exercise on cognitive function. Furthermore, the study will explore whether the magnitude of the improvements in cognitive function are modified by estradiol levels.
Detailed description
The specific aims include: 1. Compared to usual care, examine whether the 6-month exercise intervention improves cognitive function in postmenopausal women with early stage breast cancer. Hypothesis 1. Exercise will improve cognitive function in women in a domain specific fashion such that attention, executive and memory functions will be influenced more than other domains. 2. Compared to usual care, examine the direct effects of exercise on neuroimaging metrics of brain health including regional gray matter volume, white matter architecture and functional dynamics of the brain and the pro-inflammatory biomarkers (IL-6 as primary outcomes; TNF-α as secondary), and explore the direct effects of exercise on symptoms (fatigue, sleep problems, depression, anxiety). Hypothesis 2. Exercise will improve neuroimaging metrics of brain health and pro-inflammatory biomarkers. 3. Compared to usual care, explore whether the effects of exercise on cognitive function are mediated by a) neuroimaging metrics of cognitive function, b) IL-6 and TNF-α levels and c) symptoms (fatigue, sleep problems, depression, anxiety), and moderated by E2 levels.
Interventions
The intervention is moderate-intensity aerobic exercise. Walking on a motorized treadmill will be the encouraged mode of exercise; however participants may use other equipment or home exercise. Participants will begin by exercising 10-15 minutes for 3 days/week during the first 2 weeks and gradually increase the duration for the following 4 weeks until they reach 40-50 minutes per session/3 days per week. This level is then maintained for the remainder of the 6 months. The rate of increase will be tailored based on baseline cardiorespiratory fitness and response to exercise. All sessions start and end with a vital sign check (in-person) and 5-10 minutes warm-up/cool-down. Trained exercise physiologists will supervise all exercise sessions and closely monitor adherence, intensity, and safety when sessions are completed in-person, or through regular communication when home-based exercise is warranted (due to COVID-19).
Sponsors
National Institutes of Health (NIH)
National Cancer Institute (NCI)
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Postmenopausal female 2. Maximum age 80 years 3. Able to speak and read English 4. Minimum completion of 8 years of education 5. Diagnosed with Stage 0, 1, 2 or 3a Breast Cancer 6. Within 2 years post-completion of primary treatment 7. At least two weeks post-breast conserving surgery or three weeks post-breast conserving surgery with sentinel lymph node biopsy or four weeks post-mastectomy
Exclusion criteria
1\. Prior treatment with cancer chemotherapy, central nervous system radiation, or intrathecal therapy 2. Clinical evidence of distant metastases 3. Self-report of hospitalization for psychiatric illness within the last two years 4. History of neurologic illness 5. Any of the following breast cancer surgery complications unless approved by the participant's health care provider: persistent seroma requiring aspiration, wound dehiscence, infection, prolonged drain output, lymphedema 6. Reconstructive surgery unless approved by the participant's health care provider 7. Any significant medical condition that would preclude them from exercising (e.g., uncontrolled diabetes, congestive heart failure, angina, uncontrolled arrhythmia or other symptoms that indicate increased risk for an acute cardiovascular or respiratory event) If necessary, we will verify this information with a participant's health care provider 8. Eating disorders or a history of substance abuse 10. Any use of an assisted walking device 11. Recent history of falls or balance problems Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cognitive Function | Baseline to 6 months | Cognitive function was assessed with a battery of 14 measures. A data reduction technique, exploratory factor analysis with principal component extraction and varimax (orthogonal) rotation, was used to create summary factors. The cognitive factors identified included processing speed, attention, mental flexibility, working memory, learning and memory, verbal memory, and executive function were derived via this factor analysis. Individual measures with the highest loadings were included in each factor. All measures had factor loadings \>0.400. Scores from the individual measures for each factor were normed based on healthy controls of similar age and education to yield a z-score and these were summed to yield an average z-score for each factor. Z-scores range from -4 to +4, where higher z-scores indicate better performance for each factor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak VO2 | Baseline and 6 months | Fitness will be measured by submaximal VO2 test. The submaximal test is similar to the full test, but stops at 85% of the age-predicted heart rate. The protocol involves walking at a self-selected pace between 2.0-4.0 mph with increasing grade increments of 2% every two minutes. The test is terminated when the subject reaches 85% of their age-predicted heart rate or at volitional exhaustion. Higher levels (ml/kg/minute) indicate better peak VO2. |
| Fatigue | Baseline and 6 months | The Fatigue 8a Patient Reported Outcomes Measurement Information System (PROMIS) short form was used to measure fatigue. It consists of 8 items on which participants respond using a 5-point Likert scale. The scores range from 0 to 24 with higher scores indicating greater fatigue. |
| Anxiety | Baseline to 6 months | The eight-item Anxiety 8a PROMIS short form was used to measure anxiety. Participants rate each item on a scale from 1 to 5. The score is the total of the responses with higher scores indicating greater anxiety. The range of scores is 5 to 40. |
| Sleep Problems | Baseline to 6 months | Sleep problems were measured using global score of the Pittsburgh Sleep Quality Index (PSQI). The PSQI is a self-report measure that consists of 19 items. Each item is weighted on a 0-3 interval scale. The PSQI global score ranges from 0 to 21, where lower scores indicate better sleep quality, and higher scores indicate poorer sleep quality. |
| Depressive Symptoms | Baseline to 6 months | Depressive symptoms will be measured using the Beck Depression Inventory II (BDI II). The 21-item BDI II is a self-report measure on which participants rate depressive symptoms on a four-point scale. The BDI II score ranges from 0 to 63 with higher scores indicating greater depressive symptomatology. |
| Total Brain Size | Baseline and 6 months | High-resolution anatomical MPRAGE (1mm3 voxels, 256 slices) images will be used for volumetric analyses. The FreeSurfer pipeline using its longitudinal option will be employed to compute cortical volumes. |
| Pro-inflammatory Cytokines | Baseline to 6 months | Cytokine levels for interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were determined using high-sensitivity, quantitative sandwich enzyme immunoassay run according to manufacturer's directions. Greater pgs/ML indicate higher levels of both IL-6 and TNF-aplha. |
| Estradiol (E2) Levels | Baseline to 6 months | E2 was determined by a competitive binding immunoassay, according to manufacturer's directions. Greater pgs/ML indicate higher levels of estradiol. |
Other
| Measure | Time frame |
|---|---|
| Changes in Task-evoked Functional MRI Outcomes | Baseline and 6 months |
| Changes in Resting State Network | Baseline and 6 months |
| Change in White Matter Microstructure | Baseline and 6 months |
| Changes in Prefrontal Cortex | Baseline and 6 months |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Moderate-intensity Aerobic Exercise Participants engage in a supervised 6-month moderate-intensity aerobic exercise intervention.
Moderate-Intensity Aerobic Exercise Intervention: The intervention is moderate-intensity aerobic exercise. Walking on a motorized treadmill will be the encouraged mode of exercise; however participants may use other equipment or home exercise. Participants will begin by exercising 10-15 minutes for 3 days/week during the first 2 weeks and gradually increase the duration for the following 4 weeks until they reach 40-50 minutes per session/3 days per week. This level is then maintained for the remainder of the 6 months. The rate of increase will be tailored based on baseline cardiorespiratory fitness and response to exercise. All sessions start and end with a vital sign check (in-person) and 5-10 minutes warm-up/cool-down. Trained exercise physiologists will supervise all exercise sessions and closely monitor adherence, intensity, and safety when sessions are completed in-person, or through regular communication when home-based exercise is warranted (due to COVID-19). | 77 |
| Usual Care Physical activity neither limited nor withheld. Participants engage in activity in the same manner as if they were not part of an active intervention. | 76 |
| Total | 153 |
Baseline characteristics
| Characteristic | Moderate-intensity Aerobic Exercise | Usual Care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 32 Participants | 33 Participants | 65 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 43 Participants | 88 Participants |
| Age, Continuous | 61.44 years STANDARD_DEVIATION 8.96 | 62.75 years STANDARD_DEVIATION 7.25 | 62.09 years STANDARD_DEVIATION 8.27 |
| BMI, Customized | 30.46 kg/m^2 STANDARD_DEVIATION 7.21 | 31.14 kg/m^2 STANDARD_DEVIATION 6.01 | 30.8 kg/m^2 STANDARD_DEVIATION 6.7 |
| Disease Stage: DCIS, I, IIa, IIb, IIIa DCIS | 13 Participants | 8 Participants | 21 Participants |
| Disease Stage: DCIS, I, IIa, IIb, IIIa Stage 1 | 44 Participants | 54 Participants | 98 Participants |
| Disease Stage: DCIS, I, IIa, IIb, IIIa Stage 2a | 11 Participants | 10 Participants | 21 Participants |
| Disease Stage: DCIS, I, IIa, IIb, IIIa Stage 2b | 6 Participants | 1 Participants | 7 Participants |
| Disease Stage: DCIS, I, IIa, IIb, IIIa Stage 3a | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 68 Participants | 69 Participants | 137 Participants |
| Region of Enrollment United States | 77 participants | 76 participants | 153 participants |
| Sex: Female, Male Female | 77 Participants | 76 Participants | 153 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 77 | 0 / 76 |
| other Total, other adverse events | 0 / 77 | 0 / 76 |
| serious Total, serious adverse events | 0 / 77 | 0 / 76 |
Outcome results
Primary
Change in Cognitive Function
Cognitive function was assessed with a battery of 14 measures. A data reduction technique, exploratory factor analysis with principal component extraction and varimax (orthogonal) rotation, was used to create summary factors. The cognitive factors identified included processing speed, attention, mental flexibility, working memory, learning and memory, verbal memory, and executive function were derived via this factor analysis. Individual measures with the highest loadings were included in each factor. All measures had factor loadings \>0.400. Scores from the individual measures for each factor were normed based on healthy controls of similar age and education to yield a z-score and these were summed to yield an average z-score for each factor. Z-scores range from -4 to +4, where higher z-scores indicate better performance for each factor.
Time frame: Baseline to 6 months
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Moderate-intensity Aerobic Exercise | Change in Cognitive Function | Mental Flexibility | -0.05 z-score | Standard Error 0.03 |
| Moderate-intensity Aerobic Exercise | Change in Cognitive Function | Learning and Memory | 0.13 z-score | Standard Error 0.06 |
| Moderate-intensity Aerobic Exercise | Change in Cognitive Function | Attention | 0.21 z-score | Standard Error 0.04 |
| Moderate-intensity Aerobic Exercise | Change in Cognitive Function | Verbal Memory | -0.17 z-score | Standard Error 0.09 |
| Moderate-intensity Aerobic Exercise | Change in Cognitive Function | Working Memory | 0.28 z-score | Standard Error 0.11 |
| Moderate-intensity Aerobic Exercise | Change in Cognitive Function | Executive Function | -0.02 z-score | Standard Error 0.03 |
| Moderate-intensity Aerobic Exercise | Change in Cognitive Function | Processing Speed | -0.05 z-score | Standard Error 0.02 |
| Usual Care | Change in Cognitive Function | Executive Function | -0.02 z-score | Standard Error 0.02 |
| Usual Care | Change in Cognitive Function | Processing Speed | 0.01 z-score | Standard Error 0.02 |
| Usual Care | Change in Cognitive Function | Attention | 0.17 z-score | Standard Error 0.04 |
| Usual Care | Change in Cognitive Function | Mental Flexibility | -0.07 z-score | Standard Error 0.03 |
| Usual Care | Change in Cognitive Function | Working Memory | 0.13 z-score | Standard Error 0.12 |
| Usual Care | Change in Cognitive Function | Learning and Memory | 0.05 z-score | Standard Error 0.06 |
| Usual Care | Change in Cognitive Function | Verbal Memory | -0.18 z-score | Standard Error 0.09 |
Secondary
Anxiety
The eight-item Anxiety 8a PROMIS short form was used to measure anxiety. Participants rate each item on a scale from 1 to 5. The score is the total of the responses with higher scores indicating greater anxiety. The range of scores is 5 to 40.
Time frame: Baseline to 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Moderate-intensity Aerobic Exercise | Anxiety | 1.85 units on a scale | Standard Error 0.36 |
| Usual Care | Anxiety | 1.55 units on a scale | Standard Error 0.28 |
Secondary
Depressive Symptoms
Depressive symptoms will be measured using the Beck Depression Inventory II (BDI II). The 21-item BDI II is a self-report measure on which participants rate depressive symptoms on a four-point scale. The BDI II score ranges from 0 to 63 with higher scores indicating greater depressive symptomatology.
Time frame: Baseline to 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Moderate-intensity Aerobic Exercise | Depressive Symptoms | 5.51 units on a scale | Standard Error 0.71 |
| Usual Care | Depressive Symptoms | 5.27 units on a scale | Standard Error 0.61 |
Secondary
Estradiol (E2) Levels
E2 was determined by a competitive binding immunoassay, according to manufacturer's directions. Greater pgs/ML indicate higher levels of estradiol.
Time frame: Baseline to 6 months
Population: The number of participants analyzed for estradiol is smaller than what is reported in the participant flow module because the impact of COVID precluded securing blood samples for estradiol for a time.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate-intensity Aerobic Exercise | Estradiol (E2) Levels | 0.48 pg/ML | Standard Error 0.07 |
| Usual Care | Estradiol (E2) Levels | 0.67 pg/ML | Standard Error 0.12 |
Secondary
Fatigue
The Fatigue 8a Patient Reported Outcomes Measurement Information System (PROMIS) short form was used to measure fatigue. It consists of 8 items on which participants respond using a 5-point Likert scale. The scores range from 0 to 24 with higher scores indicating greater fatigue.
Time frame: Baseline and 6 months
Population: The sample size for the analysis of the fatigue data is smaller than the total numbers in the Participant Flow module because the impact of COVID precluded securing fatigue measurement for a time.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moderate-intensity Aerobic Exercise | Fatigue | Baseline | 18.60 score on a scale | Standard Deviation 0.82 |
| Moderate-intensity Aerobic Exercise | Fatigue | 6 months | 17.81 score on a scale | Standard Deviation 0.92 |
| Usual Care | Fatigue | Baseline | 18.90 score on a scale | Standard Deviation 0.86 |
| Usual Care | Fatigue | 6 months | 16.83 score on a scale | Standard Deviation 0.97 |
Secondary
Peak VO2
Fitness will be measured by submaximal VO2 test. The submaximal test is similar to the full test, but stops at 85% of the age-predicted heart rate. The protocol involves walking at a self-selected pace between 2.0-4.0 mph with increasing grade increments of 2% every two minutes. The test is terminated when the subject reaches 85% of their age-predicted heart rate or at volitional exhaustion. Higher levels (ml/kg/minute) indicate better peak VO2.
Time frame: Baseline and 6 months
Population: The number of participants analyzed for peak VO2 is smaller than what is reported in the participant flow module because the impact of COVID precluded securing VO2 for a time.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moderate-intensity Aerobic Exercise | Peak VO2 | Baseline | 17.31 ml/kg/minute | Standard Error 0.42 |
| Moderate-intensity Aerobic Exercise | Peak VO2 | 6 months | 18.44 ml/kg/minute | Standard Error 0.38 |
| Usual Care | Peak VO2 | Baseline | 17.72 ml/kg/minute | Standard Error 0.48 |
| Usual Care | Peak VO2 | 6 months | 19.74 ml/kg/minute | Standard Error 3.88 |
Secondary
Pro-inflammatory Cytokines
Cytokine levels for interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were determined using high-sensitivity, quantitative sandwich enzyme immunoassay run according to manufacturer's directions. Greater pgs/ML indicate higher levels of both IL-6 and TNF-aplha.
Time frame: Baseline to 6 months
Population: The number of participants analyzed for the pro-inflammatory cytokines, IL-5 and TNF-alpha is smaller than what is reported in the participant flow module because the impact of COVID precluded securing the blood samples for IL-6 and TNF-alpha for a time.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moderate-intensity Aerobic Exercise | Pro-inflammatory Cytokines | IL-6 | 0.47 pg/ML | Standard Error 0.07 |
| Moderate-intensity Aerobic Exercise | Pro-inflammatory Cytokines | TNF-a | 0.07 pg/ML | Standard Error 0.01 |
| Usual Care | Pro-inflammatory Cytokines | IL-6 | 0.45 pg/ML | Standard Error 0.07 |
| Usual Care | Pro-inflammatory Cytokines | TNF-a | 0.09 pg/ML | Standard Error 0.01 |
Secondary
Sleep Problems
Sleep problems were measured using global score of the Pittsburgh Sleep Quality Index (PSQI). The PSQI is a self-report measure that consists of 19 items. Each item is weighted on a 0-3 interval scale. The PSQI global score ranges from 0 to 21, where lower scores indicate better sleep quality, and higher scores indicate poorer sleep quality.
Time frame: Baseline to 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Moderate-intensity Aerobic Exercise | Sleep Problems | 12.21 units on a scale | Standard Error 1.57 |
| Usual Care | Sleep Problems | 13.36 units on a scale | Standard Error 1.62 |
Secondary
Total Brain Size
High-resolution anatomical MPRAGE (1mm3 voxels, 256 slices) images will be used for volumetric analyses. The FreeSurfer pipeline using its longitudinal option will be employed to compute cortical volumes.
Time frame: Baseline and 6 months
Population: The sample size for the total brain size analysis is smaller than the total number of participants because, imaging was planned on a subset of the overall sample, the impact of COVID precluded imaging for a time, the MRI machine was switched during the study, so it would have required some participants to use one imaging machine and another set with a second machine. Thus, the parameters of the sequences and the image quality would have been different between machines, and budget cuts.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Moderate-intensity Aerobic Exercise | Total Brain Size | Baseline | 1026742.118 mm-cubed | Standard Deviation 75232.467 |
| Moderate-intensity Aerobic Exercise | Total Brain Size | 6 Months | 1033171.625 mm-cubed | Standard Deviation 69084.048 |
| Usual Care | Total Brain Size | Baseline | 1044057.647 mm-cubed | Standard Deviation 102747.151 |
| Usual Care | Total Brain Size | 6 Months | 1058477.167 mm-cubed | Standard Deviation 103402.622 |
Other Pre-specified
Change in White Matter Microstructure
Time frame: Baseline and 6 months
Other Pre-specified
Changes in Prefrontal Cortex
Time frame: Baseline and 6 months
Other Pre-specified
Changes in Resting State Network
Time frame: Baseline and 6 months
Other Pre-specified
Changes in Task-evoked Functional MRI Outcomes
Time frame: Baseline and 6 months