The exercise intervention significantly improved processing speed, but only among those who had been diagnosed with breast cancer within the past 2 years. Slowed processing speed can have substantial implications for independent functioning, supporting the potential importance of early implementation of an exercise intervention among patients with breast cancer. Cancer 2018;124:192‐202 . © 2017 American Cancer Society .

On average, participants (n = 87) were aged 57 years (standard deviation, 10.4 years) and were 2.5 years (standard deviation, 1.3 years) post surgery. Scores on the Oral Symbol Digit subscale (a measure of processing speed) evidenced differential improvement in the exercise arm versus the control arm (b = 2.01; P < .05). The between‐group differences in improvement on self‐reported cognition were not statistically significant but were suggestive of potential group differences. Time since surgery moderated the correlation, and participants who were ≤2 years post surgery had a significantly greater improvement in Oral Symbol Digit score (exercise vs control (b = 4.00; P < .01), but no significant improvement was observed in patients who were >2 years postsurgery (b = −1.19; P = .40). A significant dose response was observed with greater increased physical activity associated with objective and self‐reported cognition in the exercise arm.

Sedentary breast cancer survivors were randomized to an exercise arm (n = 43) or a control arm (n = 44). At baseline and at 12 weeks, objective cognition was measured with the National Institutes of Health Cognitive Toolbox, and self‐reported cognition using the Patient‐Reported Outcomes Measurement Information System scales. Linear mixed‐effects regression models tested intervention effects for changes in cognition scores.

Increasing physical activity can improve cognition in healthy and cognitively impaired adults; however, the benefits for cancer survivors are unknown. The current study examined a 12‐week physical activity intervention, compared with a control condition, on objective and self‐reported cognition among breast cancer survivors.

INTRODUCTION Problems with cognition are common among breast cancer survivors, with estimates suggesting that up to 75% of patients experience deficits that can last for years after the end of cancer treatments.1-3 Research suggests that cancer‐related cognitive impairments are not solely because of chemotherapy or other treatments2, 4, 5 but may result from common risk factors for the development of both cancer and age‐related cognitive decline.3, 6 In addition, such impairment may be a symptom of accelerated aging caused by cancer treatments and associated psychological stress.2, 7, 8 Although the prevalence of cognitive deficits in breast cancer survivors is well documented, few evidence‐based interventions exist to prevent or ameliorate this decline.9 One intervention that potentially could improve cognition is increasing physical activity. The Institute of Medicine's report on cognitive aging recommends physical activity to reduce age‐related cognitive decline.10 Many physical activity interventions have been effective in improving cognition among both healthy and cognitively impaired populations.11-14 The general physical activity recommendation for breast cancer survivors is to engage in 150 minutes per week of moderate‐to‐vigorous physical activity (MVPA).15 However, National Health and Nutrition Examination Survey data indicate that breast cancer survivors spend only approximately 25 minutes per week in MVPA.16 Studies of the impact of physical activity on cancer‐related cognitive impairments have great potential to improve the lives among the growing number of cancer survivors.17 Few intervention studies have examined the effects of physical activity on cognition in a cancer population. A recent review of the literature18 indicated that there have been only 2 trials that tested the impact of aerobic physical activity interventions on cancer‐related cognitive impairments.19, 20 Focusing on aerobic physical activity is important, because it is consistent with guidelines for brain health.21, 22 These 2 studies yielded mixed findings: a 6‐week trial in 479 breast cancer survivors reported improvements in self‐reported cognition,20 but a 12‐week trial in 41 breast cancer survivors reported no improvements in self‐reported cognition.19 It is noteworthy that neither study used objective measures of cognition. We identified only 1 trial in cancer survivors that used objective cognitive measures. This recent study in 19 breast cancer survivors enrolled in a 24‐week physical activity randomized controlled trial indicated that the exercise arm had greater improvements in a measure of processing speed compared with the control group.23 Several cross‐sectional studies in cancer survivors using objective measures of cognition have indicated that greater physical activity is associated with several domains of cognition, including information processing speed,24 memory,25 executive functioning,26 and attention.26 These studies lend support to the hypothesis that increasing physical activity may be an effective intervention for improving cognition in breast cancer survivors. To our knowledge, the current study is one of the first completed randomized controlled trials among cancer survivors testing the impact of increasing physical activity on both objective measures (ie, neurocognitive testing) and self‐reported measures (ie, cognitive abilities and concerns). Because neurocognitive outcomes and self‐reported cognition reflect different aspects of cognition, assessing both provides a fuller picture of how physical activity can impact cancer survivors’ quality of life. The objective of this study was to examine the effects of a 12‐week physical activity intervention, compared with a contact control condition, on objective and self‐reported measures of cognition among breast cancer survivors. We hypothesized that the physical activity intervention would result in greater improvements in neurocognitive tests and self‐reported cognition compared with a waitlist wellness‐contact control. We also explored potential effect modifiers as well as dose‐response associations between changes in physical activity and cognition.

MATERIALS AND METHODS The Memory and Motion study was a randomized controlled trial of a 12‐week physical activity intervention compared with a waitlist wellness‐contact control to test changes in objective neurocognitive tests and self‐reported cognition among breast cancer survivors. Data were collected from February 2015 through July 2016 and were analyzed from July to November 2016. The University of California‐San Diego Institutional Review Board approved all study procedures, and all participants provided written informed consent. This trial is registered with clinicaltrials.gov as National Clinical Trial NCT02332876. Eligible participants were female breast cancer survivors, ages 21 to 85 years, who were diagnosed less than 5 years before study enrollment and had completed chemotherapy or radiation treatment. Other inclusion criteria were: 1) sedentary, defined as self‐reporting < 60 minutes of MVPA in 10‐minute bouts per week; 2) able to travel to La Jolla, California, for study visits; 3) access to the internet; and 4) self‐reported that they were experiencing “fogginess” or worsening of their memory, thinking, or concentration. Exclusion criteria were: 1) a medical condition that could make it potentially unsafe to be in an unsupervised physical activity intervention, as determined by the Physical Activity Readiness Questionnaire27; 2) other primary or recurrent invasive cancer within the last 10 years; and 3) unable to commit to a 3‐month intervention. Protocol A detailed description of the protocol was previously published.28 Briefly, participants were predominantly recruited using cancer registry lists. Potential participants were telephone‐screened to determine eligibility. Interested and eligible women were scheduled for an in‐person visit. At the baseline visit, participants provided signed informed consent, a fasting blood draw was collected, height and weight were measured, and participants completed a battery of neurocognitive tests and questionnaires assessing self‐reported cognition, as described below. At the end of this visit, all participants were given an ActiGraph GT3X+ accelerometer (ActiGraph, Pensacola, FL) to wear for 7 days and then return at the randomization visit. All baseline measures were repeated at the 12‐week visit. Participants were randomly assigned to 1 of 2 groups—an exercise arm or a control arm—in a 1:1 ratio. Randomization was stratified according to whether or not the women had received chemotherapy using a permuted block‐randomization scheme with random‐sized blocks of 6 or 8. A computerized randomization scheme was created by the Moores Cancer Center Biostatistics Shared Resource. The sample size was determined based on 80% statistical power for between‐group effect sizes of 0.32 (Cohen f). After randomization, participants in both groups reviewed the expectations and requirements of their group assignment with study staff. Physical activity intervention (exercise arm) Participants randomized to the exercise arm had a 30‐minute to 45‐minute in‐person meeting at which they went on a 10‐minute walk at moderate intensity and set physical activity goals. To promote behavior change and accountability, participants were provided a Fitbit One activity device (Fitbit, San Francisco, CA) as an intervention tool. Participants were informed that study staff would be able to see the physical activity data collected by the Fitbit and that they would receive feedback on the Fitbit data. Motivational interviewing techniques were used to set a starting goal with a specific plan for meeting that goal. Participants discussed how to gradually increase their aerobic exercise over time and meet the study goal of at least 150 minutes of MVPA per week.15 Participants received 2 telephone calls (at the 2‐week and 6‐week time points) and emails every 3 days throughout the 12‐week intervention. The intervention was delivered by a clinical psychologist with extensive training and experience in promoting behavior change (S.J.H.) and by a staff member (E.M.) who was trained by S.J.H. For further details on the intervention, see Hartman et al.28 Waitlist wellness‐contact control condition (control arm) Participants randomized to the control arm received emails on the same schedule as those in the exercise arm. Emails addressed various women's health topics, including healthy eating, stress reduction, and general brain health. After the completion of measures at the final visit, participants in the control arm were provided with the exercise intervention described above. Measures The primary outcome, objective neurocognitive functioning, was measured using The National Institutes of Health (NIH) Toolbox Cognition Domain (nihtoolbox.org) at baseline and at the 12‐week time point. The NIH Toolbox is a series of computer‐based tests that can be administered in approximately 45 minutes and has been validated and normed in individuals ages 3 to 85 years. The testing uses multiple forms and computer‐adaptive testing to minimize practice effects. It also has minimal floor and ceiling effects. The tests provide age‐standardized scores for a Fluid Cognition Composite score and a Crystallized Cognition Composite score.29 In addition, we examined 7 individual test scores of the Fluid Composite Score. Five of the 7 tests have age‐standardized scores, and the other 2 only provide raw scores (Oral Symbol Digit and Auditory Verbal Learning).30 The second primary outcome, self‐reported cognition, was measured with 2 scales from the Patient‐Reported Outcomes Measurement Information System (PROMIS): Applied Cognition Abilities (Abilities) and General Concerns (Concerns). The cognitive Abilities and Concerns measures assess patient‐perceived functional abilities and problems in the past 7 days with regard to cognitive tasks in specific areas (eg, concentration, memory). Higher scores on the Abilities measure indicate more positive perceptions of cognition, and higher scores on the Concerns measure represent worse perceptions of cognition. Both self‐report measures are standardized T‐scores that have demonstrated good reliability and validity with previous measures including the Functional Assessment of Cancer Therapy‐Cognitive Function measure.31 The GT3X+ ActiGraph, a research‐grade accelerometer that is considered the gold‐standard for measuring free‐living physical activity, was used to measure changes in physical activity from baseline to 12 weeks. Participants in both study arms wore the ActiGraph on the hip for 7 days before the randomization visit and for 7 days before the final visit. The ActiGraph provides second‐by‐second estimates of activity that can be categorized into minutes spent in sedentary, light, moderate, and vigorous activity using calibration thresholds.32 Sufficient wear time across the 7 days was defined as having 5 days with ≥ 600 minutes each of wear time or 3000 minutes (50 hours) of total wear time across 4 days. Body mass index (BMI) was calculated from height and weight collected at the baseline and final visits. Participants self‐reported demographics, including age, education, income, race/ethnicity, and marital status at baseline. All breast cancer information and treatment details were obtained from medical chart reviews. To estimate time since diagnosis, we used the date of surgery, because the exact date of diagnosis was not consistently available from the medical charts. Statistical Analysis All analyses were performed using an intent‐to‐treat principal, with missing data assumed missing at random and accounted for in the longitudinal random‐effects models by using a likelihood‐based estimation method, which uses all available data and does not omit individuals with partially missing data. Group differences in baseline characteristics were assessed using t tests, chi‐square tests, or 2‐tailed Fisher exact tests (when warranted by small cell counts) for categorical variables. Differences in baseline physical activity were assessed using a mixed‐effects regression model of day‐level activity, controlling for ActiGraph wear time, and included fixed‐effect terms for group. Logistic regression was used to assess group differences in the percentage of participants who met the study goal (150 minutes per week of MVPA) at 12 weeks. Mixed‐effects regression models with a subject‐level random intercept and an unstructured covariance structure, as determined by model Akaike Information Criterion comparisons in the main‐effects models, were used for all other models. Contrasts were used to calculate the difference of change based on the regression model when examining group difference. Because the Crystalized Cognition Composite Score was not expected to change with the intervention, it was assessed as an outcome in all cognition models to confirm expected patterns.29, 33 Models to assess the effects of the intervention on change in physical activity—measured at the day level—and changes in cognition scores controlled for ActiGraph wear time and included fixed‐effect terms for group, time‐point (baseline or 12 weeks), and time‐by‐group interactions. In the case of the Oral Symbol Digit and Auditory Verbal Learning scores, participant age was also controlled for, because these scores are not age‐adjusted. Potential effect modifiers of the intervention (age, chemotherapy, current receipt of tamoxifen or aromatase inhibitor, and time since surgery) were tested for the Fluid and Crystalized Cognition Composite Scores, any significant individual neurocognitive test scores, and self‐reported cognitive abilities and concerns from the main‐effects models. Effect modification was examined by adding the potential effect modifier and a 3‐way interaction (time, group, and effect modifier) to the mixed‐effect regression models. The significance of this interaction term was set at the .1 level, as is common practice with interactions. For significant effect modifiers, subgroup analyses stratifying the sample at the median for the effect modifier were conducted. Dose response was examined within the exercise arm using mixed‐effects regression models of average physical activity per week (MVPA or total activity) on cognition scores, controlling for ActiGraph wear time.

RESULTS In total, 911 women were screened for eligibility; of those, 108 were eligible, and 97 came to the baseline visit. The most common reasons for ineligibility included being too active (n = 225), being unable/unwilling to attend clinic visits (n = 106), underwent breast cancer surgery >5 years ago (n = 81), and medical exclusion (n = 36). At the baseline visit, 10 women were deemed ineligible (high blood pressure, n = 8; physical limitation, n = 2). Eighty‐seven participants were randomized to the exercise arm (n = 43) or the control arm (n = 44). One participant from each arm was lost to follow‐up, resulting in a 97.7% retention rate (exercise arm, n = 42; control arm, n = 43) (for a Consolidated Standards of Reporting Trials [CONSORT] diagram of the current study, see Fig. 1). Figure 1 Open in figure viewer PowerPoint Consolidated Standards of Reporting Trials (CONSORT) flow diagram. Baseline characteristics of the study participants, stratified by randomization arm, are provided in Table 1. Overall, the average age ( ± standard deviation [SD]) of women in the study was 57 ± 10.4 years; they were predominantly white (82%), non‐Hispanic (83%), and had a college education or greater (71%). Participants were an average of 30 ± 16.7 months postsurgery, 61% had stage I breast cancer, 53% had received chemotherapy, and 70% were currently receiving an aromatase inhibitor or tamoxifen. The mean ± SD, age‐adjusted, standardized composite scores were 115 ± 14.4 points for Crystalized Cognition and 103 ± 14.7 points for Fluid Cognition. The average scores (±SD) were 45.4 ± 5.7 for Cognitive Abilities and 43.3 ± 6.9) for Cognitive Concerns. At baseline, Cognitive Concerns were significantly lower in the exercise arm with mean ± SD scores of 41.8 ± 5.5 versus 44.9 ± 7.9 in the wellness control arm (P = .04). At baseline, participants were engaging in an average of 14 ± 14.4 minutes per day of MVPA and an average of 303 ± 75.2 minutes (approximately 5 hours) per day of total activity (light and MVPA), and they wore the ActiGraph on average 842 ± 103 minutes per day. There were no significant differences between the exercise and control arms in baseline characteristics (P < .05). Table 1. Baseline Characteristics by Study Arm, n = 87 Characteristic Mean ± SD or No. (%) Demographics Exercise Intervention, n = 43 Wellness Control, n = 44 P Age, y 58.2 ± 11.37 56.2 ± 9.30 .354 Education .689 ≤Some college 14 (32.7) 11 (25) College graduate 18 (41.9) 22 (50) ≥Master's degree 11 (25.6) 11 (25) Married/living with partner 32 (76.2) 31 (70.5) .679 Ethnicity .74 Not Hispanic/Latino 35 (81.4) 37 (84.1) Hispanic/Latino 8 (18.6) 7 (15.9) Race .62 White 36 (83.7) 35 (79.5) Non‐white 7 (16.3) 10 (22.8) BMI, kg/m2 26.7 ± 6.20 27.3 ± 6.40 .628 Breast cancer characteristics Time since surgery, mo 30.3 ± 17.41 30.0 ± 16.08 .997 Cancer stage .786 I 27 (62.8) 26 (59.1) II 12 (27.9) 15 (34.1) III 4 (9.3) 3 (6.8) Received chemotherapy 23 (53.5) 23 (52.3) .91 Current aromatase inhibitor/tamoxifen 31 (72.1) 30 (68.2) .691 Neurocognitive testing scoresa : Crystallized Composite 117.3 ± 12.68 113.8 ± 15.95 .272 Fluid Composite 102.3 ± 14.18 103.5 ± 15.36 .712 Dimensional Card Sort 105.3 ± 10.18 103.9 ± 10.16 .52 Flanker Inhibitory 96.3 ± 8.53 96.6 ± 9.37 .867 List Sorting 106.8 ± 11.95 107.0 ± 13.74 .935 Pattern Comparison 106.3 ± 18.01 106.6 ± 17.74 .259 Picture Sequence 116.2 ± 13.97 112.3 ± 15.24 .924 Oral Symbol Digitb 73.7 ± 14.55 77.7 ± 13.23 .185 Auditory Verbal Learningb 24.5 ± 5.50 24.6 ± 5.17 .961 Self‐reported cognitionc Cognitive abilities 46.6 ± 5.96 44.3 ± 5.27 .0619 Cognitive concerns 41.8 ± 5.45 44.9 ± 7.89 .0356 Participants in the exercise arm had greater increases in accelerometer‐measured MVPA (mean increase: 14.2 vs −0.7 minutes per day; b = 7.24; P < .0001) and total activity (mean increase: 27.4 vs 4.9 minutes per day; b = 10.05; P = .02) than participants in the control arm. The exercise arm also had greater increases in the number of participants who met the study goal of 150 minutes per week of MVPA compared with the control arm (P = .006). BMI did not change significantly over time (b = 0.01; P = .84) (see Table 2). Table 2. Changes and Differences in ActiGraph‐Measured Physical Activity and Body Mass Index at Baseline and at 12 Weeks by Study Arm Intervention Arm Control Arm Difference in Change Between Groups Variable Baseline 12 Weeks Change Pa Baseline 12 Weeks Change Pa Estimate 95% CI Pb Total MVPA: Mean ± SD, min/d 13.4 ± 12.97 27.9 ± 15.13 14.2 ± 13.98 < .0001 15.4 ± 15.67 14.9 ± 15.12 −0.7 ± 9.74 .464 7.24 5.33‐9.15 < .0001 Total activity, Light + MVPA: Mean ± SD, min/d 290.5 ± 73.26 320.4 ± 56.76 27.4 ± 71.90 < .0001 315.8 ± 75.83 320.9 ± 75.38 4.9 ± 52.30 .393 10.05 1.84‐18.26 .017 Meeting 150 min/wk: No. (%)c 8 (18.6) 25 (59.5) — < .0001 10 (22.7) 9 (20.9) — .706 — — .0003 BMI: Mean ± SD, kg/m2 26.7 ± 6.20 26.8 ± 6.21 0.1 ± 0.56 .929 27.3 ± 6.40 27.5 ± 6.61 0.1 ± 0.60 .895 0.01 −0.11, 0.14 .837 Changes in objective and self‐reported cognition scores from baseline to 12 weeks between the exercise and control arms are presented in Figure 2. Participants in the exercise arm had significantly greater improvements in the Oral Symbol Digit score, a measure of processing speed, compared with those in the control arm (b = 2.01; 95% confidence interval [CI], 0.01‐4.01; P = .049). On all other neurocognitive measures (except List Sorting, a measure of working memory), scores increased significantly from baseline to 12 weeks, but there were no significant between‐group differences. For self‐reported cognition, there was no statistically significant difference between the arms for Cognitive Abilities (b = 0.92; 95% CI, −0.14, 1.98; P = .087) or Cognitive Concerns (b = −1.38; 95% CI, −3.13, 0.37; P = .120). Figure 2 Open in figure viewer PowerPoint Changes from baseline to 12 weeks are illustrated in neurocognitive age‐adjusted scale scores and self‐reported cognition by randomization group (n = 87). CI indicates confidence interval. Age, chemotherapy, current receipt of tamoxifen or aromatase inhibitors, and time since surgery were tested as potential effect modifiers of the relation between intervention and change in the Crystalized and Fluid Composite Scores, and the Oral Symbol Digit score, and self‐reported Cognitive Abilities and Cognitive Concerns. Time since surgery was a significant effect modifier for change in the Oral Symbol Digit score (P = .079). When we stratified the sample at the median time since surgery (2 years), participants who were ≤2 years from surgery had a significant intervention effect on change in the Oral Symbol Digit score (b = 4.01; 95% CI, 1.40‐6.63; P = .0033); in contrast, there was no intervention effect in participants who were >2 years from surgery (see Fig. 3). No modification effect was observed for age, chemotherapy, or hormone therapy. Figure 3 Open in figure viewer PowerPoint Changes from baseline to 12 weeks are illustrated in Oral Symbol Digit scores by the median split of time since diagnosis, per randomization group (n = 87). Within the exercise arm, a dose response was observed for physical activity, such that a greater increase in MVPA was positively associated with a greater improvement in the Oral Symbol Digit score (b = 0.20; P = .016), self‐reported Cognitive Abilities (b = 0.99; P < .0001), and self‐reported Cognitive Concerns (b = −0.68; P < .0001). Specifically, a 15‐minute per day increase in MVPA, on average, was associated with a 3.0‐point increase in the Oral Symbol Digit score, a 14.8‐point increase in the standardized self‐report Cognitive Abilities score, and a 10.2‐point decrease in the standardized self‐report Cognitive Concerns score. A greater increase in total activity (MVPA plus light activity) was associated with a greater improvement in the Fluid Composite score (b = 0.03; P = .038) and the Picture Sequence score (b = 0.04; P = .039), indicating that a 30‐minute per day increase in total activity was associated, on average, with a 0.84‐point increase in the Fluid Composite score and a 1.3‐point increase in the Picture Sequence score. All other components of the Fluid Composite score (except List Sorting) had a nonsignificant, positive association with increased total activity (data not shown).

DISCUSSION This study is one of the first randomized controlled trials of physical activity in breast cancer survivors with comprehensive measures of cognition as the primary outcome. The intervention was successful in increasing physical activity over 12 weeks, and both groups exhibited improved performance in most cognitive domains. However, of 9 examined cognitive domains, only Processing Speed had significantly greater improvements in the exercise arm compared with the control arm. These findings are consistent with a recent randomized controlled trial of 19 breast cancer survivors in which the exercise arm had greater improvements only for a measure of processing speed23 and a cross‐sectional study of 136 breast cancer survivors demonstrating that accelerometer‐measured physical activity was only related to 1 cognitive domain: processing speed.24 Although the cross‐sectional study was also conducted by investigators from the current study, it concerned a different sample of breast cancer survivors and used a different neurocognitive test. Although the benefits of physical activity were limited to this domain, it is an important aspect of cognition, because it can impact daily life,34, 35 is sensitive to cancer‐related cognitive impairments, and is commonly impaired in breast cancer survivors.36-38 In addition, processing speed plays a central role in cognition and can impact other cognitive tasks, especially those related to learning and memory.35, 39 Therefore, improved processing speed could lead to improvements in other aspects of cognition. Future studies are needed to determine whether sustained physical activity over longer periods could lead to more widespread improvements in cognition. Between‐group differences for both measures of self‐reported cognition were not statistically significant; however, given the small sample size, the results may suggest potential group differences. This is consistent with the significant dose effect for MVPA observed for both aspects of self‐reported cognition. Although there are no guidelines for what constitutes clinically meaningful improvement on these 2 measures, for other PROMIS quality‐of‐life measures, minimally important differences among cancer survivors have ranged from 2.5 to 6 points based on standardized T‐scores.40 Therefore, with an average 2.7‐point improvement in Cognitive Abilities and a 4.8‐point reduction in Cognitive Concerns in the exercise arm, many intervention participants may have experienced clinically meaningful improvements in their everyday cognitive functioning. Larger trials are needed to fully test the impact of physical activity on self‐reported cognition. In the current study, MVPA‐associated improvement in processing speed was significantly greater for women who were closer to surgery but did not vary based on other cancer‐related factors, including whether or not they had received chemotherapy. The physical and mental impact of cancer is generally greater closer in time to diagnosis and treatment41; thus, there may be more potential for improvements to occur when physical activity is increased closer in time to treatments. The benefits observed for processing speed suggest that increasing physical activity may be most advantageous when initiated closer to the time of surgery. It is also noteworthy that neurocognitive testing improved for both groups on most domains over the 12‐week study. This improvement may be related to the practice effects from repeated measurements. For instance, familiarity with the tests may have contributed to participants feeling less nervous, which could lead to improved scores.42-44 These findings highlight the important role of a control arm in ensuring that observed changes in cognition are causally related to the physical activity intervention. There is growing evidence that cognitive problems in patients with cancer are not limited to those who have received chemotherapy.2, 45 Thus, the lack of effect modification for chemotherapy and hormone therapy in our study suggests that increasing physical activity may be helpful for improving cognitive processing speed in breast cancer survivors regardless of the treatments they received. A significant dose response between minutes of increased physical activity and improved neurocognitive test performance and self‐reported cognition in the exercise arm was observed. It is noteworthy that, for the neurocognitive tests, a dose response was observed for total activity (MVPA plus light activity). This finding suggests that all types of physical activity, not just those conducted at moderate intensity, could be beneficial for cognition. This finding is consistent with yoga and qigong interventions, which reportedly improved cognition in cancer survivors46-48 and in noncancer populations.22 Engaging in large amounts of MVPA can be challenging for most individuals; a focus on increasing all intensities of activity could be a more feasible strategy for breast cancer survivors. Future research should examine the necessary minutes needed of different activity intensities to improve cognition. There are many potential mechanisms through which physical activity could improve cognition. Self‐reported cognition is often associated with psychological factors, including fatigue, anxiety, and depression.49, 50 It has been demonstrated in patients with cancer that physical activity decreases fatigue,51-54 anxiety,53 and depression,51, 53, 54 suggesting that physical activity also may improve self‐reported cognition. In addition, psychological factors, including depression and anxiety, can impact neurocognitive testing.55 There are also several biologic mechanisms through which physical activity may improve cognition. One is through the increase of cerebral blood flow and oxygen transport to the brain.56-60 Increased cerebral blood flow achieved through physical activity can enhance the production of brain‐derived neurotrophic factor,61-63 a biomarker of brain health that plays a central role in neuron survival, neurogenesis, synaptic plasticity, and cognitive function.64-66 Physical activity may also reduce the impact of accelerated aging observed in cancer survivors.2, 3, 6 At the cellular level, dynamic, epigenetic DNA methylation profiles are associated with aging,67 cancer,67-69 physical activity,70 and cognition.71, 72 It is important to note that age‐related DNA methylation is associated with age‐related gene transcription.67 More research is needed to elucidate the mechanisms through which physical activity improves cognition to support the development of targeted interventions. Although this was a randomized controlled trial using objective and self‐reported measures for cognition and physical activity, several limitations should be noted. This was a modestly sized study with limited power to detect differences between groups; and, because of the pilot nature of the study, we did not adjust for multiple comparisons. The intervention only lasted for 12 weeks and may not have been long enough to detect the impact of physical activity on cognition. At baseline, approximately 20% of participants were engaging in 150 minutes of accelerometer‐measured MVPA per week, which may have limited our ability to detect group differences. The small sample size also limited our ability to determine the optimal dose and intensity of physical activity. These limitations highlight the need for longer, fully powered trials to determine whether the effectiveness of increased physical activity improves aspects of cognition beyond processing speed and to establish the optimal dose and intensity of activity for improving cancer‐related cognitive decline. We chose to use the NIH Cognition Toolbox rather than the 3 core tests recommended in 2011 by the International Cognitive and Cancer Taskforce.73 The goal of both initiatives was to increase comparability between studies by using common methodology. We chose the NIH Toolbox because it enhances comparability across disease populations and is more comprehensive in the domains measured. Future studies combining the NIH Cognition Toolbox with the measures suggested by the International Cognitive and Cancer Taskforce would be helpful in further comparing results across oncology and other population studies. Other limitations include the predominantly well educated, high‐intelligence (as indicated by the Crystalized Composite Score), non‐Hispanic white sample of breast cancer survivors; future research in cancer populations with greater diversity is needed. This study provides preliminary support for the efficacy of increasing physical activity to improve processing speed and, potentially, self‐reported cognition in breast cancer survivors. With the growing interest in testing the potential of physical activity to improve cognition in cancer survivors,74, 75 this and other studies are likely to contribute to our ability to make recommendations to the growing number of cancer survivors on effective interventions to improve cognition.

FUNDING SUPPORT This study was supported by a grant from the National Cancer Institute, National Institutes of Health (K07CA181323).

CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.

AUTHOR CONTRIBUTIONS Sheri J. Hartman: Conceptualization, data curation, funding acquisition, investigation, methodology, project administration, validation, and writing. Sandahl H. Nelson: Data curation, formal analysis, and writing. Emily Myers: Data curation, investigation, project administration, and writing. Loki Natarajan: Conceptualization, funding acquisition, methodology, formal analysis, supervision, and writing. Dorothy D. Sears: Conceptualization, funding acquisition, supervision, and writing. Barton W. Palmer: Conceptualization, funding acquisition, supervision, and writing. Lauren S. Weiner: Project administration and writing. Barbara A. Parker: Conceptualization, funding acquisition, supervision, and writing. Ruth E. Patterson: Conceptualization, funding acquisition, methodology, supervision, validation, and writing.