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Effect of Exercise on Markers of Inflammation in Breast Cancer Survivors: The Yale Exercise and Survivorship Study

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Physical activity is associated with improved breast cancer survival, but the underlying mechanisms, possibly including modification of the inflammatory state, are not well understood. We analyzed changes in interleukin (IL)-6, C-reactive protein (CRP), and tumor necrosis factor (TNF)-α in a randomized controlled trial of exercise in postmenopausal breast cancer survivors. Seventy-five women, recruited through the Yale-New Haven Hospital Tumor Registry, were randomized to either a 6-month aerobic exercise intervention or usual care. Correlations were calculated between baseline cytokines, adiposity and physical activity measures. Generalized linear models were used to assess the effect of exercise on IL-6, CRP, and TNF-α. At baseline, IL-6 and CRP were positively correlated with body fat and BMI and were inversely correlated with daily pedometer steps (p < .001). We found no significant effect of exercise on changes in inflammatory marker concentrations between women randomized to exercise versus usual care, though secondary analyses revealed a significant reduction in IL-6 among exercisers who reached 80% of the intervention goal compared to those who did not. Future studies should examine the effect of different types and doses of exercise and weight loss on inflammatory markers in large-scale trials of women diagnosed with breast cancer.
Research Article
Effect of Exercise on Markers of Inammation in Breast
Cancer Survivors: The Yale Exercise and Survivorship Study
Sara B. Jones
, Gwendolyn A. Thomas
, Sara D. Hesselsweet
, Marty Alvarez-Reeves
Herbert Yu
, and Melinda L. Irwin
Physical activity is associated with improved breast cancer survival, but the underlying mechanisms,
possibly including modification of the inflammatory state, are not well understood. We analyzed changes in
interleukin (IL)-6, C-reactive protein (CRP), and TNF-ain a randomized controlled trial of exercise in
postmenopausal breast cancer survivors. Seventy-five women, recruited through the Yale-New Haven
Hospital Tumor Registry, were randomized to either a six-month aerobic exercise intervention or usual
care. Correlations were calculated between baseline cytokines, adiposity, and physical activity measures.
Generalized linear models were used to assess the effect of exercise on IL-6, CRP, and TNF-a. At baseline, IL-6
and CRP were positively correlated with body fat and body mass index (BMI) and were inversely correlated
with daily pedometer steps (P<0.001). We found no significant effect of exercise on changes in
inflammatory marker concentrations between women randomized to exercise versus usual care, though
secondary analyses revealed a significant reduction in IL-6 among exercisers who reached 80% of the
intervention goal compared with those who did not. Future studies should examine the effect of different
types and doses of exercise and weight loss on inflammatory markers in large-scale trials of women
diagnosed with breast cancer. Cancer Prev Res; 6(2); 109–18. 2012 AACR.
Breast cancer is the most common cancer diagnosis
among American women, accounting for 30% of cancer
diagnoses and 15% of cancer-related deaths, with an esti-
mated 230,480 women diagnosed in 2011 (1). Increasing
incidence from 1980 to 2001 and improved treatment
strategies have resulted in large numbers of breast cancer
survivors, a group currently estimated at 2.5 million. How-
ever, long-term side effects remain, including a risk of breast
cancer recurrence and risk of cardiovascular disease (2).
Chronic low-grade inflammation is a risk factor for cardio-
vascular disease (3), metabolic diseases (4, 5), and breast
cancer recurrence and mortality (6, 7). Obesity and seden-
tary behavior are linked to chronic low-grade inflammation,
which could increase cardiovascular disease and recurrence
risk in breast cancer survivors (8–10). This potential risk is
highlighted by prior findings that more than 50% of breast
cancer survivors are overweight or obese (11) and the
combination of excess body weight and low levels of phys-
ical activity have been linked to one third to one fourth of all
breast cancer cases (12). These factors make it critical to
understand the effects of lifestyle factors on survivorship
and to identify modifiable factors such as promoting a
healthy weight and increased levels of physical activity that
may improve disease-free survival and quality of life for
women diagnosed with breast cancer.
Physical activity is a modifiable lifestyle factor, which has
been shown to decrease risk for breast cancer and improve
quality of life after a breast cancer diagnosis. In recent
systematic reviews by Ballard-Barbash and L
of and collea-
gues, the authors reviewed the relationship between phys-
ical activity and cancer-relevant biomarkers including sex
hormones, insulin, adipokines, and inflammatory markers
(13, 14). The authors concluded that there was a biologic
basis for exercise and breast cancer mortality as exercise may
benefit changes in circulating insulin, insulin-like growth
factors (IGF), IGF-binding proteins (IGFBP), as well as
inflammatory biomarkers (13, 14). The mechanisms of
change are not fully understood but could include reduc-
tion in adipose tissue, chronic inflammation (15, 16), and
through the promotion of an anti-inflammatory environ-
ment. Studies have shown that breast cancer survivors have
higher levels of circulating cytokines than women without
breast cancers; a dysregulation that may persist up to 5 years
after diagnosis (17, 18). Identifying factors that reduce
chronic inflammation and interventions, which effectively
promote an anti-inflammatory environment are important
avenues of research.
Several pleiotropic cytokines associated with cancer and
chronic low-grade inflammation correlate with sedentary
lifestyle, adiposity, and low aerobic fitness (19). Interleukin
Authors' Afliations:
Yale School of Public Health, New Haven, Connecti-
cut; and
Dana-Farber Cancer Institute, Boston, Massachusetts
Corresponding Author: Melinda L. Irwin, Yale School of Public Health,
P.O. Box 208034, New Haven, CT 06520. Phone: 203-785-6392; Fax:
203-785-6279; E-mail:
doi: 10.1158/1940-6207.CAPR-12-0278
2012 American Association for Cancer Research.
Research 109
on April 12, 2018. © 2013 American Association for Downloaded from
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(IL)-6 and TNF-aare proinflammatory cytokines secreted
by a variety of cell types and tissues, including tumor cells,
infiltrating macrophages, and adipocytes, the latter of which
may produce as much as 25% of circulating IL-6 (18). Both
cytokines can stimulate the hepatocyte-derived acute phase
protein C-reactive protein (CRP), another marker of inflam-
mation. IL-6, CRP, and TNF-aare elevated in breast and
several other types of cancer (7, 20, 21). IL-6 has been found
to correlate with both disease stage and extent of metastasis
as well as breast cancer recurrence (7). In addition, TNF-ais
a risk factor in cardiovascular disease and metabolic syn-
drome, as well as increased in obesity and aging (22, 23).
Elevated CRP concentrations are associated with mortality
in women diagnosed with breast cancer as well as increased
risk for cardiovascular disease (7, 24).
Exercise may provide beneficial changes in circulating
levels of nonspecific markers of chronic low-grade inflam-
mation. Preliminary evidence in populations with moder-
ate to high levels of inflammatory markers, such as patients
with cardiovascular disease, has found that regular aerobic
exercise is associated with reductions in circulating proin-
flammatory cytokines (25–28). In a yearlong intervention
of moderate- to vigorous-intensity aerobic exercise (5 times
a week for 45 minutes) in healthy postmenopausal women,
higher doses of exercise were associated with lower CRP
levels (29). However, participants in the study had lower
levels of CRP at baseline, making it unclear whether this
approach is beneficial in populations with breast cancer and
elevated CRP levels. Results of these studies suggest that
these markers are associated with both higher adiposity and
lower levels of physical activity (30–32). To date, very few
randomized controlled trials of exercise alone (or without
dietary weight-loss) in postmenopausal breast cancer sur-
vivors have examined the effects of exercise on inflamma-
tory markers (33–35, 37). Given the observed benefits of
physical activity interventions on these inflammatory mar-
kers in other clinical populations, it is important to under-
stand whether these effects generalize to breast cancer
The purpose of this study was to examine changes in
plasma concentrations of the proinflammatory markers IL-
6, CRP, and TNF-a, after 6 months of aerobic exercise versus
usual care in breast cancer survivors enrolled in the Yale
Exercise and Survivorship Study. Understanding the effects
of moderate-intensity aerobic exercise protocol on chronic
low-grade inflammation could provide treatment options
to decrease risk of not only breast cancer recurrence and
mortality, but also cardiovascular risk and mortality in
breast cancer survivors.
Materials and Methods
Participants were recruited into the Yale Exercise and
Survivorship Study, described in detail elsewhere (38), by
study staff using the Yale-New Haven Hospital Tumor
Registry to obtain the names of Connecticut women diag-
nosed with breast cancer by any Yale-affiliated physician
from March 1994 to January 2006 (Fig. 1). Participants were
physically inactive (<60 min/wk of recreational physical
activity reported in the past 6 months), postmenopausal
women diagnosed with stage 0 to IIIA breast cancer and who
had completed adjuvant treatment (except endocrine ther-
apy) at least 6 months before enrollment. Women taking
aromatase inhibitors or tamoxifen were eligible for partic-
ipation. Postmenopausal status was defined as women who
had not menstruated in the last 12 months before the
baseline visit. Women could have gone through natural
menopause before diagnosis or before enrollment in our
study, but women were also eligible if they went through
chemotherapy-induced menopause. Women with type II
diabetes, previous cancer, and smokers were excluded
because of the potential effect of these factors on outcomes
of interest. Seventy-five (9.5%) of 788 patients screened
were deemed eligible, consented, and were randomized.
Randomization to the exercise or usual care group occurred
after completion of all baseline measures using a random
number generation. All study procedures were reviewed and
approved by the Yale University School of Medicine (New
Haven, CT) Human Investigation Committee.
Anthropometric, dual energy X-ray absorptiometry,
dietary and medical history measurements
Demographic characteristics and medical history were
collected via an interviewer-administered questionnaire at
the baseline visit, and clinical data were later confirmed by
physician and medical record review. Height, weight, waist,
and hip circumference were measured at baseline and 6
months using a digital scale and stadiometer. Circumfer-
ence measurements were taken at the waist (minimum
circumference) and hips (greatest circumference). All mea-
surements were taken twice in succession, by the same
technician, and averaged for data entry. A dual energy X-
ray absorptiometry (DEXA) scan was completed for each
participant at both visits using a Hologic scanner (Hologic
4500, Hologic Inc.) to assess body fat and lean mass. All
DEXA scans were evaluated by 1 radiologist blinded to the
intervention group of the participant. Dietary intakes were
measured with a 120-item validated food frequency ques-
tionnaire at baseline and 6 months to control for any
changes in diet, though participants were advised to main-
tain their current dietary habits (39).
Physical activity measures
At baseline and 6 months, participants completed 3
physical activity questionnaires: the physical activity ques-
tionnaire (PAQ; ref. 38), the 7-day physical activity log (7-
Day PAL; ref. 40), and a 7-day pedometer log (41). The PAQ
was used to determine eligibility by verifying participants
past 6 months of recreational activity. The 7-Day PAL was
completed by all participants before randomization and at
the 6-month follow-up visit and was also used to measure
adherence in the exercise group recording type and duration
of any recreational activity conducted on each day, along
with their corresponding heart rate, as measured by a heart
rate monitor (Polar). Hours per week spent in moderate- to
vigorous-intensity aerobic activity were determined using
Jones et al.
Cancer Prev Res; 6(2) February 2013 Cancer Prevention Research
on April 12, 2018. © 2013 American Association for Downloaded from
Published OnlineFirst December 4, 2012; DOI: 10.1158/1940-6207.CAPR-12-0278
Ainsworth’s Compendium of Physical Activities (42). Par-
ticipants measured their daily walking steps using the 7-day
pedometer log before randomization and at the 6-month
follow-up visit.
Exercise intervention
The participants in the exercise intervention were
instructed to complete 150 minutes of moderate intensity
aerobic exercise, which consisted of 3-weekly certified exer-
cise trainer–supervised exercise sessions at a local health
club and twice-weekly unsupervised exercise sessions. Exer-
cise sessions consisted primarily of brisk walking, though
participants could meet the exercise goal through other
forms of aerobic exercise, such as stationary biking and
elliptical training. Activities that did not involve sustained
aerobic effort, such as resistance training and yoga, could be
conducted but did not count toward the exercise goal for
each week. Participants gradually increased minutes of
exercise per week by completing 3 15-minute sessions
during week 1, building to 5 30-minute moderate-intensity
No physician consent
N = 309
Consent declined (N = 202)
No response (N = 29)
No Yale MD listed (N = 78)
Cases ascertained from YNHH registry
N = 1,072
Study staff contact physician
N = 1,072
Recruitment packet mailed
N = 763
Screening call
N = 788
N = 75
Contacted us
N = 126
Physician consent given
N = 763
Usual Care group
N = 38
Returned: N = 32
Exercise group
N = 37
Returned: N = 36
Declined via mail
N = 101
N = 88
Baseline visit
N = 88
Clinic visit
N = 75
N = 314
Too active (N = 137)
Age (N = 66)
Deceased (N = 53)
(N = 31)
Other (N = 27)
Unable to contact
N = 90
Busy/no answer
(N = 62)
Wrong phone #
(N = 28)
N = 296
Vague refusal (N = 74)
Unwilling to travel to
health club (N = 75)
Too busy (N = 71)
Refused after
baseline visit (N = 13)
Other (N = 63)
Figure 1. Flow of participants through the YES study.
Exercise and Inammatory Markers in Breast Cancer Survivors Cancer Prev Res; 6(2) February 2013 111
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sessions by week 5. Exercise started at 50% of predicted
maximal heart rate (220-age) and was gradually increased in
accordance with American College of Sports Medicine
(ACSM; Indianapolis, IN) guidelines to approximately
60% to 80% of predicted maximal heart rate. Participants
wore heart rate monitors for each exercise session to enable
self-monitoring of exercise intensity (Polar Electro). Fol-
lowing each exercise session, participants recorded the type,
duration, perceived intensity of activity, and average heart
rate during exercise in physical activity logs. Physical activity
logs were collected weekly to ensure weekly compliance.
Women in the usual care group were instructed to con-
tinue with their usual activities. If a participant wanted to
exercise, she was told she could, but that the exercise
program and training materials would not be offered to
her until the end of the study.
Inflammatory marker assays
Fasting blood draws were collected at the baseline and 6-
month clinic visits and plasma samples were stored at
80C until assayed. Plasma concentrations of IL-6, CRP,
and TNF-awere measured using ELISA kits from R&D
Systems, Inc.; high-sensitivity kits were used for IL-6 and
TNF-a. The assay sensitivities for IL-6, CRP, and TNF-awere
0.039 pg/mL, 0.010 ng/mL, and 0.106 pg/mL, respectively.
Samples were assayed in batches from the same lot such that
the baseline and 6-month sample from each participant
were assayed together and the number of samples from each
intervention group was balanced within each batch. Labo-
ratory personnel were blinded to intervention group. Sam-
ples were run in duplicate with coefficients of variation for
all samples less than 10% and averaging 3.0% for IL-6, 3.1%
for CRP, and 3.2% for TNF-a.
Statistical analyses
Baseline and 6-month blood samples were available for
68 of 75 participants (32 usual care and 36 exercisers)
because of missing blood draws for 7 women. Participants
with CRP concentrations indicative of acute infection, that
is, 15 mg/L or higher (43), were excluded from analyses.
One woman randomized to the usual care group met these
criteria with a CRP concentration of 124 mg/L, resulting in a
final sample size of 67. Baseline differences between inter-
vention groups were assessed using x
statistics for categor-
ical variables and ttests for continuous variables. Spearman
correlation coefficients were calculated between baseline
cytokine and CRP concentrations, adiposity, and physical
activity measures. Percentage changes in biomarker con-
centrations from baseline to 6 months were calculated as
follows: [mean baseline to 6-month difference]/[mean
baseline value] 100. The ttests and generalized linear
models (GLM) were used to assess intervention effects
according to the intent-to-treat principle. Multivariate mod-
els controlling for baseline characteristics including marker
concentration, age, race, education, time since diagnosis,
tumor stage, radio- and/or chemotherapy treatment, hor-
mone therapy, weight, body mass index (BMI), percentage
body fat, and physical activity were similar to univariate
models, and therefore only unadjusted results are pre-
sented. All analyses were repeated after logarithmically
transforming cytokine values to account for their skewed
distributions but are not shown as the results were
unchanged. We used GLM to assess a priori effect modifi-
cation of baseline variables (tumor stage, hormone therapy
use, radio- and/or chemotherapy treatment, time since
diagnosis, BMI, percentage body fat, and body weight) and
change in percentage body fat. Finally, the effect of adher-
ence to the intervention within the exercise group was
determined using GLM controlling for baseline biomarker
concentration. Adherence was defined as meeting 80% of
the exercise prescription, that is, 120 min/wk of activity, or
1,590 steps/d based on 1 mile composed of 1,987 steps
(44). All analyses were conducted using SAS version 9.1
software (SAS Institute Inc.).
Study subjects
There were no significant differences between the exercise
and usual care groups at baseline with regard to demo-
graphics, clinical characteristics, body composition,
pedometer steps per day, or inflammatory marker concen-
trations (Table 1). Exercisers had lower stage tumors than
usual care women (P¼0.04) and borderline significantly
higher minutes per week of physical activity; though, activ-
ity levels for both groups were quite low. Overall, partici-
pants ranged in age from 34 to 79 years with a mean of 56
years and were predominately non-Hispanic White. A
majority of women were overweight or obese (mean BMI
¼30.0 6.6 kg/m
) and had low physical activity levels
(mean duration physical activity ¼21.8 38.0 min/wk).
The mean baseline cytokine levels for women were 2.79
4.70 pg/mL for IL-6, 2.45 2.43 mg/L for CRP, and 1.21
0.56 pg/mL for TNF-a.
Baseline correlations
At baseline there was a moderate correlation between IL-6
and CRP (r¼0.46; P<0.0001) and modest, nonsignificant
correlations between IL-6 and TNF-a(r¼0.21; P¼0.09)
and CRP and TNF-a(r¼0.22; P¼0.08; Table 2). IL-6 was
positively correlated with percentage body fat, body weight,
and BMI (r¼0.49; r¼0.63; r¼0.65; P<0.0001,
respectively) as was CRP (r¼0.43, P<0.001; r¼0.57, P
<0.0001; r¼0.60, P<0.0001). There was a modest
correlation between TNF-aand weight (r¼0.25; P¼
0.04) but not with either percentage body fat or BMI. IL-
6 and CRP were inversely correlated with pedometer steps
per day (r¼0.42, r¼0.44; P<0.001), but not with
minutes per week of physical activity. TNF-awas not
associated with either measure of baseline physical activity.
Physical activity levels and intervention adherence
At 6 months, the exercise group had a significant increase
in moderate-to vigorous-intensity recreational activity
compared with the usual care group (129 min/wk vs.
45 min/wk; P<0.001) as well as a significant increase in
daily pedometer steps (1,621 steps or 0.8 miles vs. 38 steps
Jones et al.
Cancer Prev Res; 6(2) February 2013 Cancer Prevention Research
on April 12, 2018. © 2013 American Association for Downloaded from
Published OnlineFirst December 4, 2012; DOI: 10.1158/1940-6207.CAPR-12-0278
or 0.02 miles, P<0.001; data not shown). The exercise goal
was 150 min/wk of moderate-intensity aerobic exercise;
33% of women achieved this amount. 56% of women
achieved 80% of the exercise goal or 120 min/wk, and
75% of women achieved 90 min/wk. Comparison of food
frequency questionnaires revealed no significant dietary
changes in either exercisers or usual care (data not shown).
Main effects
After 6 months, plasma concentrations of IL-6, CRP,
and TNF-adid not differ between randomization groups
(Table 3). In the exercise group, IL-6 increased 0.04 pg/mL
(1.13%), CRP decreased 0.08 mg/L (3.24%), and TNF-a
increased 0.02 pg/mL (1.74%). In the usual care group,
there was no change in IL-6, whereas CRP decreased 0.21
mg/L (8.64%) and TNF-aincreased 0.08 pg/mL (5.74%).
Adjustments in GLMs for baseline characteristics, including
tumor stage, which was slightly unbalanced at baseline, did
not significantly affect the results. Results were also
unchanged when inflammatory marker concentrations
were logarithmically transformed to achieve normality.
Stratified analyses
Analyses were conducted stratified by baseline BMI, per-
centage body fat, weight, percentage body fat change, tumor
stage, hormone therapy, radio- and/or chemotherapy
Table 1. Baseline characteristics of randomized participants (N¼67)
Exercise group
Usual care group
(N¼31) Pvalue
Age, y 56.4 (9.6) 55.4 (7.6) 0.64
Non-Hispanic White 30 (83%) 27 (87%) 0.16
African-American 6 (17%) 2 (6%)
Asian/Pacic Islander 0 (0%) 1 (3%)
Unknown 0 (0%) 1 (3%)
High school graduate 6 (17%) 6 (19%) 0.86
Some school after high school 9 (25%) 9 (29%)
College graduate and beyond 21 (58%) 16 (52%)
Time since diagnosis, y 3.5 (2.1%) 3.1 (2.4%) 0.51
In situ 4 (11%) 4 (13%) 0.04
Stage I 20 (56%) 7 (23%)
Stage II 9 (25%) 14 (45%)
Stage III 3 (8%) 6 (19%)
None 2 (6%) 4 (13%) 0.36
Radiation only 15 (42%) 7 (23%)
Chemotherapy only 7 (19%) 7 (23%)
Radio- and chemotherapy 12 (33%) 13 (42%)
Hormone therapy
None 15 (42%) 9 (29%) 0.22
Tamoxifen 11 (31%) 7 (23%)
Aromatase Inhibitors 10 (28%) 15 (48%)
Weight, kg 81.3 (17.0) 77.3 (20.0) 0.38
BMI, kg/m
30.6 (6.0) 29.4 (7.3) 0.46
% Total body fat (DEXA) 41.3 (6.5) 38.6 (5.7) 0.08
Physical activity
, min/wk
moderate-to-vigorous intensity
recreational exercise
30.3 (41.4) 11.9 (31.3) 0.05
Pedometer average, steps/d 5083 (2,313) 5661 (2,740) 0.35
IL-6, pg/mL 3.55 (6.29) 1.91 (1.01) 0.13
CRP, (mg/L 2.47 (2.35) 2.43 (2.55) 0.95
TNF-a, pg/mL 1.15 (0.52) 1.28 (0.60) 0.36
Data are presented as mean (SD) for continuous variables and frequency (percentage) for categorical variables. Percentages may not
sum to 100 due to rounding.
Assessed from the 7-day physical activity log administered at baseline.
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treatment, and time since diagnosis, all of which were
selected a priori. No statistically significant within-group
effects or interactions were found, though statistical power
was limited. However, we did observe a borderline statis-
tically significant correlation between change in percentage
body fat and change in CRP among women randomized to
exercise (r¼0.27; P¼0.069). The relationship though
between change in body fat and change in CRP was not
observed in women randomized to usual care.
Adherence effects
Exercisers were stratified by adherence based on achieving
80% of the exercise goal, that is, an increase over baseline of
120 min/wk of physical activity or an increase of 1,590
steps/d. Among women who increased physical activity by
120 min/wk, IL-6 concentrations decreased 0.56 pg/mL
(14.29%), whereas among women who did not increase
physical activity by 120 min/wk, IL-6 concentrations
increased by 0.66 pg/mL (18.54%; P<0.01; data not
shown). Results using pedometer logs to measure adher-
ence were similar, though did not reach statistical signifi-
cance. Changes in CRP and TNF-adid not differ by either
measure of adherence.
In a 6-month moderate-intensity aerobic exercise inter-
vention, we observed no significant effect of exercise on
CRP, IL-6, or TNF-aconcentrations between women ran-
domized to exercise versus usual care, though secondary
analyses revealed a significant reduction in IL-6 among
exercisers who exercised at least 120 min/wk compared
with those who exercised less than 120 min/wk. Consistent
with prior studies (45), we found that IL-6 and CRP were
associated with higher adiposity as well as with lower levels
of physical activity at baseline. Our study also observed
changes in body fat associated with changes in CRP among
women randomized to exercise.
Fairey and colleagues also conducted a randomized exer-
cise trial in postmenopausal breast cancer survivors and
found a nonsignificant 1.39 mg/L decrease in CRP in
women randomized to a 15-week, 3 times weekly cycling
intervention compared with a 0.10 mg/L increase in the
control group (37). Although the authors did not examine
circulating IL-6 or TNF-a, they reported no change in the
production of either cytokine by cultured blood mononu-
clear cells (46). This assessment of cytokine production is
not reflective of in vivo concentration nor does it measure
production from other sources including adipocytes.
Compared with a prior study of a yearlong aerobic
exercise intervention in healthy women, we did not find
differences in CRP. This may be due to design differences.
For example, the prior study exceeded ACSM recommenda-
tions for weekly exercise over a 12-month time period (26).
The present study’s exercise prescription met current ACSM
recommendations over a shorter duration of 6 months,
although on average participants only completed 81% of
the recommended weekly exercise, and only 56% of our
women randomized to exercise conducted at least 120 min/
wk of exercise. Thus, our null findings may be because of too
low of a dose of exercise conducted. Changes in IL-6 were
Table 3. Concentrations of IL-6, CRP, and TNF-aat baseline and 6 months
Exercise group (N¼36) Usual care group (N¼31)
Marker Baseline 6 mo Mean change Baseline 6 m Mean change
IL-6, pg/mL 3.55 (6.29) 3.59 (6.03) 0.04 (1.32) 1.91 (1.01) 1.91 (1.19) 0.00 (1.20) 0.04 0.91
CRP, mg/L 2.47 (2.35) 2.39 (2.26) 0.08 (0.74) 2.43 (2.55) 2.23 (2.60) 0.20 (1.80) 0.12 0.73
TNF-a, pg/mL 1.15 (0.52) 1.17 (0.40) 0.02 (0.22) 1.28 (0.60) 1.35 (0.63) 0.08 (0.47) 0.06 0.54
Data are presented as mean (SD).
Mean change in exercise group minus mean change in usual care group.
Table 2. Correlations with IL-6, CRP, and TNF-a(N¼67)
IL-6 (pg/mL) CRP (mg/L) TNF-a(pg/mL)
CRP, mg/L 0.46 P<0.0001
TNF-a, pg/mL 0.21 P¼0.09 0.22 P¼0.08
Percentage total body fat (DEXA) 0.49 P<0.0001 0.43 P<0.001 0.03 P¼0.79
Weight, kg 0.63 P<0.0001 0.57 P<0.0001 0.25 P¼0.04
BMI, kg/m
0.65 P<0.0001 0.60 P<0.0001 0.19 P¼0.13
Physical activity, min/wk recreational activity
0.004 P¼0.97 0.13 P¼0.28 0.07 P¼0.53
Pedometer average, steps/d 0.42 P<0.001 0.43 P<0.001 0.11 P¼0.38
Assessed from the 7-day physical activity log administered at baseline.
Jones et al.
Cancer Prev Res; 6(2) February 2013 Cancer Prevention Research
on April 12, 2018. © 2013 American Association for Downloaded from
Published OnlineFirst December 4, 2012; DOI: 10.1158/1940-6207.CAPR-12-0278
observed among women exercising at least 120 min/wk,
further strengthening our hypothesis that exercising at
recommended doses of exercise (i.e., 150 min/wk) is nec-
essary. Interestingly, as previously reported, we did observe
an effect of exercise on insulin and IGF-1 in this sample of
women (47); thus, the dose necessary to elicit favorable
changes in breast cancer biomarkers may differ for each
There have been several other randomized exercise trials
and interventions that, while not conducted in breast cancer
populations, have examined circulating cytokines and CRP
with inconsistent results (48–56). The interventions have
ranged in duration from 4 weeks to 2 years and have
included resistance training, aerobic exercise of varying
amounts and intensities, and lifestyle changes combining
exercise with diet. Consistent with our findings, several
reported no change in IL-6 (49, 51, 53, 55, 56), CRP
(48, 52, 53, 55), or TNF-aafter exercise (49, 53, 55),
whereas others have reported decreases in IL-6
(48, 50, 54), CRP (49–51, 54, 56), and TNF-a(54). Some
of these studies did not include a control group and most
combined exercise with dietary changes (48–50, 54, 56).
One trial with positive results (CRP reduction of 3 mg/L)
was conducted in premenopausal, overweight women and
used a 1-year, twice-weekly resistance training intervention
(51). A second intervention study among nondiabetic lean
and obese men and obese male type II diabetics examined
the effect of a 12-week, 60-minute, 5-session/wk aerobic
exercise intervention on inflammation (48). The authors
found a 0.9 pg/mL decrease in IL-6 concentration in the lean
and obese nondiabetics and a 3.2 pg/mL decrease in IL-6 in
the diabetic group, but no changes in CRP. In addition,
there were significant reductions in visceral fat and waist
circumference. One of the trials that found no exercise effect
randomized 189 overweight/obese men and postmeno-
pausal women to 6 months of inactivity or 1 of 3 exercise
groups: low-amount-moderate-intensity, low-amount-vig-
orous-intensity, or high-amount-high-intensity (53). Fat
mass decreased significantly across the exercise groups
(6%–13%) relative to the inactive group and adherence
rates were high (84%–93%), but no changes occurred for
IL-6, CRP, or TNF-ain any of the exercise groups. Finally,
in another trial, 316 overweight/obese older adults with
osteoarthritis were randomized to 1 of 4, 18-month
interventions: control, diet-induced weight loss, exercise
(60 minutes of weight training and walking 3 times/wk),
or combined diet and exercise (55). Exercise training had no
effect on IL-6, CRP, or TNF-acompared with the control
group, though these markers were all significantly reduced
in the diet alone group. These exercise trials examining
changes in inflammation have variable results perhaps
owing to the different study populations, the variety
in intervention type, duration, and intensity, and the diffe-
rent changes in adiposity occurring over the course of
Mechanisms through which physical activity may reduce
inflammation are not entirely understood but may include
release of anti-inflammatory cytokines during exercise, inhi-
bition of TNF-aproduction by epinephrine, effects of
muscle-derived IL-6, and reduction in adipose tissue
(23, 28, 57). In our study, we found significant decreases
in percentage body fat among the exercise group compared
with the usual care group (0.8% vs. 0.4%; P<0.01), but
not for change in BMI or body weight. Several of the exercise
trials discussed earlier, which found reductions in proin-
flammatory markers also found decreases in adiposity
(48, 50, 56). For example, in Dekker and colleagues,
decreases in IL-6 and CRP occurred concurrently with
decreases in total fat mass and waist circumference (48).
In addition, a study among obese women showed that an
approximate 3 kg loss of adipose tissue after a very low-
calorie diet was associated with a 0.46 pg/mL, or 17%,
reduction in levels of IL-6, but no significant changes in
CRP or TNF-a(58). In contrast, some trials reported reduc-
tions in inflammation after exercise without any concurrent
change in adiposity (49, 51, 54). Further still, some exercise
trials have achieved significant fat losses without simulta-
neous decreases in proinflammatory markers (48, 53, 56).
Nicklas and colleagues noted that the decreases in cytokines
and CRP seen in the diet-only group were unrelated to
changes in BMI. Assessment of body composition in these
trials varied, from direct measurement of body fat to indirect
measurements such as BMI, and could explain some of the
discrepancies across studies. Still, the mediating effect of fat
loss remains unclear and may differ for different markers.
IL-6 and CRP seem to be more amenable to change through
fat loss as compared with TNF-aperhaps because adipose
tissue is a significant producer of IL-6, which in turn is a
regulator of hepatic CRP synthesis (59), whereas the major-
ity of adipocyte-produced TNF-ais sequestered and con-
tributes a relatively small amount to circulation (60).
Indeed, we observed measures of adiposity to be more
strongly correlated with IL-6 and CRP than with TNF-a.
Another factor that may modify or mediate the effect of
exercise on inflammatory markers, as well as other cancer
biomarkers, is endocrine therapy. Evidence suggests that
tamoxifen and aromatase inhibitors affect inflammatory
and metabolic biomarkers, likely through cross-talk with
sex steroid pathways (61–63) In a study of breast cancer
survivors initiating endocrine therapy with an aromatase
inhibitor, specifically letrozole, increases in CRP were
observed within the first 6 months after aromatase inhibitor
treatment started (64) Another endocrine therapy trial
showed that c-peptide levels increased significantly in breast
cancer survivors in the 4 months after initiating tamoxifen
(P<0.001), whereas IGF-1 levels decreased (P<0.001;
ref. 61) However, other studies consistently show an
increase in IGF-1 levels upon initiation of an aromatase
inhibitor (62, 63). These findings provide evidence of an
interaction between endocrine therapy and biomarkers
linked to breast cancer outcomes. Future, appropriately
powered, studies should examine the effect of exercise on
cancer biomarkers stratified by endocrine therapy. Several
factors and study limitations could have influenced our trial
results. First, if physical activity’s effects on cytokine con-
centrations are mediated predominantly through fat loss,
Exercise and Inammatory Markers in Breast Cancer Survivors Cancer Prev Res; 6(2) February 2013 115
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our prescribed intervention may not have achieved the
necessary reduction in body fat. Although significantly
different from the usual care group, changes in percentage
body fat among the exercise group were modest (0.8%), as
were changes in BMI (0.12 kg/m
) and weight (0.55 kg).
Second, imperfect adherence to the intervention may have
impacted results; this was explored in secondary analyses.
Among women who met 80% of the exercise goal, IL-6
levels decreased 14.4%, whereas those not meeting 80% of
the goal had an 18.5% increase; a mean between group
difference of 0.69 pg/mL. No significant differences were
detected for either CRP or TNF-a. It is also noteworthy that
adherers had a mean decrease in body fat of 1.6%, whereas
nonadherers had a decrease of only 0.3% (P¼0.04). These
findings from subanalyses, while suggestive of a possible
effect of physical activity on IL-6, must be interpreted with
caution as they are not based on the intent-to-treat principle
and women who are more adherent may differ from less
adherent women. Other limitations include the small sam-
ple size for stratified analyses and potential nondifferential
measurement error of cytokine concentrations, which were
based on single blood draws.
Advantages of this study include randomization to
treatment group, inclusion of women with low baseline
physical activity, good adherence, and retention rates
assessed by thorough exercise monitoring, and prescription
of a lengthy, supervised exercise intervention. In addition,
valid, objective measures were used for assessment of
percentage body fat, physical activity, and biomarker
In our trial, we found that baseline inflammatory markers
were associated with higher adiposity and lower levels of
exercise, but we did not find that the moderate-intensity
aerobic exercise intervention significantly altered concen-
trations of IL-6, CRP, or TNF-a. Future studies should
examine the effects of different doses and types of physical
activity on cytokines in large-scale trials of breast cancer
survivors, as well as determine whether certain factors,
including body fat loss and endocrine therapy, modify the
potential effect of exercise on inflammatory markers.
Disclosure of Potential Conicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: S.B. Jones, M.L. Irwin
Development of methodology: S.B. Jones, H. Yu, M.L. Irwin
Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): S.B. Jones, S.D. Hesselsweet, H. Yu, M.L. Irwin
Analysis and interpretation of data (e.g., statistical analysis, biosta-
tistics, computational analysis): S.B. Jones, G.A. Thomas, S.D. Hessels-
weet, H. Yu, M.L. Irwin
Writing, review, and/or revision of the manuscript: S.B. Jones, G.A.
Thomas, H. Yu, M.L. Irwin
Administrative, technical, or material support (i.e., reporting or orga-
nizing data, constructing databases): S.B. Jones, H. Yu, M.L. Irwin
Study supervision: H. Yu, M.L. Irwin, M. Alvarez-Reeves
Grant Support
This study was supported by American Cancer Society (MRSG-04-006-01-
CPPB) and the Susan G. Komen Breast Cancer Foundation (BCTR0201916).
Supported in part by a General Clinical Research Center grant from the
National Center of Research Resources, NIH (grant # M01-RR00125)
awarded to Yale University School of Medicine and the National Institute
of Nursing Research (Research Training: Self and Family Management
Research T32 NR008346).
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate
this fact.
Received July 9, 2012; revised November 2, 2012; accepted November 19,
2012; published OnlineFirst December 4, 2012.
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2013;6:109-118. Published OnlineFirst December 4, 2012.Cancer Prev Res
Sara B. Jones, Gwendolyn A. Thomas, Sara D. Hesselsweet, et al.
Survivors: The Yale Exercise and Survivorship Study
Effect of Exercise on Markers of Inflammation in Breast Cancer
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... Of the 10 trials, 8 studies were 2-arm randomized controlled trials [40] with exercise groups and control groups; one study was a 3-arm randomized controlled trial including two exercise groups (high-intensity interval exercise plus resistance exercise, high-intensity interval exercise plus aerobic exercise) and control groups, which were analysed separately in the text; another study was a 4-arm randomized controlled trial including an exercise group, a ginger-taking group, the taking ginger plus exercise group and the placebo group, and then we extracted data only from the exercise and placebo groups. Among the 11 articles, nine studies examined IL-6 [33,[40][41][42][43][44][45][46][47], five studies examined CRP [38,42,[44][45][46], five studies examined TNF-α [41-43, 45, 47], four studies examined IL-10 [38,40,41,43], three studies examined IGF-1 [33,45,48] and IGFBP-3 [33,45,48], and 1 study examined IL-1β [41] (not analysed). The number of individuals in each study ranged from 16 to 240, with a total number of 696 individuals. ...
... Of the 10 trials, 8 studies were 2-arm randomized controlled trials [40] with exercise groups and control groups; one study was a 3-arm randomized controlled trial including two exercise groups (high-intensity interval exercise plus resistance exercise, high-intensity interval exercise plus aerobic exercise) and control groups, which were analysed separately in the text; another study was a 4-arm randomized controlled trial including an exercise group, a ginger-taking group, the taking ginger plus exercise group and the placebo group, and then we extracted data only from the exercise and placebo groups. Among the 11 articles, nine studies examined IL-6 [33,[40][41][42][43][44][45][46][47], five studies examined CRP [38,42,[44][45][46], five studies examined TNF-α [41-43, 45, 47], four studies examined IL-10 [38,40,41,43], three studies examined IGF-1 [33,45,48] and IGFBP-3 [33,45,48], and 1 study examined IL-1β [41] (not analysed). The number of individuals in each study ranged from 16 to 240, with a total number of 696 individuals. ...
... This is similar to the findings of our study, which found a nonsignificant trend of improved IGFBP-3 levels after exercise. Among the included studies that examined levels IGFBP-3 that we included, two of them [42,46] reported elevated IGFBP-3 levels after exercise, while another 6-month aerobic exercise study [49] found a significant reduction of 4.1% (p = 0.006) in IGFBP-3 levels in the intervention group compared to the control group. ...
Full-text available
Background At present, there are multiple hypotheses regarding the mechanisms underlying the effect of exercise on the postoperative inflammatory factors and the IGF system among breast cancer patients, especially. To determine the underlying mechanisms, prevent the recurrence of breast cancer and improve its prognosis, this paper will systematically evaluate the impact of exercise on inflammatory factors and the IGF system in breast cancer survivors. Methods The PubMed, Embase, Web of Science, CNKI, Wanfang and VIP (Chinese scientific and technical journals) databases were systematically searched until April 2021. The search terms included 'exercise', 'inflammatory factor', 'IGF system' and 'breast cancer'. A total of 1066 relevant articles were retrieved. The articles were screened according to inclusion and exclusion criteria, such as study population, intervention method and type of experiment, and 11 articles were ultimately included. All statistical results were analysed using STATA 14.0 and Rstudio 4.1.1. Results We found that exercise significantly reduced the level of IGF-1 (WMD, -19.947 ng/ml; 95% CI, -22.669 to -17.225; P = 0.000). Subgroup analysis showed that in the studies with an intervention period > 12 weeks, exercise significantly reduced IL-6 levels (WMD, -0.761 pg/ml; 95% CI, -1.369 to -0.153; p = 0.014), while in the studies with an intervention period ≤ 12 weeks, exercise significantly reduced CRP (WMD, -2.381 mg/L; 95% CI, -4.835 to 0.073, P = 0.001) and IL-10 levels (WMD, -7.141 pg/ml, 95% CI, -10.853 to -3.428; P = 0.000). In addition, aerobic exercise plus resistance training significantly reduced IL-6 levels (WMD, -1.474 pg/ml; 95% CI, -1.653 to -1.296; P = 0.000). The results of the sensitivity analysis showed that after excluding the studies with high heterogeneity, exercise significantly reduced the TNF-α levels in patients with breast cancer (WMD, -1.399 pg/ml; 95% CI, -1.718 to -1.080; P = 0.000). Conclusion Exercise reduces the postoperative levels of IGF-1, IL-6, CRP, IL-10 and TNF-α among patients with breast cancer, which may have a significant impact on inhibiting breast cancer recurrence and improving its prognosis. Future studies should examine the effects of different durations and types of exercise to develop individualized exercise prescriptions for breast cancer patients.
... Combined aerobic and resistance exercise has more advantages in improving fat levels, muscle mass, bone density, and proinflammatory cytokines in cancer patients. 39,56,83 We encourage ongoing research to explore and analyze the effectiveness of combined exercise interventions for managing cancer-related fatigue. ...
OBJECTIVE: To determine the most effective exercise modalities for managing cancer-related fatigue during and after cancer treatment. DESIGN: Network meta-analysis (NMA) of randomized controlled trials. LITERATURE SEARCH: Seven electronic databases were systematically searched from inception to January 2022. STUDY SELECTION CRITERIA: RCTs testing the effects of exercise on relieving cancer-related fatigue in adult patients with cancer. DATA SYNTHESIS: An NMA of 56 studies was conducted and the PRISMA-NMA guidelines were followed when reporting results. To determine the most effective interventions, the surface under the cumulative ranking curve (SUCRA) value was calculated for each exercise modality. RESULTS: Combined aerobic and resistance exercise [standardized mean difference (SMD):1.57, credible interval (CrI) :1.03-2.10], yoga (SMD:1.02, CrI: 0.44-1.60), and regular physical activity (SMD:1.07, CrI: 0.21-1.92) could significantly alleviate cancer-related fatigue compared to control groups (usual care, wait-list, and regular physical activity). Combined aerobic and resistance exercise [surface under the cumulative ranking curve (SUCRA): 97.2%] had the highest probability of efficacy, followed by yoga (SUCRA: 75.5%) and regular physical activity (SUCRA: 74.1%). During cancer treatment, combined aerobic and resistance exercise (SUCRA: 94.5%) ranked first in efficacy, followed by regular physical activity (SUCRA: 82.1%) and yoga (SUCRA: 73.8%). After cancer treatment, only combined aerobic and resistance exercise (SMD: 0.99, CrI: 0.13-1.84) had a significant effect on cancer-related fatigue. CONCLUSIONS: Combined aerobic and resistance exercise, yoga, and regular physical activity were the most effective exercise modalities for alleviating cancer-related fatigue. Combined aerobic and resistance exercise is recommended during and after cancer treatment.
... Concerning aerobic exercise carried out in clinical studies, although some analyses report no significant benefits related to inflammation [120,138], other research stresses that this form of training, along with diet, helps decrease TNF-α and IL-6 serum concentrations in women with breast cancer [102]. In addition, the increase in total exercise time is associated with greater reduction in IL-6 serum levels [102]. ...
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Growing evidence suggests that, among the different molecular/cellular pathophysiological mechanisms associated with cancer, there are 14 hallmarks that play a major role, including: (i) sustaining proliferative signaling, (ii) evading growth suppressors, (iii) activating invasion and metastasis, (iv) enabling replicative immortality, (v) inducing angiogenesis, (vi) resisting cell death, (vii) reprogramming energy metabolism, (viii) evading immune destruction, (ix) genome instability and mutations, (x) tumor-promoting inflammation, (xi) unlocking phenotypic plasticity, (xii) nonmutational epigenetic reprogramming, (xiii) polymorphic microbiomes, and (xiv) senescent cells. These hallmarks are also associated with the development of breast cancer, which represents the most prevalent tumor type in the world. The present narrative review aims to describe, for the first time, the effects of physical activity/exercise on these hallmarks. In summary, an active lifestyle, and particularly regular physical exercise, provides beneficial effects on all major hallmarks associated with breast cancer, and might therefore help to counteract the progression of the disease or its associated burden.
... This mechanism is particularly plausible given that the hippocampus can be degenerated by toxic chemotherapy agents [84,85], whereas exercise has shown to not only improve hippocampus-dependent cognitive capacities but also increase the volume of the hippocampus [86][87][88][89]. Furthermore, neurological degeneration is significantly influenced by inflammatory markers [90], and exercise training can create a systemic anti-inflammatory environment to fight against and restore chemotherapy-induced cognitive decline [91][92][93]. ...
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Background: More than 75% of patients with breast cancer treated with chemotherapy experience cognitive impairments (eg, memory and attention problems), commonly known as chemo-brain. Exercise, especially aerobic high-intensity interval training (HIIT), is associated with better cognitive function in healthy populations. However, clinical trials testing the impact of exercise interventions on chemotherapy-induced cognitive decline in patients with cancer are lacking, and the mechanisms through which exercise could improve cognitive function are unclear. Objective: The objective of the Improving Cognitive Function Through High-Intensity Interval Training in Breast Cancer Patients Undergoing Chemotherapy trial is to examine the effects of HIIT on cognitive function in patients with breast cancer undergoing chemotherapy. Methods: This 2-arm, single-center, pilot randomized controlled trial will randomize 50 patients with breast cancer undergoing chemotherapy to HIIT or attention control. The HIIT group will perform a supervised 16-week, thrice-weekly intervention, with each session including a 5-minute warm-up at 10% maximal power output (POmax), 10 sets of alternating 1-minute high-intensity (90% POmax) and 1-minute recovery (10% POmax) intervals, and a 5-minute cooldown (10% POmax). The attention control group will receive a stretching program with no exercise components and be asked to maintain their exercise levels for 16 weeks. The primary outcomes of the study are executive function and memory measured using the National Institutes of Health toolbox and resting-state connectivity and diffusion tensor imaging microstructure evaluated using magnetic resonance imaging. The secondary and tertiary outcomes include cardiorespiratory fitness, body composition, physical fitness, and psychosocial health. The study has been approved by the institutional review board of the Dana-Farber Cancer Institute (20-222). Results: The trial was funded in January 2019, with recruitment started in June 2021. As of May 2022, a total of 4 patients have consented and been randomized (n=2, 50% to exercise; n=1, 25% to control; and n=1, 25% nonrandomized). Trial completion is expected in January 2024. Conclusions: This first-of-its-kind study incorporates a novel exercise intervention (ie, HIIT) and comprehensive cognitive measures. If positive, our findings will establish the pilot efficacy of HIIT on chemotherapy-induced cognitive function in patients with breast cancer, providing the foundation for future larger phase-II and phase-III trials to confirm the findings and potentially establish HIIT as a standard of care for women undergoing chemotherapy for breast cancer. Trial registration: NCT04724499; International registered report identifier (irrid): DERR1-10.2196/39740.
... C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), and other inflammatory cytokines have been shown to correlate with body mass index (BMI) in women with BC and to increase following chemotherapy. [13][14][15][16][17] Weight loss programs among women with BC have been associated with decreases in CRP and may contribute to improved outcomes. 18 A large, international, randomized controlled trial of a weight loss intervention with the primary outcome of disease-free survival is currently being conducted and should shed light on the impact of weight loss after BC diagnosis on prognosis. ...
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Background Chemotherapy is associated with decreased quality of life (QOL), fatigue, depression, and weight gain in patients with breast cancer. Weight gain is associated with poorer prognosis. Yoga improves QOL, fatigue, and mood in women with breast cancer but its effect on treatment-related weight gain has not been studied. The aim of this trial was to determine the feasibility of personalized yoga therapy in women receiving treatment for early-stage or locally advanced breast cancer and assess its impact on weight gain. Methods Thirty women were randomized 1:1 to receive yoga therapy by a certified yoga therapist during treatment or a control group. Participants in the yoga arm were asked to complete three 30 minute yoga sessions weekly (which included movement, breath work, mindfulness, and relaxation) throughout adjuvant or neoadjuvant chemotherapy (N = 29) or endocrine (N = 1); the control arm received breast cancer treatment without yoga. For comparability between participants randomized to yoga therapy, the single patient treated with endocrine therapy was excluded from the analysis. Primary outcomes were feasibility and weight change. Additional outcomes were mood, fatigue, QOL, serum tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) as immune mediator biomarkers. Results Mean age was 51.6 years, 75.9% were white and 24.1% were people of color, reflecting the cancer center population. 80% had stage II-III disease. Enrollment was completed in 9 months. Compliance was lower than predicted; however, participants participated in on average 1.7 yoga sessions/week for a mean 15.6 weeks duration. There were no adverse events. Control arm participants gained on average 2.63% body weight during treatment while yoga participants lost 0.14% body weight (weight change = −0.36 in yoga arm vs. 2.89 in standard of care arm, Wilcoxon rank sum test P = .024). Control participants reported increased fatigue and decreased QOL, while yoga participants reported no change in QOL. No significant change in TNF-alpha or CRP was noted in either arm. Conclusion This feasibility study suggests that personalized yoga therapy is beneficial for QOL and weight maintenance among women undergoing chemotherapy for early-stage or locally advanced breast cancer. Weight maintenance associated with yoga therapy may be of clinical significance in this population given the poorer prognosis associated with weight gain in breast cancer survivors. Trial Registration NIH #NCT03262831; August 25, 2017.
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Introduction The aim of this systematic review was to summarize the current literature on wearable technologies in oncology patients for the purpose of prognostication, treatment monitoring, and rehabilitation planning. Methods A search was conducted in Medline ALL, Cochrane Central Register of Controlled Trials, Embase, Emcare, CINAHL, Scopus, and Web of Science, up until February 2022. Articles were included if they reported on consumer grade and/or non-commercial wearable devices in the setting of either prognostication, treatment monitoring or rehabilitation. Results We found 199 studies reporting on 18 513 patients suitable for inclusion. One hundred and eleven studies used wearable device data primarily for the purposes of rehabilitation, 68 for treatment monitoring, and 20 for prognostication. The most commonly-reported brands of wearable devices were ActiGraph (71 studies; 36%), Fitbit (37 studies; 19%), Garmin (13 studies; 7%), and ActivPAL (11 studies; 6%). Daily minutes of physical activity were measured in 121 studies (61%), and daily step counts were measured in 93 studies (47%). Adherence was reported in 86 studies, and ranged from 40% to 100%; of these, 63 (74%) reported adherence in excess of 80%. Conclusion Wearable devices may provide valuable data for the purposes of treatment monitoring, prognostication, and rehabilitation. Future studies should investigate live-time monitoring of collected data, which may facilitate directed interventions.
Obesity is highly prevalent in breast cancer (BC) survivors. Adipose tissue promotes inflammation, affecting recurrence, morbidity, and quality of life. This study aimed to determine the relationship of body composition parameters with the levels of C-reactive protein (CRP) and interleukin 6 (IL-6) in female BC survivors. Additionally, we evaluated the association of log-transformed serum concentrations of CRP and IL-6 with the appendicular skeletal lean mass index (ASMI). The results showed that CRP was positively associated with body fat percentage (BFP; β adjusted = .08, 95% CI: .02–.14) in all participants, and with fat mass index (FMI; β = .24, 95% CI: .08–.40) only in premenopausal women. IL-6 was positively associated with FMI (β adjusted = .16, 95% CI: .03–.29), while ASMI decreased as CRP levels increased (β adjusted = −.30, 95% CI: −.53 to −.06). Interventions to improve body composition in BC survivors should also consider the role of inflammatory markers in changes in body composition to avoid sarcopenic obesity (SO) and the risk of BC recurrence.
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Background Cardiovascular disease (CVD) has become the leading cause of competitive mortality in female breast cancer (BC). Regular aerobic exercise (AE) has been widely accepted as an effective intervention to reduce cardiovascular risk in a variety of different clinical conditions. This study is aimed at evaluating the efficacy and safety of AE on cardiovascular risk factors in female BC and assessing the quality of the synthesized evidence. Methods We searched five English databases (Cochrane Library, PubMed, Embase, Scopus, and Web of Science) from inception to January 2023. Randomized controlled trials (RCTs) and cohort trials studying the effects of AE were included. We used Stata 16 for data synthesis, Risk of Bias 2, and the Newcastle-Ottawa Scale for methodological quality evaluation and assessed the certainty of the synthesized evidence in the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Results Forty RCTs and 6 cohort trials involving 59,050 BC patients showed AE reduced the incidence of CVD events by 29.4% [RR = 0.706, 95% CI (0.659, 0.757), low certainty] and coronary artery disease events by 36% (risk ratio [RR]: 0.64, 95% confidence interval [CI] [0.561, 0.729]; risk difference [RD] = 23.2%, 95% CI [17.6%, 29.6%], low certainty]. AE improved LVEF, and reduced weight and hip circumference. The subgroup analysis results showed that nonlinear AE increased VO2max by 5.354 ml·kg·min− 1 [MD 5.354, 95% CI (2.645, 8.062), very low certainty] and reduced fat mass by 4.256 kg [MD 4.256, 95% CI (-3.839, -0.094), very low certainty]. While linear AE reduced low-density lipoprotein cholesterol (LDL-C) by 8.534 mg/dL [MD -8.534, 95% CI (-15.511, -1.557), low certainty]. The sensitivity analysis results showed that each trial did not affect the impact index of the highly heterogeneous outcomes. Conclusions Our study indicates that AE has a positive effect in reducing cardiovascular risk factors. The principles of AE especially nonlinear design deserve more attention in the future. This will provide new ideas to reduce CVD events and improve the quality of life in female BC patients. However, further research on AE in female BC should take into account long-term and well-designed administration to draw definitive conclusions.
Background: As the effectiveness of breast cancer treatment has improved, a growing number of long-term breast cancer survivors are seeking help for unique health problems. These patients may be at increased risk of cardiovascular disease due to the side effects of treatment. The positive impact of most types of exercise has been repeatedly reported in people with cancer, but the most effective exercise approaches for maximum beneficial adaptations remain controversial. Thus, this study aimed to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on inflammatory indices, adipokines, metabolic markers, body composition, cardiorespiratory fitness, and quality of life in breast cancer patients during adjuvant endocrine therapy. Methods: Thirty non-metastatic breast cancer patients during adjuvant endocrine therapy who had been treated with chemotherapy and/or radiotherapy were recruited from Iran and randomized to HIIT, MICT, or control groups for a supervised exercise intervention that took place 3 times a week for 12 weeks. The training intensity was determined based on the peak oxygen uptake (VO2peak), and the volume of training was matched in HIIT and MICT based on the VO2peak. Body composition, functional capacity, cardio-respiratory fitness, metabolic indices, sex hormones, adipokines, and inflammatory markers were assessed before and after the intervention. Results: The VO2peak increased by 16.8% in the HIIT group in comparison to baseline values (mean difference = 3.61 mL/kg/min). HIIT significantly improved the VO2peak compared to control (mean difference = 3.609 mL/kg/min) and MICT (mean differences = 2.974 mL/kg/min) groups. Both HIIT (mean difference = 9.172 mg/dL) and MICT (mean difference = 7.879 mg/dL) interventions significantly increased high-density lipoprotein cholesterol levels compared to the control group. The analysis of covariance showed that physical well-being sginificantly improved in MICT compared to control group (mean difference = 3.268). HIIT significantly improved the social well-being compared to the control group (mean difference = 4.412). Emotional well-being subscale was significantly improved in both MICT (mean difference = 4.248) and HIIT (mean difference = 4.412) compared to the control group. Functional well-being scores significantly increased in HIIT group compared with control group (mean difference = 3.35) . Significant increase were also observed in total functional assessment of cancer therapy-General scores in both HIIT (mean difference = 14.204) and MICT groups (mean difference = 10.036) compared with control group. The serum level of supressor of cytokine signaling 3 increased significantly (mean difference = 0.09 pg/mL) in the HIIT group compared to the baseline. There were no significant differences between groups for body weight, body mass index, fasting blood glucose, insulin resistance, sex hormone binding globulin, total cholesterol, low-density lipoprotein cholesterol, adipokines, interleukin-6, tumor necrosis factor-α, and interleukin-10. Conclusion: HIIT can be used as a safe, feasible, and time-efficient intervention to improve cardiovascular fitness in breast cancer patients. Both HIIT and MICT modalities enhanced quality of life. Further large-scale studies will help determine whether these promising results translate into improved clinical and oncological outcomes.
Introduction: The aim of this study was to explore the associations among physical activity (PA), inflammatory markers, and quality of life (QoL) from preradiotherapy to 1-year postradiotherapy for patients with head and neck cancer (HNC). Methods: This was an observational longitudinal study. Mixed-effect models incorporating within-subject correlation were used to examine the relationship among the three key variables. Results: Aerobically active patients had significantly lower levels of sTNFR2 (but not other inflammatory markers) than aerobically inactive patients. Being aerobically active and lower inflammation were independently associated with better total QoL scores after adjusting covariates. The trend was similar for patients engaged in strength exercises. Conclusions: Being aerobically active was associated with lower inflammation as represented by sTNFR2 but not with other inflammatory markers. Higher PA (aerobic and strength) and lower inflammation were linked to better QoL. More research is warranted to validate the association among PA, inflammation, and QoL.
Regular exercise offers protection against all cause mortality and there is evidence from randomised intervention studies that physical training is effective as a treatment in patients with chronic heart diseases, type 2 diabetes and symptoms related to the metabolic syndrome. Chronic diseases such as cardiovascular disease, type 2 diabetes and cancer are associated with chronic low-grade systemic inflammation. It has been demonstrated that regular exercise induces anti-inflammatory effects with elevated levels of anti-inflammatory cytokines and suppression of TNF-alpha production. Thereby, exercise offers protection against TNF-alpha-induced insulin resistance. Otherwise, the exercise-induced production and release of IL-6 from myofibers may contribute to abrogate an atherogenic lipid profile, which is often associated with chronic diseases. This review focuses on the anti-inflammatory effects of exercise and how this may contribute to mediate the beneficial health effects of exercise training in patients with chronic diseases associated with chronic low-grade inflammation.
The objective of this study was to review and summarise the published evidence for an association between circulating concentrations of C reactive protein (CRP) and cancer through a systematic review. 90 discrete studies were identified. 81 (90%) were prevalent case-control or cross-sectional studies, and only 9 studies had a prospective design. In most prevalent studies, CRP concentrations were found to be higher in patients with cancer than in healthy controls or controls with benign conditions. Of the nine large prospective studies identified in this review, four reported no relationship between circulating CRP levels and breast, prostate or colorectal cancers, and five studies found that CRP was associated with colorectal or lung cancers. Most of the studies evaluating CRP as a diagnostic marker of cancer did not present relevant statistical analyses. Furthermore, any association reported in the prevalent studies might reflect reverse causation, survival bias or confounding. The prospective studies provided no strong evidence for a causal role of CRP in cancer. Instead of further prevalent studies, more large prospective studies and CRP gene-cancer association studies would be valuable in investigating the role of CRP in cancer.
The aim of this study was to investigate the potential role of adipose cytokines in the obesity-associated insulin resistance. To that end, we compared: 1) serum concentrations of interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), and leptin in eight healthy lean control females and in android obese female without (n = 14) and with (n = 7) type 2 diabetes; and 2) the levels of these cytokines both in serum and in sc adipose tissue in the 14 obese nondiabetic women before and after 3 weeks of a very low-calorie diet (VLCD). As compared with lean controls, obese nondiabetic and diabetic patients were more insulin resistant and presented increased values for leptin, IL-6, TNFalpha, and C-reactive protein. In the whole group, IL-6 values were more closely related to the parameters evaluating insulin resistance than leptin or TNFalpha values. VLCD resulted in weight loss and decreased body fat mass (approximately 3 kg). Insulin sensitivity was improved with no significant change in both serum and adipose tissue TNFalpha levels. In contrast, VLCD induced significant decreases in IL-6 and leptin levels in both adipose tissue and serum. These results suggest that, as for leptin, circulating IL-6 concentrations reflect, at least in part, adipose tissue production. The reduced production and serum concentrations after weight loss could play a role in the improved sensitivity to insulin observed in these patients.
Aims Physical reconditioning of patients with chronic heart failure (CHF) improves exercise capacity and restores endothelial function and skeletal muscle changes. The effects of 4 months combined endurance/resistance exercise training on cytokines and cytokine receptors in patients with CHF were studied. In addition, changes in submaximal and maximal exercise performance were addressed. Methods and Results Twenty-three patients with stable CHF due to coronary artery disease (CAD, n=12) or idiopathic dilated cardiomyopathy (IDCM, n=11) were trained for 4 months. Blood sampling for measurement of plasma concentrations (ELISA) of interleukin (IL)-6, tumour necrosis factor (TNF)-α, soluble TNF receptor 1 (sTNFR1) and 2 (sTNFR2), as well as cardiopulmonary exercise testing were performed at baseline and after 4 months. Training induced a significant decrease in sTNFR1 ( P =0·02) for the total population, and in both sTNFR1 ( P =0·01) and sTNFR2 ( P =0·02) concentrations for the CAD group only. IL-6 and TNF-α levels were not altered. Cytokine concentrations remained unchanged in an untrained age- and sex-matched control group. NYHA functional class, submaximal and maximal workrate were significantly improved in both patient groups. Oxygen uptake at the anaerobic threshold ( P =0·002) and at peak exercise increased in the CAD patients only ( P =0·008). Conclusion Besides an overall beneficial effect on exercise capacity, combined endurance/resistance exercise training has an anti-inflammatory effect in patients with CHD and CAD. Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.
Background: Both C-reactive protein and low-density lipoprotein (LDL) cholesterol levels are elevated in persons at risk for cardiovascular events. However, population-based data directly comparing these two biologic markers are not available. Methods: C-reactive protein and LDL cholesterol were measured at base line in 27,939 apparently healthy American women, who were then followed for a mean of eight years for the occurrence of myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. We assessed the value of these two measurements in predicting the risk of cardiovascular events in the study population. Results: Although C-reactive protein and LDL cholesterol were minimally correlated (r=0.08), base-line levels of each had a strong linear relation with the incidence of cardiovascular events. After adjustment for age, smoking status, the presence or absence of diabetes mellitus, categorical levels of blood pressure, and use or nonuse of hormone-replacement therapy, the relative risks of first cardiovascular events according to increasing quartiles of C-reactive protein, as compared with the women in the lowest quintile, were 1.4, 1.6, 2.0, and 2.3 (P<0.001), whereas the corresponding relative risks in increasing quintiles of LDL cholesterol, as compared with the lowest, were 0.9, 1.1, 1.3, and 1.5 (P<0.001). Similar effects were observed in separate analyses of each component of the composite end point and among users and nonusers of hormone-replacement therapy. Overall, 77 percent of all events occurred among women with LDL cholesterol levels below 160 mg per deciliter (4.14 mmol per liter), and 46 percent occurred among those with LDL cholesterol levels below 130 mg per deciliter (3.36 mmol per liter). By contrast, because C-reactive protein and LDL cholesterol measurements tended to identify different high-risk groups, screening for both biologic markers provided better prognostic information than screening for either alone. Independent effects were also observed for C-reactive protein in analyses adjusted for all components of the Framingham risk score. Conclusions: These data suggest that the C-reactive protein level is a stronger predictor of cardiovascular events than the LDL cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score.