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

Abstract

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.

Full text

Research Article
Effect of Exercise on Markers of Inflammation in Breast
Cancer Survivors: The Yale Exercise and Survivorship Study
Sara B. Jones
1
, Gwendolyn A. Thomas
1
, Sara D. Hesselsweet
1
, Marty Alvarez-Reeves
2
,
Herbert Yu
1
, and Melinda L. Irwin
1
Abstract
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.
Introduction
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' Affiliations:
1
Yale School of Public Health, New Haven, Connecti-
cut; and
2
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: melinda.irwin@yale.edu
doi: 10.1158/1940-6207.CAPR-12-0278
2012 American Association for Cancer Research.
Cancer
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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
survivors.
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
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.
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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
Randomized
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
Eligible
N = 88
Baseline visit
N = 88
Clinic visit
N = 75
Ineligible
N = 314
• Too active (N = 137)
• Age (N = 66)
• Deceased (N = 53)
• Premenopausal
(N = 31)
• Other (N = 27)
Unable to contact
N = 90
• Busy/no answer
(N = 62)
• Wrong phone #
(N = 28)
Refused
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.
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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
80C 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
2
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.).
Results
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
2
) 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.
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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)
a
Exercise group
(N¼36)
Usual care group
(N¼31) Pvalue
Age, y 56.4 (9.6) 55.4 (7.6) 0.64
Ethnicity
Non-Hispanic White 30 (83%) 27 (87%) 0.16
African-American 6 (17%) 2 (6%)
Asian/Pacific Islander 0 (0%) 1 (3%)
Unknown 0 (0%) 1 (3%)
Education
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
Stage
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%)
Treatment
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
2
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
b
, 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
a
Data are presented as mean (SD) for continuous variables and frequency (percentage) for categorical variables. Percentages may not
sum to 100 due to rounding.
b
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.
Discussion
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
a
Exercise group (N¼36) Usual care group (N¼31)
Marker Baseline 6 mo Mean change Baseline 6 m Mean change
Difference
between
groups
b
Pvalue
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
a
Data are presented as mean (SD).
b
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
2
0.65 P<0.0001 0.60 P<0.0001 0.19 P¼0.13
Physical activity, min/wk recreational activity
a
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
a
Assessed from the 7-day physical activity log administered at baseline.
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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
biomarker.
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
intervention.
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 Inflammatory Markers in Breast Cancer Survivors
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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
2
) 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
concentrations.
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 Conflicts 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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