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Vol. 7, 477-481, June 1998 Cancer Epidemiology, Biomarkers & Prevention 477
Anthropometric and Hormone Effects of an Eight-Week Exercise-Diet
Intervention in Breast Cancer Patients: Results of a Pilot l
Anne McTiernan,2 Cornelia Ulrich, Claudia Kumai,Deanna Bean, Robert Schwartz, Jan Mahloch,Rob Hastings, Julie Gralow, and John D. Potter
Cancer Prevention Research Program. Fred Hutchinson Cancer Research
Center. Seattle. Washington 98104 IA. M.. C. U., C. K.. D. B.. J. M., J. 0. P.1:
University of Washington School of Public Health. Seattle. Washington 98195
[A. M.. C. U.. J. 0. P.1: and University of Washington School of Medicine.
Seattle. Washington 98195 IR. S.. J. G.. R. H.l
Abstract
To assess the feasibility of an exercise-diet intervention insedentary, overweight breast cancer patients, weconducted a pilot 8-week intervention. Recruitmentletters and interest surveys were sent to 99 stage 1 or 2breast cancer patients, ages 25-75 years, who wereidentified through two Seattle breast surgery practicesand the University of Washington Breast Clinic. Tenpatients were eligible and interested and were enrolled inthe intervention, which consisted of thrice-weeklymonitored aerobic exercise sessions and a low-fat (20% ofcalories from fat) diet. Nine patients completed theprogram; all adhered well to the intervention and datacollection protocol. The patients, ages 40-74 years, lost,on average, 2.6 pounds of body weight, 3.4 cm in waistcircumference, 4.6 cm in hip circumference, 2.3% bodyfat, 3.3 systolic blood pressure points, 0.67 diastolic bloodpressure points, and 4.0 pulse beats/mm, and they gainedan average of 2.3% lean mass. Slight, nonsignificantdecreases were observed in serum concentration of totaland free estradiol, estrone sulfate, total testosterone,
androstenedione, and dehydroepiandrosterone.These pilot data indicate that breast cancer patients
are highly motivated to join and adhere to an intenseexercise-diet intervention and can experience significantmeasurable changes in anthropometric and fat massmeasures.
Introduction
Women with one breast cancer are at particularly high risk of
developing a second primary breast cancer ( 1 ). There has beenlittle to offer breast cancer patients, following completion ofprimary therapy, however, that might improve survival and
Received 10/20/97: revised 3/3 1/98: accepted 4/7/98.The costs of publication of this article were defrayed in part by the payment of
page charges. This article must therefore be hereby marked adrertise,nenz in
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
I A portion of this work was conducted through the Clinical Research Center
facility of the University of Washington. which is supported by NIH GrantMO I-00037.2 To whom requests for reprints should be addressed. at Cancer Prevention
Research Program. Fred Hutchinson Cancer Research Center, I 124 Columbia
Street. MP 002. Seattle, WA 98104.
reduce risk of recurrence or new disease in the long term (2).
Women who are obese or who gain weight after diagnosis ofbreast cancer have a poorer survival than lighter women (3).
The relationship between weight and survival may have ahormonal mechanism: high endogenous estrogen levels havebeen shown to be associated with shortening of disease-freeinterval in postmenopausal patients with recurrence (4); ele-vated levels of endogenous estrogens and androgens are linkedwith increased risk for initial breast cancer occurrence (5. 6):and overweight postmenopausal women have elevated produc-tion of estrogen from adrenal androgens (7). Overweightwomen also have high plasma insulin levels. which have been
found, in one study, to be positively associated with risk ofbreast cancer development, independent of body weight (8).Reduction of fat mass might reduce endogenous estrogen, an-
drogen, and insulin concentrations and, therefore, may be auseful adjunct therapy for breast cancer patients.
We tested the feasibility of recruiting, screening, enrolling,
and maintaining breast cancer patients in an intensive 8-weekexercise and low-fat diet program. We tested the effect of thisshort intervention on weight (fat mass) loss and on serum sexhormone concentrations in 10 women with stage I or 2 breastcancer.
Materials and Methods
We conducted a feasibility study of an exercise-diet program
for breast cancer patients to investigate whether breast cancerpatients could be recruited to and retained in an intervention
exercise-diet program and to assess changes in various physi-ological measures. Patients served as their own controls, and
comparisons were made between pre- and postinterventionparameters. The study was approved by the Fred HutchinsonCancer Research Center Institutional Review Board, and allstudy participants gave written informed consent before theywere enrolled in the study.
Breast cancer patients between the ages of 25 and 75 years
were recruited from three Seattle-area oncology practices. Thestudy recruitment nurse (J. M.) visited the three practices (two
private breast surgeons and one academic oncology group) andmet with clinic nurses to go over patient rosters. On the basis
of patient eligibility criteria (ages 25-75 years, �4 monthssince active treatment, and stage I or 2 invasive breast cancer)
and approval of the nurses (illness and patient emotional fac-tors), the recruitment nurse developed a list of eligible patients.
Patients were sent a recruitment letter signed by the studyprincipal investigator (A. M.) and coinvestigator/oncologist
(J. 0.) and a screening questionnaire to complete. The letterindicated that the patient’s physician had given us her name tocontact about the study. Women who were found to be eligibleon review of these questionnaires were contacted by phone bya physician assistant (C. K.). The study was explained in full,and patients were invited to a screening clinic visit. Table I lists
eligibility and exclusion criteria. We excluded patients who
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478 Exercise-Diet Effects in Breast Cancer Patients
Table 1 Inclusion and exclusion criteria
Inclusion/.
exclusion
.Cntena
Inclusion Female
Stage I or 2 invasive breast cancer. in remission
Between the ages of 25 and 70 years at screening
Four or more months posttreatment (surgery. radiation therapy.
or chemotherapy)
Sedentary (exercising less than twice a week at a,20 mm per
session)
Overweight or obese (body mass index of >25.0)
Exclusion Illnesses or conditions that contraindicate exercise or low-fat diet
(e.g.. myocardial infarction or stroke in past 6 months.
congestive heart failure. and so on)
Use of hormone replacement therapy or oral contraceptives in
the past 4 months
Currently pregnant or planning to become pregnant during the
study period
Special diet that could not accommodate study diet
Currently suffering from nausea or anorexia
Weight loss of > 10 pounds in the previous 3 months
Eating > 10 meals/week outside of home
Not having control of food ingredients in diet
Smokers
Current uncontrolled thyroid disorder
Alcohol use of >2 drinks/day
Selected medications that might interfere with the measurement
of serum sex hormones
were currently undergoing treatment for breast cancer, exceptfor use of Tamoxifen, because most of the otherwise eligible
patients were using this adjuvant therapy.Patients were further screened with a physical exam, com-
plete blood count, blood chemistry, and a lipid panel. They had
a resting electrocardiogram and an exercise treadmill test (9).Women who continued to be interested and eligible were en-rolled into the exercise-diet program.
Exercise Program
The exercise program consisted of moderate intensity exercise
(e.g., stationery bicycle or brisk walking). The goal was 30-45mm per day, 6 days per week, by the end of the 8-week
intervention period. The program was individually prescribed,based on the woman’s level of fitness, as determined on thetreadmill test, with a goal of 70-80% maximal heart rate. Theprogram was based on similar successful programs conductedat the University of Washington Exercise Physiology Labora-
tory ( 10). Initially, patients met individually or in small groupswith the exercise physiologist (D. B.) in monitored exercisesessions three times per week. Starting at about halfwaythrough the program, patients also exercised at home on non-monitored days. All exercise sessions were monitored with
upper and lower pulse alarms. Patients kept a daily exercise
diary, where they recorded exercise done, length of session, and
pulse rate.
Dietary Program
The dietary program consisted of a low-fat (20% calories fromfat) diet. The dietary change program was modified from theWomen’s Health Initiative Dietary Change program (I I) to fit
into the time and resource constraints of this feasibility study.Patients met once individually or in a group with a nutritionist
(C. U.). At this meeting, patients learned skills to change eatingbehaviors to adopt the dietary program. Patients were given
programmatic written intervention materials that explained insequential detail the nutritional concepts and behavioral tech-niques needed to change to the new diet. They were also
instructed in completion of a daily self-monitoring measure-ment, which they used for about 2 weeks. Patients were giventhe phone number of the nutritionist and invited to call her ifthey had any questions. In addition, the nutritionist called eachwoman about 3 weeks after the counseling session to assess
adherence and to provide additional counseling, if needed.
Adherence to the dietary program was measured with a mod-ified Block 98-item food frequency questionnaire (12), admin-istered at baseline and at 8-week follow-up, in which patients
were asked to recall the frequency at which they had eaten
selected foods over the preceding month.
Outcome Measures
The primary study outcomes were changes in weight and adi-posity, as determined by percentage fat mass (measured by RJL
Multifrequency Bioelectnical Impedance). Anthropometrtcmeasures were taken by the physician assistant. Weight was
measured at baseline and at 8-10 weeks after baseline. Patientswere weighed consistently in light clothing (hospital gown), on
the same recalibrated balance scale, rounded up to the nearest
0.5 pound. Waist circumference was measured at the narrowestpoint between hips and chest with the participant standing. Hipcircumference was measured at the widest point below thewaist. Additional outcome measures included fat-free mass and
serum sex hormone concentrations (a priori, it was acknowl-
edged that this was a pilot feasibility study and that the studydid not have sufficient power to detect measurable changes inoutcome variables).
Sex Hormone Measurements
Blood was collected (in the morning, after a I 2-h fasting) from
participants at baseline and at the 8-week follow-up visit, cen-trifuged, aliquoted as serum into 2-ml cryovials, and stored at-70#{176}C for 2-3 months before being shipped to EndocrineBiosciences Laboratory for hormone assays. Each individual
assay (for both baseline and follow-up) was performed in onebatch.
Total El3 and Total E2. The estrogens were separated frombinding globulins by organic extraction ([3H]E1 and [3H]E2were added to monitor recovery) and Sephadex LH-20 chro-
matography using benzene methanol. Total E2 and total Elwere determined by RIA. Aliquots of purified samples wereincubated 3 h at room temperature with an antiserum to anestrone-6-oxime BSA conjugate for the El RIA and an anti-serum to 17f3-estradiol-6-oxime for the E2 RIA. CVs were
10.8% for E2 and 9.2% for El.
Free E2. Percentage free or non-protein-bound E2 was deter-mined by equilibrium dialysis of serum samples at 37#{176}Cfor16 h against pH phosphosaline buffer containing 50,000 dpm of
purified 3H-estradiol. Radioactivity was determined by liquidscintillation counting. The free E2 concentration was derivedfrom the product of serum E2 by RIA and percentage freesteroid obtained by dialysis. CVs ranged from 10.3 to 13.9%.
SHBG. The binding capacity of SHBG was directly measuredin serum using a displacement technique. Sensitivity was 0.1�sg/dl. CVs ranged from 4.1 to 14.4%.
3 The abbreviations used are: El, estrone; E2, estradiol; CV, coefficient ofvariation; SHBG, sex hormone-binding globulin; DHEA, dehydroepiandros-
terone; DHEA-S, DHEA sulfate.
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Cancer Epidemiology, Biomarkers & Prevention 479
El Sulfate. El sulfate was measured by RIA after purificationof Sephadex LH-20 columns. Serum was extracted with hex-ane-ethyl acetate to remove unconjugated E 1 and then dilutedin buffer and incubated overnight with a sulfatase enzyme
preparation to hydrolyze El sulfate. After column chromatog-raphy, the El content of the column was determined by RIA
using a sensitive and specific antiserum developed against an
estrone-6-oxime albumin conjugate. CVs ranged from 9.3 to
12.0%.
Free and Total Testosterone. Free testosterone was measuredby equilibrium dialysis in a method similar to that used for free
E2, with [3H]E2 replaced by [3H]testosterone. Testosteronewas measured with RIA, after extraction and column chroma-
tography, using a specific antibody to testosterone (testoster-one-3-oxime BSA conjugate). CVs ranged from 5.7 to 10.9%.
Androstenedione. Androstenedione was extracted from serumwith hexane-ethyl acetate and then purified by celite chroma-tography. The purified extract was assayed by a RIA using an
antiserum raised to androstenedione-6-thioether-BSA. CVsranged from 6.2 to 10.8%.
DHEA. Samples were extracted using hexane-ethyl acetate
and purified on small aluminum oxide columns. DHEA recov-
ery was monitored by the addition of [3H}DHEA. Aliquots ofchromatographed samples were transferred to duplicate tubesand incubated with a rabbit antibody to DHEA-17-oxime-BSAfor 3 h. Free and antibody-bound steroid were separated by theaddition of ammonium sulfate. The free DHEA fraction was
quantified by liquid scintillation counting. CVs ranged from 8.4to 17.2%.
DHEA-S. DHEA-S was measured by a highly specific RIA.Twenty-pA aliquots of serum were diluted with acetate buffer
and hydrolyzed overnight with a large excess of sulfatase
enzyme. The DHEA content was determined by RIA using ahighly specific antibody developed to a DHEA-7-oxime-anti-
gen. CVs ranged from 5.2 to 8.3%.Two blind duplicate specimens from each of four nonen-
rolled breast cancer patients were included with all laboratoryassays, as a measure of assay reliability.
Results
Ninety-nine invitation letters with screening surveys weremailed, and 40 completed surveys were received. After reviewof the survey, 17 subjects were deemed preliminarily eligible
and were invited to a screening clinic visit. The primary reasonsfor ineligibility, as determined by the screening questionnaire,were a body mass index of <25.0 and a nonsedentary lifestyle.Thirteen patients came to a screening visit. After the screening
visits, 1 1 remained interested and eligible and were scheduledfor an exercise treadmill test with one of the study physicians(R. S. or A. M.). Of these, 10 were cleared for an exerciseprogram and one had exercise-induced cardiac arrhythmia (re-
ferred to a cardiologist for evaluation). Those ten patients werethen enrolled in the program.
Enrolled participants’ ages ranged from 40 to 74 years;eight patients were postmenopausal (� 1 year since their lastmenstrual period). Nine were white and 1 was Asian-American,
and 7 of the 10 were currently employed outside the home.
Most (8 of 10) had stage 1 breast cancer; the remaining 2 hadstage 2 disease. Patients were 1-5 years post-active treatmentfor breast cancer, and 6 of 10 were currently using Tamoxifen
(none were on chemotherapy at the time of recruitment or
during the study). Only two patients had received chemother-apy for treatment: one had cytoxan and Adriamycin; and the
Table 2 Change in average daily dietary intake of macronutrients
(a = 8 patients)”
Baseline Follow-up P’
Fat(g) 55.3)18.4) 35.2(14.2) 0.05
%caloriesfromfat 32.2(7.2) 24.7)6.1) 0.05
Vegetables (no. of servings) 1 .9 (0.79) 2.0 ( 1 .5 ) 0.95
Fruits (no. of servings) 1.4 ) 1.0) 2.1 ( 1.4) 0.16
Vitamin C (mg) 82.9 (45.6) I 16 (5.4) 0.20
a-Carotene (mg) 4867 (3229) 4621 (4531) 0.84
‘, Values are mean (SD).b Two-tailed Wilcoxon rank-order test.
other had methotrexate, 5-fluorouracil, and cytoxan. Sevenpatients had a history of radiation therapy for breast cancer.
Adherence to the program was excellent. One patientcompleted some of the exercise sessions but, for personalreasons, declined future sessions, the follow-up visit, and data
collection. Outcome data are presented for the nine patientswith follow-up data. Patients had excellent performance in the
exercise program. On average, the nine patients completed 22.1of 24 possible monitored sessions (average, 2.8 per week).
Patients began the endurance exercise program at -65-70% ofmaximal heart rate and advanced, as they were able, to an
average of 80%-85% (range, 70-90%) of maximal heart rate.Sessions lasted from an average of 10.2 mm on the treadmill
and 10.1 mm on the bicycle at baseline to 30 mm on thetreadmill and 20 mm on the bicycle by the end of the 8-weekprogram. On average, the patients also completed two 30-mmsessions at home, doing such activities as walking, bicycling,
and gardening. Compliance with performance in the dietaryaspects of the program was also excellent. As shown in Table2, for the eight patients with baseline and follow-up dietary
data, the average decline in daily percentage of calories from fatwas 7.5. They also decreased total fat grams (P 0.05) and
increased daily intake of fruits and vitamin C (P > 0.1).On average, patients experienced statistically significant
decreases in body weight, percentage fat mass, and waist andhip circumference and increases in percentage lean mass be-
tween baseline and 8-10 weeks follow-up (Table 3). Small,statistically nonsignificant declines in systolic blood pressure,diastolic blood pressure, and resting pulse were noted.
Slight, statistically nonsignificant decrements were ob-served in serum concentrations of total and free E2, El sulfate,total testosterone, androstenedione, and DHEA-S (Table 4).
SHBG decreased by 8% (P 0.05). When the analysis waslimited to the seven women who lost fat mass during theintervention period, the results were unchanged. Pearson cor-
relation coefficients for blind duplicates for specific assaysranged from 0.98 for free testosterone to I .00 for SHBG.
We examined change in all outcome variables separatelyfor women using and not using Tamoxifen and found no dif-ference between the two groups.
Discussion
The effect of excess weight and obesity on prognosis and
survival from breast cancer has been assessed only throughobservational studies (3, 12-15). Weight, dietary intake, andphysical activity are highly intercorrelated ( 16), however, lead-ing to difficulties in assessing independent and interrelated
effects of each component on breast cancer prognosis. Womenwho are physically active are more likely to have diets that are
lower in fat and higher in fiber, fruits, and vegetables and to use
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480 Exercise-DIet Effects in Breast Cancer Patients
Table 3 Changes in physical meas ures after an 8-week exercise -diet program”
Factor Baseline Change I” jY�
Weight (pounds)
Waist (cm)
Hip (cm)
Waist:hip ratio
% body fat
% lean mass
Systolic blood pressure (mm Hg)
Diastolic blood pressure
(mm Hg)
Resting pulse (bpm)
169.2
93.9
I I 3.6
0.828
39.0
61.0
133.1
79. I
74.6
-2.6 (3.0)
-3.4 (3.5)
-4.6 (4.4)
+0.002 (0.03)
-2.3 (2.9)
+2.3 (2.9)
-3.3 (18.0)
-0.67 (9.8)
-4.0 (10.3)
0.04
0.02
0.02
0.82
0.06
0.06
0.61
0.84
0.28
0.05
0.008
0.02
0.77
0.05
0.05
a Values are mean (SD). The exercise component consisted of training and
monitoring three times per week with an exercise physiologist (moderate intensity
exercise for 30-45 mm). The diet component consisted of low-fat foods (�20%
calories from fat) and high fruit and vegetable intake (eight or more per day).
b Two-tailed I test for paired samples.
‘. Two-tailed Wilcoxon rank-order test.
vitamin supplements, as compared with sedentary individuals
(17, 18). Furthermore, it has been proposed that obese individ-uals systematically underreport intake of total calories, fat, andcarbohydrates (19); the same biased reporting may be true forphysical activity.
Randomized controlled intervention trials can minimizethese biases (20) because individuals inclined to follow a life-
style cluster of behaviors would be assigned by chance to thelifestyle intervention or control group.
Exercise coupled with dietary caloric reduction is an ef-
fective method to reduce weight and maintain ideal bodyweight parameters (21, 22). The effect of low-fat and high-fruitand -vegetable diets on breast cancer recurrence and survival is
being tested in the Women’s Intervention Nutrition Study, a
large-scale clinical trial of postmenopausal women with re-sected breast cancer (23). The association between exercise andprognosis and survival from breast cancer have been subject to
only minimal observational study (24), and no exercise inter-vention studies have been done to assess prognostic effects.
The results of this study of exercise for breast cancerpatients give useful preliminary information on the feasibility
of recruiting, enrolling, and maintaining breast cancer patientsin a combined diet-exercise intervention. Very high rates of
interest were observed among invited women, as indicated bythe 38% response to an initial mailing. This compares to re-
sponses of 0.5-7.0% observed in intervention studies in healthypersons or individuals with other diseases (25). Approximately10% of approached patients were eventually enrolled into the
intervention, which represents a high rate of recruitment into anintense and time-consuming behavioral intervention study (25).The patients made substantial changes to their diet and exercisehabits in a relatively short time, with resulting significantchanges in body weight, fat and lean mass, and waist and hipcircumferences. This highly motivated compliant group may
not be representative of all women but may be characteristic ofbreast cancer patients who are willing to adopt lifestyle
changes. Breast cancer patients have shown excellent adher-
ence to dietary interventions in previous studies (26).Minimal effects were observed on circulating concentra-
tions of sex hormones. The statistically borderline decrease in
SHBG may have been due to chance because many secondaryvariables were assessed. The lack of significant effect in hor-
mones is not surprising, given the small sample size and shortintervention time. The measurement of sex hormones in post-menopausal women is subject to large within-person variabil-
Table 4 Changes in serum sex hormones after an 8-w
program”eek exercise-diet
Hormone (mg/dl) Baseline Follow-up P” PC
Total E2
Free E2
Total El
El sulfate
Total testosterone
Free testosterone
Androstenedione
SHBG
DHEA
DHEA-S
1 .6 (1 .7) 1 .4 (1 .4)
0.56 (0.68) 0.53 (0.65)
2.8 (0.87) 3.0 (0.89)
67.0 (35.1) 54.4 (13.2)
16.9 (7.3) 16.2 (8.8)
1.3 (0.41) 1.2 (0.43)
55.1 (18.7) 51.2 (14.2)
2.4 (I .2) 2.2 (1.1)
201.3 (92) 187.1 (91)
45.7 (28.7) 40.8 (14.1)
0.58
0.90
0.34
0.28
0.56
0.36
0.49
0.06
0.61
0.45
0.45
0.72
0.29
0.81
0.21
0.40
0.48
0.05
0.51
0.64
a Values are mean (SD). The exercise component consisted of training and
monitoring three times per week with an exercise physiologist, (moderate inten-
sity exercise for 30-40 mm). The diet component consisted of low-fat foods(�20% calories from fat) and high fruit and vegetable intake.b Two-tailed t test for paired samples.
C Two-tailed Wilcoxon rank-order test.
ity, with resultant large sample sizes needed to detect a signif-icant effect. To observe a 20% decrease in total E2 (with 80%
power), for example, it would be necessary to enroll and main-tan 78 women in an intervention arm. No previous study hasreported an exercise effect on endogenous sex hormones inbreast cancer patients. However, studies of dietary interventionsuggest that an intensive low-fat dietary pattern may reducecirculating levels of estrogen and androgens (27).
The major limitation of this study is the small sample size.Because of the study design, we could not separate effects of
exercise and diet on the study outcomes. Six of the 10 enrolling
patients were using Tamoxifen at enrollment (and at follow-up), and results did not differ in those using or not using
Tamoxifen. Yet, we were able to observe a number of signif-icant results in the predicted direction, which is consistent witha true effect of the exercise-diet intervention on physiological
parameters of interest.The powerful effects of the antiestrogen Tamoxifen in
certain breast cancer patients (28) and of oophorectomy inpremenopausal breast cancer patients (29) on improving sur-
vival and reducing recurrence suggests that interventions toreduce circulating sex hormones may also benefit breast cancer
patients. Behavioral exercise and diet interventions, if effective,would have the advantages of being self-directed, noninvasive,
and beneficial to a variety of health outcomes and may be auseful adjunct to conventional therapy. The high level of inter-est by approached patients indicates that interventions of this
type may be very attractive to breast cancer patients.This pilot study suggests that overweight and obese breast
cancer patients can achieve substantial improvements in fat andlean mass and anthropometnic measures with an exercise-dietintervention. We are currently conducting a randomized clinicaltrial to test the effect of moderate-intensity aerobic exercise
intervention on endogenous sex hormones in sedentary over-weight women, ages 55-75 years (a group at elevated risk forbreast cancer). Our experience lays the groundwork for devel-
opment of large-scale clinical trials of exercise in breast cancer
patients.
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1998;7:477-481. Cancer Epidemiol Biomarkers Prev A McTiernan, C Ulrich, C Kumai, et al. pilot study.exercise-diet intervention in breast cancer patients: results of a Anthropometric and hormone effects of an eight-week
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