1. Energy Balance, Adiposity, Physical
Activity and Breast Cancer
Cheryl L. Rock, PhD, RD
Dept. of Family and Preventive Medicine
Cancer Prevention and Control Program
2. Obesity and Risk and Progression of
Breast Cancer
Breast cancer is the most common cancer
worldwide in women, accounting for 23% of the
total number of new cancers diagnosed
Death rates from breast cancer have been
steadily declining, and there are now an
estimated 2.9 million women in the US alone with
a history of breast cancer
The relationship with BMI and incident breast
cancer is complex: Positively related in
postmenopausal women, but inversely related in
premenopausal women
3. Relative Risk of Breast Cancer Across Quintiles of
BMI in Premenopausal and in Postmenopausal
Women Who Did Not (or Did) Use Hormone Therapy
Pischon et al. Proc Nutr Soc 2008;67:128–145
4. Multivariate Adjusted RR of Breast Cancer by BMI and
Current Hormone Use Among Postmenopausal Women
(N=103,344), EPIC Study
Lahmann et al. Int J Cancer 2004;111:762–771
5. Physical Activity and Breast Cancer
Risk
The majority of epidemiological studies have
found a significant risk reduction among the
most (vs. least) physically active women, with an
average risk reduction of 25-30%, and a dose-
response effect
Evident in both pre- and postmenopausal
women, but greater in magnitude for
postmenopausal women and also in leaner (vs.
obese) women
Stronger risk reduction for recreational, lifetime
or later life and vigorous activity, in non-white
women and women without a family history
Friedenreich et al. Br J Sports Med 2008;42:636–647
6. Case-Control Studies of Physical Activity
and Breast Cancer Risk
Friedenreich et al. Br J Sports Med. 2008;42:636–647
7. Cohort Studies of Physical Activity and Breast Cancer Risk
Friedenreich et al. Br J Sports Med. 2008;42:636–647
8. Obesity and Cancer Progression
and/or Survival
Consistent evidence suggests that obesity is a
negative prognostic factor in breast cancer
Excess adiposity is a major risk factor for breast
cancer recurrence and mortality in both pre- and
postmenopausal women
Higher BMI is a significant independent predictor
of mortality regardless of tumor characteristics
In women who have been diagnosed with breast
cancer, obesity is associated with a 30%
increased risk of breast cancer outcomes
(recurrence, all-cause and breast cancer-specific
mortality)
10. Disease-free Survival of 557 Patients with Breast Cancer
and Negative Nodes According to Obesity at Diagnosis
Non-obese
Disease-free Survival (%)
Obese
Disease-free Months
The number of patients at risk at time 0, at 5 years, and at 10 years is shown for each set of survival
curves. Hazard ratio, 1.93 (95% CI, 1.29 to 2.88: P= 0.001). (Senie et al. Ann Int Med 1992;116:26-32)
11. Meta-Analysis and Pooled Hazard Ratio of the Effect of
Obesity on Breast Cancer-Specific Survival in
Breast Cancer Patients
Protani et al. Breast Cancer Res Treat 2010;123:627–635
12. Meta-Analysis and Pooled Hazard Ratio of the Effect of
Obesity on Overall Survival in Breast Cancer Patients
Protani et al. Breast Cancer Res Treat 2010;123:627–635
13. Physical Activity and Breast Cancer
Prognosis
Consistent evidence from epidemiological studies
suggests that physical activity before or after
breast cancer diagnosis is associated with reduced
all-cause and breast cancer-specific mortality, and
with a dose response effect
Some evidence for effect modification by BMI, but
not consistent, and no differences for pre- and
postmenopausal women or race or ethnicity
Higher level of physical activity appears to be
associated with a 30% decreased risk of mortality
15. Forest Plot of Risk Estimates from Observational Studies
of Physical Activity and Mortality Outcomes in
Breast Cancer Survivors
Indicate hazard ratios (HRs)
95% Confidence intervals (CIs)
Indicates point of unity
Ballard-Barbash et al. J Natl Cancer Inst 2012;104:815-840
16. Obesity: Possible Mechanisms
Several mechanisms have been proposed to explain
the adverse effect of excess adiposity (and physical
activity) on the risk and progression of breast cancer
Circulating reproductive steroid hormones
Insulin and interactions with growth factors
Inflammatory cytokines
17. Reproductive Steroid Hormones
Adipose tissue is an important extragonadal source
of estrogens from precursor adrenal androgens
Endogenous circulating estrogens are 50-100%
higher in postmenopausal obese (vs. normal
weight) women
Obesity is associated with decreased sex-hormone
binding globulin (SHBG)
High circulating estrogen levels are a risk factor for
breast cancer recurrence (Rock et al. CEBP
2008;17:614-620)
18. Adipose Tissue Production of Estrone and
Estradiol from Androstenedione and the Bioavailability of
Estradiol in Postmenopausal Women
Rose & Davis. Maturitas 2010;66:33-38
19. Insulin, Growth Factors, and
Inflammation
Insulin exhibits mitogenic effects that influence both
premalignant and cancerous stages of cell growth, and
insulin and insulin like growth factor (IGF) – I stimulate
mammary cell proliferation in vitro
Insulin also stimulates the synthesis of sex hormone
steroids and inhibits the synthesis of SHBG
Obesity is characterized by chronic mild inflammation,
and weight loss reduces inflammatory factors
Inflammation plays a central role in the insulin
resistance associated with obesity: Cytokines decrease
insulin action by affecting insulin receptor activity
20. 120
r=.54
100
Insulin ųIU/ml
80
60
40
20
0
15 20 25 30 35 40 45 50 55 60
Body Mass Index (kg/m2)
21. Potential Effect of Weight Loss on Proposed Hormonal and
Biological Factors Linking Obesity to Breast Cancer
22. Primary Prevention
In the general population, even a modest degree of
intentional weight loss favorably affects many
breast cancer-relevant risk factors and potential
mediators (Byers & Sedjo. Diabetes Obesity Metab
2011;1312:1063-1072)
Reduced levels of estrogens (30% reduction expected
with 10% weight loss) and increased SHBG
CRP levels decline with similar magnitude after weight
loss
Reductions in TNF-α and IL-6 also observed but of smaller
magnitude
23. Issues Specific to Cancer Survivors
Body image issues related to cancer and cancer
treatments
Enduring psychosocial symptoms, such as
depression and fatigue, affect efforts to make
changes in behaviors
Changes in family dynamics and social support
Increased physical activity is particularly
important, due to effects of treatments on body
composition, and the relationship between lean
body mass and resting energy expenditure
24. Reach Out to ENhancE Wellness in
Older Survivors (RENEW)
• Test the impact of a diet-exercise mailed
material/telephone counseling program on weight loss
and physical functioning in prostate, colorectal and
breast cancer survivors (N=641)
• Study participants: >65 years of age and overweight,
within 5 years of diagnosis, 45% male
Morey et al. JAMA 2009;301:1883-1891
28. Combining Weight Loss Counseling
With Weight Watchers
• Obese breast cancer survivors (N=48) assigned to
individualized weight loss counseling, referral to the
Weight Watchers program, a combination of both, or
control
• Weight change after 12 months of intervention was
0.85 + 6.0 kg (<1% of initial weight) in controls, -2.6 +
5.5 kg (2.7% of initial weight) in the Weight Watchers
only group, -8.0 + 5.5 kg (8.4% of initial weight) in the
individualized counseling only group, and -9.4 + 8.6
kg (9.8% of initial weight) in the combined group
Djuric et al. Obesity Res 2002;10:657-665
29. Weight Loss with Time in Each Study Arm:
Mean and SD of Change in Body Weight
30. Reducing Breast Cancer Recurrence
with Weight Loss: A Vanguard Trial
Exercise and Nutrition to Enhance Recovery and Good
Health for You (ENERGY) Trial (Rock et al. Contemp Clin
Trials 2013;34:282-295)
Randomized controlled study with the primary endpoint of
clinically significant weight loss in 693 overweight or obese
breast cancer survivors, with demonstration of
improvements in quality of life and co-morbidities
Prospective collection of blood and DNA samples to
examine effects on hormones and other factors to explain
the mechanism and probable differential response across
subgroups
Serves as vanguard for a larger cancer outcome study with
sufficient statistical power to assess effects of weight loss
on cancer outcomes in overweight or obese breast cancer
survivors
31. Preliminary Studies
Healthy Weight Management Study, N=85, group-based
cognitive-behavioral weight loss program plus telephone contacts
(Mefferd et al. Breast Cancer Res Treat 2007;1042:145-152)
• Intervention group mean 83.9 kg at baseline, 78.2 kg at 16 wks
(7% of initial weight), and 77.3 kg (8% of initial weight) at 12
mos; reported 7.4 hrs/wk mod + vig activity at 12 months
• Favorable changes in % body fat, waist circumference, SHBG,
bioavailable estradiol, and total and LDL cholesterol
Breast Cancer Survivors Health and Physical Exercise (SHAPE)
Study N=259, group-based behavioral weight loss program (Rock
et al. Clin Breast Cancer 2013)
• Intervention participants lost -4.6 kg (5.5% of initial body
weight) at 6 months and -3.8 kg (4.5% of initial body weight) at
18 months
• Weight loss of >5% associated with favorable changes in
depression, self-esteem, insulin, leptin, and estrogens (in
postmenopausal women)
32. SHAPE Study: Biological Factors by
Follow-up Weight Loss Category*
6-Month Follow-up 18-Month Follow-up
≥5% Weight <5% Weight ≥5% Weight <5% Weight
Loss Loss Loss Loss
(n = 74) (n = 139) P Value (n = 63) (n = 140) P Value
Insulin, µIU/mL
Baseline 16.9 (9.0) 16.3 (8.1) .64 16.9 (7.1) 17.1 (8.3) .08
Follow-up 13.2 (6.1) 19.8 (17.4) <.0001 15.8 (7.3) 23.0 (13.0) <.0001
Leptin, ng/mL
Base 36.4 (18.6) 39.5 (22.4) .32 34.5 (20.3) 40.3 (22.1) .08
Follow-up 20.3 (11.4) 34.5 (18.2) <.0001 20.1 (15.7) 29.8 (14.9) .0001
Sex hormone binding globulin, nmol/L
Baseline 58.9 (35.2) 58.4 (32.6) .92 64.9 (37.9) 55.5 (31.0) .06
Follow-up 71.7 (37.6) 56.3 (33.2) .004 63.9 (29.6) 45.1 (26.6) <.0001
* Values shown are mean (SD). P values represent results of t-tests between weight loss groups.
33. ENERGY Trial
Four sites; UCSD is the Coordinating Center
Subjects: Women aged > 21 years; diagnosed
with breast cancer (Stages I [≥1 cm], II, or III)
between 6 months and 5 years earlier; BMI
between 25 and 45 kg/m2
Intervention: Cognitive-behavioral closed group
sessions, tailored newsletters, individual
participant contacts (by email and/or telephone)
Control: Two individual counseling sessions,
health seminars, monthly contacts
34. ENERGY Trial: Comparability of Study Groups
Control Intervention
(n = 348) (n = 345)
Age, years (mean [SD]) 56.5 (9,5) 56.1 (9.5)
Education, years (mean [SD]) 15.5 (2.4) 15.6 (2.5)
Hispanic (%) 5.8 7.6
Race (%)
White 84.5 83.1
African-American 10.6 10.5
Asian-American 2.0 1.5
American Indian 0.3 0.6
Hawaiian/Pacific Islander 0 0.3
Mixed/Other 2.0 3.8
Missing or refused 0.6 0.3
Postmenopausal at study entry (%) 85.0 85.7
Weight, kg (mean[SD]) 84.7 (13.8) 85.0 (14.3)
Body mass index, kg/m2 (mean [SD]) 31.4 (4.6) 31.6 (4.7)
Years between diagnosis and study entry (mean) 2.83 2.72
Breast cancer stage (%)
I 31.9 32.0
II 51.7 48.6
III 16.4 19.5
35. Measurements and Outcomes
Measurements
• Blood pressure
• Questionnaires: Quality of life, physical activity
• Weight, waist circumference, step test
• Blood sample collection
Outcomes
• Weight loss and weight loss maintenance over a
two-year period (goal is 7% of initial weight)
• Quality of life
• Co-morbidities
• Cancer outcomes in preparation for a larger trial
• Biological samples
36. Transdisciplinary Research in
Energetics and Cancer (TREC)
Cooperative agreement initiative (U54) that explores the
relationship between obesity and cancer, funded by the
National Cancer Institute (Patterson et al. Cancer Causes
Control 2013)
Integrates the study of diet, weight, and physical activity
and their effects on energy balance and cancer
Projects: Biologic and physiologic mechanisms of energy
balance; behavioral, sociocultural, and environmental
influences on diet, physical activity and weight in cancer
survivors and other populations
Across the four centers, two (at UCSD and Univ. of Penn.)
are focused on energy balance and weight loss
interventions in breast cancer prevention and control
37. Considerations
Limitations of observational studies
Confounding: Difficult if not impossible to control for
other influencing factors, clustering of behaviors
Obesity is inextricably linked to behavioral determinants
Measurements are crude: Few if any physical activity
studies used objective measures, and few include full
assessment of all types and doses
Obesity and breast cancer risk and progression
Potential modulators, such as obesity-related
comorbidities
Energy restriction versus reduced adiposity
Manage metabolic changes associated with obesity
rather than focus on weight loss?
38. Weight Loss Interventions for Breast
Cancer Survivors
This target population is motivated and able to make
modifications in diet and physical activity to promote
weight loss
Individualized counseling (in person or telephone),
group sessions, and mailed material can promote
weight loss
More intensive interventions produce greater weight
loss
Evidence suggests that proposed biological
mediators are favorably affected
39. ENERGY Research Team
ENERGY Trial investigators (in alphabetical order):
Tim Byers, MD, MPH, Graham Colditz, MD, DrPH
(Data Management and Analysis), Wendy Demark-
Wahnefried, PhD, RD, Patricia Ganz, MD, Bilgé
Pakiz, EdD, Barbara Parker, MD, Cheryl Rock, PhD,
RD (PI of Parent Grant and Coordinating Center),
Rebecca Sedjo, PhD, Kathleen Wolin, ScD, Holly
Wyatt, MD
NCI: Catherine Alfano, PhD (program officer) and
Julia Rowland, PhD, Office of Cancer Survivorship;
also Robert Croyle, PhD, Division of Cancer Control
and Population Sciences
