The Role of Dietary Interventions and Dietary Supplements in Breast Cancer Management

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The Role of Dietary Interventions and Dietary
Supplements in Breast Cancer Management

• Cynthia Thomson, PhD, RD
• Associate Professor
• Nutritional Sciences,
• Public Health,
• and Medicine
• University of Arizona
• cthomson_at_u.arizona.edu

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Over 10.5M cancer survivors Comprise 3-4 of
U.S. population
Data source 2005 Submission. U.S. estimated
prevalence counts were estimated by applying U.S.
populations to SEER 9 and historical Connecticut
Limited Duration Prevalence proportions and
adjusted to represent complete prevalence.
Populations from January 2003 were based on the
average of 2002 and 2003 population estimates
from the U.S. Bureau of the Census
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ESTIMATED OF PERSONS ALIVE DIAGNOSED W/CANCER
BY SITE
Data source 2005 Submission. U.S. estimated
prevalence counts were estimated by applying U.S.
populations to SEER 9 and historical Connecticut
Limited Duration Prevalence proportions and
adjusted to represent complete prevalence.
Populations from January 2003 were based on the
average of 2002 and 2003 population estimates
from the U.S. Bureau of the Census
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AT RISK LIFESTYLE MODULATION OF BREAST CANCER
RISK

• New York Breast Cancer Study
• Lifetime risk among female BRCA mutation
  carriers 82
• Delayed onset among probands was demonstrated
  for
• Physically active during adolescence
• Healthy weight at menstruation onset
• Healthy weight at age 21
• Implies lifestyle can modify risk in at-risk
  subjects

King, MC et al, Science, vol 302, pp. 643- 646,
October, 2003
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WEIGHT AND BREAST CANCER KEY ISSUES

• Higher BMI associated with increased risk of
  breast cancer after menopause
• Higher BMI in childhood, pre-menopausal
  associated with decreased risk
• Weight change over adulthood
• Weight gain of 21 kg over adult life has been
  associated with an almost 75 increase in risk
  for developing breast cancer
• Inconsistent weight and risk of recurrent
  disease

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WEIGHT GAIN DURING TREATMENT

• Women who gain weight during treatment have
  reduced long term survival
• Less of an issue with current treatment
• Unique weight gain significant gain in body fat
  and loss of lean mass (sarcopenia)
• Change from baseline may be most significant
  factor
• Evidence of reduced REE (metabolism) during
  treatment
• Interventions focused on diet and physical
  activity have proven successful to prevent weight
  gain
• If exercise is included
• Best with regular RD counseling (face-to-face)

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BODY COMPOSITION CHANGE AFTER DIAGNOSIS OF BREAST
CANCER
Adjuvant Chemotherapy (CT) vs. Radiation (XRT)
alone
Fat Mass CT
Lean Mass XRT
Fat Mass XRT
Lean Mass CT
Baseline
6 Months
12 Months
Demark-Wahnefried W et al. J Clin Oncol. 192381,
2001
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PROPOSED MODEL TO EXPLAIN WEIGHT GAIN IN BREAST
CANCER
Chemotherapy
? Ovarian Function
? Physical Activity
? Muscle Mass
? Metabolic Rate
? Energy Needs
Weight Gain
Stable Energy Intake
Harvie et al. Breast Cancer Res Treat.83201,
2004.
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TOTAL PHYSICAL ACTIVITY BEFORE AND AFTER BREAST
CANCER DIAGNOSIS
Hours/week
Age in Years
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Total Physical Activity Before and After Breast
Cancer Diagnosis by Treatment
Hours/week
Age in Years
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Why weight control and physical activity?

• Reduced levels of circulating hormones
• Reduced levels of insulin and insulin-like growth
  factors
• Reduced levels of pro-inflammatory cytokines
  (immune cells)
• May improve bioavailability of drugs to treat
  disease (Tamoxifen, AIs, Chemo, etc)
• Improved psychosocial well being / QOL

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Low Fat Diet Physical Activity as Regulators
of Insulin
OBESE INDIVIDUAL HIGH Fasting Insulin LOW Fasting
Ghrelin BLUNTED feedback response to meal
consumption resulting in satiety HIGH
Adiposity UNSTABLE Glucose/Insulin
Regulation HIGHER Estradiol, IGF-1, Insulin levels
High Risk Breast Cancer Recurrence
LEAN INDIVIDUAL LOW Fasting Insulin HIGH Fasting
Ghrelin INTACT feedback response LOW
Adiposity STABLE Glucose/Insulin Regulation LOWER
Estradiol, IGF-1, Insulin levels
45 of BrstCaSurvivors w/BMI gt 25 undiagnosed
metabolic syndrome
Low Risk Breast Cancer Recurrence
Impact of Dietary Intervention on Breast Cancer
Promoters
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METABOLIC SYNDROME IN BREAST CANCER SURVIVORS

• Study Mean (SD) (n42)
• Fasting glucose (mg/dl)
  98.7 (12.9)OGTT at 2hrs (N23)
  119.0 (32.4)Insulin
  (uU/ml)
  16.1 (13.2)Glycosylated hemoglobin (HbA1c,
  ) 6.0 (0.53)
• Triglycerides (TG, mg/dl)
  129.4 (55.72)Total cholesterol (mg/dl)
  199.9 (33.69)HDL
  cholesterol (mg/dl)
  57.7 (17.46)LDL cholesterol (mg/dl)
  116.4 (28.60)
• C-reactive protein (hsCRP, mg/L)
  5.12 (5.31)Systolic blood pressure (mmHg)
  129.9 (18.13)Diastolic blood pressure
  (mmHg) 79.1 (11.45)
•  Metabolic SyndromeNCEP ATP III revised criteria
  23 (53.5)TG/HDL
  
  12 (27.9)

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Change in Weight with Change in Diet
JAMA 2006 295 39-49
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Prevention of Frailty in Breast Cancer Survivors

• Goal Determine if muscle health physical
  function can be improved w/weight bearing
  exercise
• Intervention
• Group based flexibility, balance, and muscle
  strength training 2 days per week at UMC Health
  and Wellness Center
• Home based aerobic training 3-5 days per week
• Who Is Eligible?
• Overweight breast cancer survivors with early
  stage disease
• Post-menopausal
• Currently inactive or minimally active
• Those not currently on weight loss diet
• Willing to perform moderate exercise most days of
  the week for 8 weeks
• Willing to come to UMC Health and Wellness Center
  2 days per week
• Contact Jennifer W. Bea, PhD at 520-626-0912 or
  jwright_at_azcc.arizona.edu

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Womens Intervention Nutrition Study (WINS)

• HYPOTHESIS
• Dietary fat reduction will reduce the
  incidence of recurrence and increase survival for
  women treated for early stage breast cancer.

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WINS TRIAL DESIGN
Dietary Intervention (n975) to reduce fat intake

• Women 48-79 yrs
• Early breast cancer
• Primary surgery /- R
• Systemic therapy
• Dietary fat intake gt 20 of
  calories

Randomization 6040 within 365 days from 1o
surgery n2437
Control (n1462)
Recruitment 1994-2001 Median follow-up 60 months
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WINS Inclusion Criteria

• Women 48 to 79 years of age
• Histologically confirmed, resected, unilateral
  invasive breast cancer
• Lymph nodes examined
• Acceptable adjuvant systemic therapy
• Dietary fat intake gt 20 of calories
• Able to accept either randomization
• Provide informed consent

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WINS Fat Gram Intake by Treatment Group
300 kcals fat/d of 1850 total kcals
Significantly different by T test from control
and baseline, plt0.0001
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WINS Relapse Free Survival
Diet Control HR, 95 CI
P-value 96/975 181/1462 0.76,
0.60-0.98 0.034
PATIENTS ()
Absolute difference 1
3
3
3
4
7
YEARS
Diet 975 949 907
807 647 490 342
201 96 Control 1462
1416 1352 1197 965
756 529 326 151
From adjusted Cox proportional hazards model
including stratification factors, ER status,
tumor size, and surgery (mastectomy/lumpectomy),
p value 0.067 by unadjusted log rank
test Chlebowski, Blackburn, Elashoff, et al Proc
Amer Soc Clin Oncol 2410, 2005
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WINS Relapse Rate Curve for ER
WINS RFS In ER Positive
Diet Control HR, 95 CI
P-value 68/770 122/1189 0.85, 0.63-1.14
0.277
PATIENTS ()
Control ------ Diet _____
Absolute difference 1
2
1
2
2
YEARS
Diet 770 753 725
641 512 385 265
156 71 Control 1189 1165
1122 995 802 613
440 271 125
P-value from adjusted Cox proportional hazard
model Chlebowski, Blackburn, Elashoff, et al
Proc Amer Soc Clin Oncol 2410, 2005
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WINS RFS In ER Negative
Diet Control HR, 95 CI P-value 28/205
59/273 0.58,0.37-0.91 0.018
Control ------ Diet _____
PATIENTS ()
Absolute difference6
6
8
11
11
YEARS
Diet 205 196 182
166 135 105 77
45 25 Control
273 205 230 203
163 133 88 55
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P-value from adjusted Cox proportional hazard
model
Chlebowski, Blackburn, Elashoff, et al Proc Amer
Soc Clin Oncol 2410, 2005
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Plant Foods and Breast Cancer Recurrence
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Oxidant Stress?
Inflammation
Milner JA. J Nutr 20041342492S.
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WHEL Diet
Healthy cancer prevention diet
One of the diets was more intensive than the
other.
Women who enrolled in the study were randomly
assigned to one of two healthy cancer prevention
diets
NCI-Based Diet
Healthy cancer prevention diet
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WHEL Study CONSORT Flow Diagram
Pierce JP et al JAMA 2007 298(3)
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DEMOGRAPHIC CHARACTERISTICS OF THE WHEL COHORT
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CLINICAL CHARACTERISTICS OF THE WHEL COHORT
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DISEASE FREE SURVIVAL BY INTERVENTION ARM
STAGE AT DIAGNOSIS
Solid line Comparison Dashed line WHEL
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OVERALL SURVIVAL BY INTERVENTION ARM STAGE AT
DIAGNOSIS
Solid line Comparison Dashed line WHEL
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CAROTENOIDS AND RECURRENCE-FREE SURVIVAL COHORT
STUDY

• Subjects assigned to the control group in the
  Womens Healthy Eating and Living (WHEL) Study
  women in that group did not change their diets in
  response to study participation
• 1,551 women followed for a median of 7 years
• Early-stage (Stage I, II or IIIA) breast cancer,
  who were within four years post-diagnosis at
  randomization (between 3/1995 and 11/2000), and
  had completed initial treatments
• 205 women had a breast cancer recurrence or a new
  primary breast cancer before July 31, 2004 that
  was medically confirmed by mid-November 2004

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Cox Proportional Hazards Model Breast Cancer
Endpoint
Controlled for age at diagnosis, clinical
center, plasma cholesterol, BMI, tumor hormone
receptor status, and adjuvant chemotherapy.
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Does the WHEL diet Modulate Biomarkers of
Oxidative Stress?

• Sub-study of 204 WHEL study participants
• 24 urine analyzed for
• 8-Epi-prostaglandin-F-2a8-hydroxy-2-deoyguano
  sine
• Results
• Low baseline oxidative stressTrend toward
  reduction by treatment group (non-significant)8
  EPG 8 OHdG inversely associated w/ vitamin E
  intake8-EPG positively associated with BMI
  polyunsaturated fatIncreased 8OHdG w/ increase
  arachidonic acid intake higher BMI

Thomson CA, Guiliano AR, Shaw J et al Nutr Cancer
200551(2)146-54
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BREAST CANCER DIETARY BIOMARKERS AS PREDICTORS
OF DISEASE RECURRENCE

• 317 cases
• median of 8 years post-diagnosis
• Increased risk of recurrence associated with
  highest (vs. lowest) tertile of plasma
  lipoperoxide (RR 2.1, 95 CI 1.1, 4.0)
• and alpha-tocopherol (RR 1.7, 95 CI 1.0, 3.0)
  concentrations
• (Saintot et al. Int J Cancer 200297574)

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BASELINE ESTROGENS (IN POSTMENOPAUSAL WOMEN) AND
RECURRENCE NESTED CASE CONTROL ANALYSIS

• Estradiol pg/ml HR - 1.51
• Free E2 HR pg/ml HR - 1.36
• Bioavailable E2 pg/ml HR - 1.41
• Significant reduction associated with increase in
  dietary fiber intake
• Reductions in estrogen also shown with dietary
  fat reduction when habitual diet is high in fat
  (gt 40 total energy)

Rock CL, CEBP, 2008 Rock CL, J Clin Oncol, 2004
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Effect of WHEL Diet Intervention on Serum
Estrogen-related Hormones
Rock CL, Flatt S and Thomson CA et al. J Clin
Oncol 2004
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Indole-3-carbinol chemoprotective actions

• Anti-estrogenic effect
• Inhibit growth of ER human breast cancer cells
• Enhanced effect of Tamoxifen (Cover et al, 1999)
• Stimulate apoptosis of ER- human breast cancer
  cells
• Reduced adduct formation
• Induction of apoptosis and cell cycle arrest
• Anti-proliferation
• Up-regulation of tumor suppressor gene PTEN and
  adhesion molecule E-cadherin
• Anti-angiogenesis

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CRUCIFEROUS VEGETABLES, TAM AND BREAST CANCER
RECURRENCE
Unpublished data from WHEL study population,
Thomson CA, 2008
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DIETARY SUPPLEMENT USE AMONG BREAST CANCER
SURVIVORS

• Norm not exception (gt 80 of patients)
• Used to treat symptoms and to reduce perceived
  risk of recurrence
• Use greatest among physically active, nl BMI,
  non-smokers, low fat diet, higher education
• Polysupplementation more common in those with
  metastatic disease, fatigue, cancer-related pain
• 50 of patients on chemotherapy
• Report higher QOL
• Bardia et al. J Supportive Oncol, 2007 Politi et
  al. Supportive Care Ca, 2006 Velicer C and
  Ulirch, J Clin Oncol, 2008

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Evidence? Or lack thereof?

• Limited well-designed studies no conclusive
  evidence to date
• Symptoms
• Ginger nausea
• Melatonin sleep
• Black cohosh, soy hot flashes
• Alpha-lipoic acid neurotoxicity
• Coenzyme Q-10 - cardiotoxicity
• Secondary prevention
• Antioxidants
• Fish oil
• Turmeric

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VITAMIN D SUPPLEMENTATION AND RESPONSE TO AI
REASON FOR CONCERN?

• Aromatase inhibitors widely used to treat ER
  disease
• AI inhibits estrogen biosynthesis via inhibition
  of P450 aromatase, encoded by CYP19 gene
• AIs lead to bone loss
• Many breast cancer survivors advised to take
  vitamin D for bone health
• Vitamin D stimulates CYP19 transcription and
  aromatase activity

Letter to editor Dizdar, The Breast, 2008
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Folate vs Folic Acid

• Dietary intake food fortification
• Fortification increased folic acid intake by
  approx. 200 µg/day
• Dietary sources folate
• Multivitamin use and fortified cereals primary
  sources of exposure
• Alcohol use effect modification
• Risk promoting of etoh can be reduced if diet is
  sufficient in folate
• Gene-diet interactions
• DHFR 19-bp deletion polymorphism high folic
  acid may increase risk

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ACKNOWLEDGEMENTS
Mentors David Alberts Cheryl
Ritenbaugh Anna Guiliano John
Pierce Collaborators Cheryl Rock
Bette Caan Patty Thompson Alison
Stopeck Iman Hakim Emily Ho
Funding NCI K07 Award Pierce RO1 Susan G.
Komen Atkins Foundation
Staff /Students Emily Nardi Julie West
Jennifer Wright Bea Letitia McCune Nicole
Stendell-Hollis Jessie Miller Amy Butalla
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Questions?