1. Marian L Neuhouser, PhD, RD
366. The Women’s Health Initiative (WHI): Two Decades of Knowledge Ready for Dissemination: Cancer
Marian L Neuhouser, PhD, RD

2. Marian L Neuhouser, PhD, RD
Disclosures
Marian L Neuhouser, PhD, RD
Board Member/Advisory Panel
American Society for Nutrition (Past-President )
Member, 2015 Dietary Guidelines Advisory Committee
Consultant
None
Employee
Fred Hutchinson Cancer Research Center, Seattle, WA
University of Washington, Seattle, WA
Research Support
National Institutes of Health: NIDDK, NCI, NHLBI
Speaker’s Bureau
Stock/Shareholder

3. Learning Outcomes
Understand the relationship between nutrition and cancer risk in postmenopausal women
Describe how various research study designs can answer different questions about nutrition and health
Describe the initial and follow-up analyses for breast and colorectal cancer in the WHI Dietary Modification Trial
Describe selected findings for diet and cancer risk in the WHI Observational Study

4. Common cancers in postmenopausal women

5. Cancer is a complex disease

6. Relationship of nutrition with carcinogenesis

7. Cancer Prevention
Lifestyle factors, including diet, are responsible for about 30% of all cancers
Diet influences carcinogenesis at several points in the disease process
Weight, particularly overweight and obesity, are linked to nearly every common cancer in both men and women
Can research guide practitioners in implementing cancer prevention for their clients and patients?

8. Research Study Designs
Different study designs answer different questions
Randomized Controlled Trials:
Test a single (or at most two) intervention
Intervention is assigned (controlled) by investigators
A dietary modification
A dietary supplement
Follow-up is relatively short (5 to 10 years)
Analysis compares intervention to control
Cause-effect inference/highest level of evidence
Observational Study
Gathers data from a large group at baseline
Follows over time to evaluate disease incidence
Real world, usual habits of people, longer follow-up
WHI had both an RCT and an Observational Study

9. RCT and Cohort Study Designs

10. WHI Dietary Modification Trial
Tested the hypothesis that a low-fat dietary pattern (vs no diet change) would reduce incidence of invasive breast cancer and colorectal cancer as primary outcomes
Testing 20% vs. 40% energy from fat plus > 5 fruit and vegetables serving/d
Assumptions were that breast cancer incidence would be 14% lower in intervention vs comparison
Mammography required every 2 years
Participants self-reported new clinical outcomes, including cancers twice yearly. Adjudicated with medical records.

11. Hazard Ratio for Breast Cancer
Prentice et al JAMA 2006

12. Hazard Ratio for Colorectal Cancer
Beresford et al JAMA 2006

13. What happens post-intervention?
During post-intervention follow-up (+ 5.2 years), no effects on either breast or colorectal cancer incidence or cancer mortality.
Both incidence and mortality were lower in the intervention vs. comparison, but not statistically different.
C Thomson et al Cancer Epi Biomarkers Prev 2014
After additional follow-up (16.1 years), lower death after breast cancer (22% ↓; statistically significant)
R Chlebowski et al J Clin Oncol 2017

14. Important points!
In the WHI-DM, significant reduction in breast cancer was linked to:
Trial adherence – those who were more ‘adherent’ had a 15% lower risk of breast cancer
Baseline diet - participants who started the trial at a higher baseline percent energy from fat (> 36.8% energy from fat) – 22% reduction in breast cancer risk
R Prentice et al JAMA 2006
Colorectal polyps 9% lower in intervention vs comparison
Statistically significant.
Polyps are a precursor lesion for colorectal cancer
S Beresford et al JAMA 2006
Cancer is a complex disease that takes many years to develop (15-20yrs); an RCT may be too short

15. Nutrition and Cancer in the Observational Cohort Setting
Are general population guidelines for cancer risk reduction effective?
We examined the American Cancer Society (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines in relation to cancer risk and mortality in the WHI-OS
ACS guidelines give a score of 0-8 from a combined measure of diet, physical activity, BMI and alcohol
C Thomson et al Cancer Prev Res 2014

16. ACS Healthy Lifestyle Scoring Criteria
Worst Score (0)
Middle Score (1)
Best Score (2)
1. Maintain a healthy weight throughout life
BMI > 30 kg/m2
BMI kg/m2
BMI<25kg/m2
2. Adopt a physically active lifestyle - > 30 minutes moderate-vigorous PA at least 5 d/wk min better
<8.75 MET hr/wk
MET hr/wk
<17.5 MET hr/wk
3. Consume healthy diet with emphasis on plant sources
0-2 diet points
3-6 diet points
7-9 diet points
3a. Eat > 5 fruit +vegetable/d from a variety of sources
1 point for > 5 svg/d fruit +veg, + 1 or 2 points for being in 2nd or 3rd Q of serum carotenoids
3b. Choose whole grains over refined/ processed
% of grains consumed as whole grains; divided into quartiles and assigned score of 0-3
3c. Limit consumption of red and processes meats
Svgs/wk of red/processed meat divided into quartiles and assigned score 0-3 (reverse score)
4. If you drink, limit to 1/d
>1/d
>0-<1/d
Non-drinker

17. Methods 93,676 postmenopausal women in the WHI-OS
Women were excluded from this analysis
Prior history of cancer
Underweight, unknown or unreliable BMI
Missing data on diet, physical activity or outcomes
Analytic cohort = 65,838
ACS scores for each participant were created from baseline food frequency questionnaire and recreational physical activity assessment. Height and weight measured at WHI study visits.
Cox proportional hazards models estimated multivariate-adjusted association across tertiles of ACS scores with cancer risk and cancer mortality

18. Results Higher vs. lower ACS scores: Higher vs lower ACS scores:
17% lower risk of any cancer
22% lower risk of breast cancer
52% lower risk of colorectal cancer
No associations for endometrial, ovarian or lung cancers
Higher vs lower ACS scores:
27% lower death from any cause
20% lower total cancer death
41% lower colorectal cancer death
C Thomson et al Cancer Prev Res 2014

19. Diet Quality in the WHI-OS
Diet quality measures the whole diet; diet is complex and people eat foods, not nutrients
“The quantities, proportions, variety or combination of different foods, drinks, and nutrients (when available) in diets and the frequency with which they are habitually consumed”
Nutrition Evidence Library. A Series of Systematic Reviews on the Relationship Between Dietary Patterns and Health Outcomes. U.S. Department of Agriculture, Center for Nutrition Policy and Promotion, March 2014.
Scientific Report of the 2015 Dietary Guidelines Advisory Committee
Diet quality is assessed with scoring systems such as the “Healthy Eating Index” that assess adherence to the US Dietary Guidelines

20. Diet Quality & Mortality in the WHI-OS
Postmenopausal women (50-79 yrs) at 40 US clinical centers 93,676 in WHI OS. 63,805 in this analysis after excluding baseline CVD, Cancer, DM
Enrollment
~12.9 years follow-up
Baseline WHI-FFQ and demographic and lifestyle questionnaires
Vital status updated annually, cause of death confirmed with medical records
Participants were followed from study enrollment until death, loss to follow-up, or the end of the previously described WHI-Extension Study 1 on September 30, 2010.
Vital status of participants was collected through annual clinical center follow-up of participants and proxies. In addition, periodic searches of the National Death Index were conducted. Cause of death was determined by medical record and death certificate review at the WHI CCC with oversight from the WHI physician adjudicators and outcomes committee.
Weight, height, and waist circumference measured in clinic
S George et al Am J Epi 2014

21. Methods Calculated HEI, AHEI, aMED, & DASH scores
Points are given (or not) for consumption of fruit, vegetables, whole grains, legumes, low- fat dairy, lean meat, fish. No points for SSB, added sugars, trans fat, saturated fat.
Slight variations between scoring systems
Estimated multivariate hazard ratios and 95% confidence intervals for death
Subgroup analyses by BMI and waist circumference
We adjusted for covariates commonly examined in published studies of recommendation-based diet quality scores and mortality so that we could build on the existing evidence base. This covariate list was standardized in the DPMP.
with person-years as underlying time metric
Focus for comparison was better vs. poor quality diet (q5 versus q1)

22. Results
5,692 deaths over 12.9 years of follow up

23. Hazard Ratios (95% CI) for Mortality According to Quintiles (Q5 vs
Hazard Ratios (95% CI) for Mortality According to Quintiles (Q5 vs. Q1) of Diet Quality Indices
All Cause
CVD
Cancer
a statistically significant 20-23% reduced risk of cancer mortality was observed for Higher HEI, aMED, and DASH scores
-Additional adjustment for hypertension and high cholesterol did not result in changes to the HRs (data not shown).
-Models without BMI as a covariate yielded similar results (data not shown).
-All p < (except ahei with cvd mortality p=0.017 and cancer mortality p=0.275)
Adjusted for age, race/ethnicity, education, marital status, physical activity, smoking, energy, body mass index, alcohol (HEI and DASH only), hormone therapy. George et al Am J Epi 2014

24. By BMI status: Cancer Mortality
<25 kg/m2 (n=26,551)
kg/m2 (n=21,628)
30+ kg/m2 (n=14,936)
Adjusted for age, race/ethnicity, education, marital status, physical activity, smoking, energy, alcohol (HEI and DASH only), hormone therapy. S George et al Am J Epi 2014

25. Practice Applications
RDs and RDNs played a crucial role in the delivery and implementation of the largest dietary intervention trial ever conducted in postmenopausal women
In the WHI Dietary Modification Trial, we found a modest, but not significant reduction in breast cancer risk. The signal was stronger in women who started the study with a higher fat intake and among the ‘adherent’.
In the WHI Observational Study, over the long term, postmenopausal women who followed a diet consistent with ACS guidelines and other healthy diet indicators had significantly lower cancer risk and cancer mortality
RDs and RDNs can guide clients and patients in making healthy food choices that should be maintained long-term for the maximum health benefit
Cancer takes years to develop; healthy diet should be followed throughout the life course

26. Thank you
Special thanks to WHI Investigators and the Dietary Patterns Methods Project.