1. Women’s Health Initiative (WHI) Extension 2010-15 OPPORTUNITIES FOR COLLABORATION Marcia L. Stefanick, Ph.D. Professor of Medicine Stanford Prevention Research Center Professor of Obstetrics and Gynecology Stanford University School of Medicine UCSF K Scholars Seminars – March 4, 2011

2. Women’s Health Initiative (WHI) Clinical Trials (Diet, Hormones, Calcium/Vit D) Observational Study Conducted at 40 Clinical Centers + Clinical Coordinating Center (Fred Hutchinson Cancer Research Center) EXTENSION STUDY (2005-2010) EXTENSION STUDY (2010-2015) Funded by National Institutes of Health National Heart, Lung, and Blood Institute www.whi.orgwww.whiscience.org

3. WHI Clinical Trials Postmenopausal Women, aged 50-79; Not moving < 3 yrs Diet Modification (DM) Trial Primary Outcomes: Breast & Colorectal Cancer Secondary Outcome: Coronary Heart Disease (CHD) Hormone Trials Primary Outcome: CHD Secondary Outcomes: Hip Fracture, Breast Cancer Ancillary Study: Memory (Dementia) 11.8% Overlap Design ~ 9 years average follow-up Hormone 27, 347 (50:50) Diet (DM) 48,836 (40:60) Total CT = 68,133

4. WHI Calcium Vitamin D Trial: Relationship to CT Calcium + Vitamin D (CaD) Primary Outcome: Hip Fracture Secondary Outcomes: Colorectal Cancer; Other Fractures CaD 36,282 at 1st (or 2nd) Annual Visit Total CT = Total CT = 68,133 Annual Clinic Visits Baseline & 1 Yr blood 1000 mg calcium carbonate + 400 IU vitamin D * Diet (DM) 25,210 of 48,836 (52%) Hormone 16,089 of 27,347 (59%) Placebo 53.3% of CT * Choice: Chewable or Swallowable Pills 1/2 in morning, 1/2 in evening (500 mg Ca + 200 IU Vit D)

5. WHI: Observational Study (OS) OS 93, 676 Total WHI Sample (CT + OS) = 161,809 Women screened for the DM or HT trials could enroll in the OS, if ineligible for the CT, or chose not to join either DM or HT trials. Some women enrolled directly in the OS. Annual Questionnaires Purpose of OS: l secular control for the CT l improve risk prediction for primary outcomes l case-control approach to study sub-clinical markers for disease l associations between genetic, biochemical, psychosocial, physiological factors and events l impact of changes in risk factors on incident disease and mortality Clinic Visits Baseline & 3 Yr (blood) 1% subsample

6. Women’s Health Initiative (WHI) Hormone Therapy (HT) Trials Hysterectomy CEE (Conjugated equine estrogens, 0.625 mg/d) CEE + MPA (medroxy- progesterone acetate, 2.5 mg/d) NO N= 16,608 YES N= 10,739 Placebo = Premarin® = Prempro® E-alone Trial E+P Trial Generally Healthy Postmenopausal Women aged 50-79 years *Initially: CEE only (N=331), CEE+MPA, or Placebo (Post-PEPI: CEE only were converted to CEE+MPA) Current HT required 3-month wash-out before baseline testing.

7. E-Alone 10,739 WHI HT Trials: Sample Size, Outcomes, Follow-up Women, aged 50-79 Total HT trials = 27,347 Hormone Trials Primary Outcome: Coronary Heart Disease Secondary Outcomes: WHI Memory Study (WHIMS) - for women aged ≥ 65: Dementia Average Follow-up 5.6 years* Average 7.1 years * E+P 16,608 *design ~ 8.5 years Stroke, Blood Clots l Lungs (PE, pulmonary emboli) l Legs (DVT, deep vein thrombosis) Breast, Colorectal, Uterine Cancers Hip Fracture; Other Deaths

8. Stroke? Threshold Level Early STOPPING for HARM Threshold Level Early STOPPING for BENEFIT Coronary Artery Disease (Heart Attacks) Breast Cancer Anticipated RiskExpected Benefit Plan to follow to 2005 (average 8.5 years) Additional Benefits: Hip (Bone) Fractures Overall Mortality Additional Risks: Blood Clots, VTE Lungs=PE; Legs=DVT WHI Hormone Trials: Baseline (1993-1998) Hypotheses Colon Cancer Global Index: overall balance of benefits and risks Earliest occurrence of CHD, Stroke, PE, Breast Cancer, Hip Fracture, Colorectal Cancer, Death from other causes, Endometrial Cancer

9. E-Alone (post-hystX) 2947 WHI Memory Study (WHIMS) - ancillary study (Postmenopausal Women, aged 65-79 ) WHIMS E+P and E-only trials = 7,479 Primary Outcome: l Probable Dementia (PD) Secondary Outcomes: l Combined PD & Mild Cognitive Impairment (MCI) - Supporting Data: Global Cognitive Function (by annual Modified Mini-mental State Examination, 3MSE)) Average Follow-up 4.1 years* Average 5.2 years * E+P (women with a uterus) 4532 *design ~ 7 years

10. Summary: WHI E+P * vs. E-Alone ** Trial published: *July 2002 **April 2004  Concordant results n Heart Disease – no benefit (for E+P, early harm) n Strokes, Blood Clots – harmful n Fractures – beneficial n Dementia (if ≥ 65 yrs of age) – harmful  Disparate Results n Breast Cancer n Increased in E+P Trial (women with a uterus) n Not increased in E-Alone Trial (women with prior hysterectomy) n Increased in women with highest baseline risk (Gail Model) n Global Index n Increased in E+P (CEE + MPA) Trial n Neutral in E-Alone (CEE) Trial

11. WHI E+P Trial: HR (95% CI) - 5.6 Years Follow-up  Cardiovascular n CHD: 1.24 (1.00-1.54); Yr 1: 1.81 (1.09-3.01) NEJM 2003; 349: 523-34 n Stroke: 1.31 (1.02-1.68); Ischemic:1.41(1.09-1.90) JAMA 2003; 289: 2673-84 n Venous Thrombosis: HR 2.06 (1.57-2.70) JAMA 2004; 292: 1573-80  Fractures n Hip Fracture: 0.76 (0.69-0.83) [risk analysis] JAMA 2003; 290: 1729-38  Cancer n Breast Cancer: 1.24 (1.01-1.54) JAMA 2003; 289: 3243-53 n Colorectal Cancer: 0.56 (0.38-0.81) NEJM 2004; 350:991-1004 n Gynecologic Cancers: JAMA 2003; 290: 1739-48 n Ovarian Cancer: 1.58 (0.77-3.24) n Endometrial Cancer: 0.81 (0.48-1.36) n Others: too few cases

12. WHI E+P: Post-Intervention Follow-up Heiss et al, JAMA 2008; 299: 1036-1045 After E+P trial was stopped early, WHI followed study participants through the planned termination of the trial (March 31, 2005) Except for stopping the intervention and unmasking, the same trial protocol was followed, e.g. semi-annual monitoring to identify and classify study outcomes Post-intervention information (July 8, 2002 - March 31, 2005) was available on 95% of the women: mean of 2.4 years of follow-up WHI is continuing to follow the participants. WHI E-Alone trial follow-up data will be published next year.

13. WHI E+P: Post-Intervention Follow-up CHD Heiss et al, JAMA 2008; 299: 1036-1045

14. WHI E+P: Post-Intervention Follow-up  Cardiovascular risks disappeared n CHD, (Stroke ?), Blood Clots – no longer increased  Fracture benefits disappeared n Hip Fracture - no longer decreased  Cancer n Breast Cancer - 27% (ns) more diagnosed post-Intervention n Colorectal Cancer - no longer decreased n TOTAL CANCER - increased 1.24 (1.04-1.48) n Due to increase in variety of cancers, including Lung Cancer (E+P: 33 events vs placebo:15)  All-cause Mortality -15% (ns) higher n Most due to Cancer (E+P: 101 vs placebo: 69) n only 27 (E+P) and 16 (placebo) due to pre-specified CA Heiss et al, JAMA 2008; 299: 1036-1045

15. WHI CEE+MPA vs Placebo: Breast Cancer Risk Black line = sensitivity analysis: censored 6 mo. after changing pills HR=1.62 (1.10, 2.39) HR=1.26 (0.73, 2.20) HR=1.26 (1.02, 1.53)HR=1.27 (0.91, 1.72) During Intervention Postintervention Chlebowski et al, N Engl J Med 2009;360(6): 573-87

16. Observational Study: Estrogen plus Progestin Users vs. Non-users At Entry: Breast Cancer and Serial E+P Use Chlebowski et al, N Engl J Med 2009;360(6): 573-87

17. WHI Extension Study (ES) - 2005- 2010 Hormone 27,347 Eligible:25,193 ES:20,425 (81.1%) Diet 48,836 Eligible: 45,560 ES: 37,844 (83.1%) OS 93,676 Eligible: 86,744 ES: 63,207 (72.9%) Total CT Eligible: 63,331 ES: 52,156 (82.4%) Total WHI Sample (CT + OS) = 161,809 Eligible: 150,075 Extension Study = 115,363 (76.8%)

18. WHI Estrogen Plus Progestin Trial First/Second/Third Efficacy Analyses (cutoff dates 7July2002 / 31March2005 / 14August2009) First: End of intervention period (Per DSMB) Second: Original trial completion date Third: Current pre-planned analysis (note: re-consent required after original completion date) Mean follow-up time: 5.6 / 7.9 / 11.0 years Invasive breast cancers (n): 349 / 488 / 678 Breast cancer mortality information reported for first time Chlebowski, Anderson, Gass, et al JAMA 2010;304:1684-92 Chlebowski, Hendrix, Langer, et al JAMA 2003;289:3243 Chlebowski, Kuller, Prentice, New Eng J Med 2009;360:573

19. WHI E+P: Invasive Breast Cancer Incidence Quintiles for duration of intervention indicated by shaded regions Hazard ratio (HR) 95% CI and P values from Cox proportional hazards regression models Chlebowski, Anderson, Gass, et al JAMA 2010;304:1684-92

20. WHI E+P: Deaths After Breast Cancer Diagnosis Mortality due to breast cancer All-cause mortality after breast cancer Chlebowski, Anderson, Gass, et al JAMA 2010;304:1684-92

21. Summary of NHLBI Project Office Report to WHI OSMB, November 2010 Original mission: To address etiology and prevention of morbidity and mortality in postmenopausal women –First study period 1993-2005: 161,808 women age 50-79 3 Clinical Trials (Menopausal Hormones, Low-Fat Diet, Calcium/Vitamin D Supplements) Observational Study –Follow-up 2005-2010: 115,406 (77% of eligible) age 57-91 –Follow-up period 2010-2015 Goal enrollment 100,000 (80% of eligible) age 62-96 Includes 24,000 in “Medical Records Cohort” which will get complete Outcomes Assessment (HT Trial, African American and Hispanic – most of whom have GWAS data)

22. WHI 2010-2015: Progress Report to OSMB 4 Regional Centers funded October 1, 2010 –Marcia Stefanick, Stanford – Western Region –Becky Jackson, OSU– Midwestern Region –Jean Wactawski-Wende, NYU-Buffalo – Northeastern Region –Sally Shumaker, WFU – Southeastern CCC renewal, April, 2011 NIA taking over lead in funding WHIMS, WHIMS-Y NCI funding adjudication of cancer outcomes in “Self-reported Cohort” (no central adjudication of CVD outcomes in this cohort)

23. New Mission, per NHLBI: 2010-2015 Study factors leading to increased risk of CVD in older women of diverse race and ethnicity CHD, Stroke, Heart Failure, Atrial Fibrillation, Peripheral Artery Disease (no ABI data, Venous Thromboembolism Conversely what factors determine absence of CVD as part of successful aging Facilitate ancillary studies, consortium studies, and clinical trials requiring large numbers of clinical outcomes Mentor new investigators Restructure study field centers and committees to train new investigators and increase collaborations

24. Make data and biologic resources widely available-current status  Cohort workshop at NWU Chicago, July 2010  NAMS workshop in Chicago, October 2010  Collaboration welcomed—see www.whiscience.org  Study data up to 2005 available from NHLBI Data Repository; 2009 update scheduled for May 1, 2011  WHI SHARe GWAS data available from NCBI/dbGAP since January 13, 2010 New Mission, per NHLBI: 2010-2015

25. WHI 2010-2015 Study factors leading to increased risk of CVD in older women of diverse race and ethnicity  Add Atrial Fibrillation (self-report, CMS/HMO)  Add improved Heart Failure documentation & adjudication (self-report, records abstraction, adjudication, CMS/HMO)  Add valvular heart disease (self-report, HMO/CMS)  Face to face visit in 8,000 women aged >80 years  Physical exam (includes Short Physical Function Battery)  Blood Collection (including DNA)  Objective assessment of physical activity (if AS funded*) *includes Validation Study at Stanford and one other site  Continue longitudinal assessment of cognition and dementia (WHIMS)

26. WHI 2010-2015 CVD Biomarkers on SHARE & EA GWAS cohorts, N~24,000 (insulin, glucose, CRP, creatinine, Total, HDL, LDL Cholesterol, TG) Additional WHI genomics data to be added to dbGAP, e.g. PAGE, GARNET, planned EA GWAS, WHISP Funding for BAA3 secured (2012 and 2014) –Objective is to encourage the wider scientific community to maximize the return on the WHI cohort by applying newer high-throughput technologies to the biological specimens –Example: serial archived bloods plus bloods to be collected in 2011-2012 provide an opportunity study such questions as the determinants of change over time in biomarkers, DNA methylation, RNA expression, proteome, metabolome, telomere length, and the association of these changes on subsequent health outcomes Make data and biologic resources widely available

27. WHI 2010-2015 Facilitate ancillary studies, consortium studies, and clinical trials requiring large numbers of clinical outcomes. In early development: Dietary supplements (vitamin D, ALA, resveratrol) Physical activity Program to enhance use of EMR for clinical outcomes GWAS and CVD biomarkers in ~12,000 EA women in addition to the ~12,000 AA and Hispanic women in SHARe Mentor new investigators Deliverable for Regional Centers BAA3

28. WHI 2010-2015 Cohort, as of 2/28/11 Current AgeTotalMedical Records Cohort 60-64607207 65-69135303473 70-74226045865 75-79224535865 80-84193545007 85-89100892655 90-942539728 95-994513 TOTAL91,22121625

29. WHI 2010-2015 Cohort, as of 2/28/11 Race/EthnicityTotalMedical Records Cohort White (non Hispanic)79,83214,297 Black (African American) 5821 Hispanic2375 Asian/Pacific Islander1831232 American Indian/Alaskan Native 30568 Other871162 Not specified18629 TOTAL91,22121,625