2. Tenth Anniversary of Initial Women’s Health Initiative (WHI) Report Richard Santen, MD University of Virginia 12/2/11

3. Tenth Anniversary of Initial Women’s Health Initiative (WHI) Report What have we learned? How should the public be informed? What should a post-menopausal woman do, based on what we now know?

4. WHI First report 2002 Two arms –Placebo versus conjugated equine estrogen plus MPA (E+P) –Placebo versus conjugated equine estrogen alone (E) 80% reduction in menopausal hormone use over the next five years

5. WHI 10 years later: key conclusions after a decade of reflection Need to consider all information based on excess risk and benefit and not relative risk and benefit Only women just entering menopause are candidates for menopausal hormone therapy

6. Initial WHI Report 2002 major finding 26% increase in risk of breast cancer

7. Do I have a 26% chance of getting breast cancer since I have taken hormones for more than 5 years? That is a one in four chance. Is this really true? My wife immediately asked me

8. My answer No, the 26% increase represents only relative risk. Her reply What does that mean for me?

9. Important Issue We need to distinguish between: –relative risk –absolute risk –excess risk

10. This is how I explain this to my wife

11. One Million Women who marched in Washington

12. 120,000 of these women or 12% will develop breast cancer in their lifetimes This is absolute risk

13. 12,000 or 1% will develop breast cancer in five years Absolute risk

14. Lets consider just 1000 of these marchers

15. How many of these women will get breast cancer within five years?

16. 18 Women not receiving MHT will develop breast cancer over a five year period Absolute risk

17. 26% increase in relative risk in WHI

18. If these 1000 women take MHT for five years, 22 women will develop breast cancer

19. However, only 4 of these 1000 women would develop a breast cancer that they would not otherwise have developed. Technically this is called attributable risk. 18 with breast cancer without MHT 22 with breast cancer with MHT Excess risk 4

20. My Answer: Based on the WHI study, you will only have a 4 in 1000 chance of getting a breast cancer that you would not otherwise have gotten if you take MHT for 5 years

21. WHI 10 years later Relative risk is only important when absolute risk is high Example from common experience

22. Example of relative vs absolute risk If you take one plane flight your chances of crashing are one in ten million (absolute risk) Your relative risk of crashing is increased by 500% if you take five plane flights. Your excess risk by taking five flights rather than one is four per ten million Bottom line: relative risk means little when absolute risk is low This is the reason to convert all WHI data to excess risk or benefit

23. WHI 10 years later Need to consider all risk and benefit data consistently The Endocrine Society has expressed all risks and benefits as the number of women per 1000 using MHT for 5 years who will experience event

24. What are the major excess risks reported in the original WHI study?

25. WHI Estrogen plus Progestin MHT Excess Risks

26. Risks Benefits WHI E+P Average age 63

27. What are the under-reported benefits?

28. Reduction in Mortality

29. Under-reported Benefits (WHI)

30. Timing Hypothesis Early vs. late treatment Early Late

31. Timing Hypothesis Early vs. late treatment EarlyLate

32. VTE and Stroke Similar relative increase in risk but younger women experience these problems less commonly

33. MHT 10 years after WHI only used at start of menopause Risks Benefits

34. For Some in Menopause, Hormones May Be Only Option By TARA PARKER-POPE New York Times August 15, 2011

36. MHT 10 years after WHI women with severe symptoms Risks Benefits

37. What to do about breast cancer risk?

38. Benefit Low risk of breast cancer Risk High risk of breast cancer

39. Assess risk of breast cancer and only treat those at low risk Low risk (i.e. 0.5% chance of breast cancer in 5 year) excess risk is 2.5/1000 per 5 years High risk (i.e. 4% chance of breast cancer in 5 years) excess risk 20/1000/5 years

40. RR Estrogen Related Risk Factors 0 1 2 3 4 5 6 Breast Density Breast Cancer Risk Factors by Group Plasma E2 Age at Menopause Age at 1 st Live birth BMI Age at Menarche MHT

41. RR Estrogen Related Risk Factors 0 1 2 3 4 5 6 Other Risk Factors Breast Density Plasma E2 Age at Menopause Age at 1 st Live birth BMI Age at Menarche MHT 1 o Relative 2 o Relative Alcohol Breast Cancer Risk Factors by Group

42. Calculation of Breast Cancer Risk Gail Model (http://www.cancer.gov/bcrisktoolmobile) Tyrer-Cuzick Model (http://pulsescreening.co.uk/Corporate/Breast_can cer_prediction_model-1.pdf)

43. For Some in Menopause, Hormones May Be Only Option By TARA PARKER-POPE New York Times August 15, 2011

44. WHI after 10 years The Ultimate Goal is to provide the most benefit to the patient while avoiding the most risks