1. Postmenopausal Hormone Therapy and Risk of Cancer A CME Slide Library From the Council on Hormone Education

2. Postmenopausal Hormone Therapy and Risk of Cancer Section 1: Evaluation of Cancer Risk in the Women’s Health Initiative (WHI) Section 2: Hormone Therapy (HT) and Breast Cancer Risk 2a.WHI Breast Cancer Results 2b.Million Women Study 2c.Additional Studies of Breast Cancer and HT 2d.Can Estrogen Be Used Safely in Breast Cancer Survivors? Section 3: HT and Colorectal Cancer Risk Section 4: HT and Ovarian Cancer Risk Section 5: HT and Endometrial Cancer Risk Section 6: Recommendations for Patient Education

3. Section 1: Evaluation of Cancer Risk in the WHI Postmenopausal Hormone Therapy and Risk of Cancer

4. Women’s Health Initiative (WHI)  Large, randomized, placebo-controlled trial to evaluate the balance of risks and benefits of postmenopausal HT  WHI results include risk estimates for –Breast cancer –Colorectal cancer –Ovarian cancer –Endometrial cancer Anderson GL, et al. JAMA. 2003;290:1739-48; Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004; Chlebowski RT, et al. JAMA. 2003;289:3243-53; Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.

5. WHI: Preliminary Cancer Outcomes E+P = estrogen plus progestin; nCI = nominal confidence interval; aCI = adjusted confidence interval. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33. Hazard Ratio Placebo Invasive breast cancers, E+P users Colorectal cancers, E+P users Endometrial cancer, E+P users All cancer, E+P users 0.10.51.05.02.0 95% nCI 95% aCI

6. The Women’s Health Initiative Study Group. Control Clin Trials. 1998;19:61-109. Overview of E+P Component of WHI 373,092 Women Initiated Screening 18,845Provided Consent and Reported No Hysterectomy 16,608 Randomized 8506Assigned to Receive Estrogen + Progestin 8102 Assigned to Receive Placebo Exclusion Criteria Included: Moderate-to-severe menopausal symptoms Dementia

7. WHI: Primary Outcomes  Primary outcome –CHD (nonfatal MI, CHD death)  Primary adverse outcome –Invasive breast cancer  Global index –Untested summary measure of the effects of HT on major disease outcomes recorded during the trial CHD = coronary heart disease; MI = myocardial infarction. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.

8. WHI: Factors Included in the Global Index  CHD events (nonfatal MI, CHD death)  Invasive breast cancer  Stroke  Pulmonary embolism  Endometrial cancer  Colorectal cancer  Hip fracture  Deaths due to other causes

9. WHI: Factors Not Included in the Global Index  Menopausal symptoms  Diabetes  Gallbladder disease  Cognitive function Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.

10. WHI: Baseline Characteristics *Values are means (SD). † Overall incidence of prior cardiovascular disease = 7.7%. ‡ P =.04 vs E+P. CABG = coronary artery bypass graft; PTCA = percutaneous transluminal coronary angioplasty. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33. Characteristic E+P n = 8506 Placebo n = 8102 Age at screening, years*63.2 (7.1)63.3 (7.1) Prior hormone use, %26.125.6 Body mass index, kg/m2*28.5 (5.8)28.5 (5.9) Never smokers, %49.650.0 Diabetes, %4.4 Hypertension, %35.736.4 Statin use at baseline, %6.96.8 History of MI, %†1.61.9 History of CABG/PTCA, %†1.11.5‡ Family history of breast cancer, %16.015.3

11. WHI: Statistical Analyses  Outcome comparisons presented as hazard ratios (HRs) with nominal and adjusted 95% confidence intervals (CI)  Nominal CI (nCI): describes variability in risk estimates that would result from a trial with a single outcome –Used by WHI investigators for primary outcomes (CHD, breast cancer) and global index  Adjusted CI (aCI): variability of risk estimates corrected for multiple comparisons over time –Applicable for all other outcomes Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

12. Data and Safety Monitoring Board (DSMB)  Asymmetric upper and lower boundaries –1-sided 0.025-level upper boundary for benefit –1-sided 0.05-level lower boundary for adverse effects Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

13. Data and Safety Monitoring Board (DSMB)  After completion of 5 interim analyses, a small but consistent adverse effect was noted in CHD and the global index  At the 10th interim analysis, the DSMB recommended early stopping of the E+P arm of the trial Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.

14.  The DSMB’s decision to stop E+P arm early was based on a monitoring boundary for breast cancer that was designated before study began 1  At that time, the DSMB recommended that the E-alone arm of the WHI continue  In March 2004, the E-alone study was stopped after 7 years of use 2 –Small increased risk of stroke –No increased risk of breast cancer 1 Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33. 2 NIH News. Available at: http://www.nhlbi.nih.gov/new/press/04-03-02.htm. Data and Safety Monitoring Board (DSMB)

15. Section 2: HT and Breast Cancer Risk Postmenopausal Hormone Therapy and Risk of Cancer

16. Section 2a: WHI Breast Cancer Results Postmenopausal Hormone Therapy and Risk of Cancer

17. WHI: Effect of E+P on Risk of Invasive Breast Cancer Cumulative Proportion Time (years) Unweighted HR = 1.24 (95% CI, 1.01–1.54) Chlebowski RT, et al. JAMA. 2003;289:3243-53. E+P Placebo

18. WHI: Effect of E+P on Risk of In Situ Breast Cancer Cumulative Proportion Time (years) E+P Placebo Chlebowski RT, et al. JAMA. 2003;289:3243-53. Unweighted HR = 1.18 (95% CI, 0.77–1.82)

19. WHI: Risk of Invasive Breast Cancer in Women With and Without Prior HT Use Hazard Ratio (95% CI) 0.10.51.04.02.0 Prior HT Use None <5 Years  5 Years Overall % of WHI Population 74.0 14.8 11.2 100 6.0 Chlebowski RT, et al. JAMA. 2003;289:3243-53.

20. E+P (n = 199) Placebo (n = 150)P-Value Tumor size, mean ± SD (cm)1.7 ± 1.11.5 ± 0.9.04 Positive lymph nodes, %25.915.8.03 SEER stage, % Localized74.682.7 Regional24.414.0.048 Metastatic1.02.0 Morphology, grade, % Well differentiated25.020.3 Moderately differentiated43.347.7.61 Poorly differentiated/anaplastic31.732.0 WHI: Characteristics of Invasive Breast Cancers SEER = Surveillance, Epidemiology, and End Results. Chlebowski RT, et al. JAMA. 2003;289:3243-53.

21. E+P (n = 199) Placebo (n = 150)P-Value ER status, % Positive86.888.2.72 Negative13.211.8 PR status, % Positive75.069.9.33 Negative25.030.0 Deaths attributed to breast cancer, n (%)4 (2.0)4 (2.7)— ER = estrogen receptor; PR = progesterone receptor. Chlebowski RT, et al. JAMA. 2003;289:3243-53. WHI: Characteristics of Invasive Breast Cancers (continued)

22. WHI: Mammography Results *Abnormal mammograms included those that were associated with recommendations for short-term follow-up, showed a suspicious abnormality, or were highly suggestive of malignancy † P <.001 vs E+P. Chlebowski RT, et al. JAMA. 2003;289:3243-53. % Abnormal* E+P Placebo Year 1 Overall 9.4 31.5 5.4 † 21.2 †

23. WHI Observational Study: Exercise and Breast Cancer Risk in Postmenopausal Women  Self-reported strenuous exercise,* 3 or more times/week, at age 35 years associated with a 14% reduction in breast cancer risk  Current exercise equivalent to 1.25–2.5 hours/week of brisk walking associated with 18% risk reduction  In women with body mass index (BMI)  24.13 kg/m 2, increased benefit with increased levels of current exercise  Less benefit from current exercise in women with BMI 24.14–28.44 kg/m 2 ; no benefit if BMI  28.44 kg/m 2  Risk reductions not changed by current, past, or never use of HT *Defined as long enough to work up a sweat and make one’s heart beat fast. McTiernan A, et al. JAMA. 2003;290:1331-6.

24. WHI Observational Study: Obesity, Body Size, and Risk of Postmenopausal Breast Cancer  No association between anthropometrics* and breast cancer risk in current or former HT users  Among never-users of HT –Weight at study enrollment was strongest predictor of breast cancer risk (  285% for highest quintile vs lowest) –RR of 2.52 for BMI >31.1 kg/m 2 at study enrollment compared with BMI  22.6 kg/m 2 (95% CI, 1.62–3.93) –Effect more pronounced in younger (50–69 years of age) compared with older postmenopausal women *Included height; weight; BMI at age 18 years, age 50 years, and study enrollment; maximum BMI; BMI change since age 18 years; BMI change since age 50 years; waist circumference; hip circumference; waist-to-hip ratio. Morimoto LM, et al. Cancer Causes and Control. 2003;13:741-51.

25. Risk of Postmenopausal Breast Cancer  Body weight and BMI were highly correlated with postmenopausal breast cancer risk 1,2  HT use did not change risk in women of average size or less who exercised regularly 1  In non-lean women (BMI  28.4 kg/m 2 ), exercise did not decrease risk, but risk was not increased with HT use 1 1 McTiernan A, et al. JAMA. 2003; 290:1331-6. 2 Morimoto LM, et al. Cancer Causes and Control. 2003;13:741-51 Summary From WHI Observational Study

26. Perception and Knowledge of WHI Results Ettinger B, et al. Obstet Gynecol. 2003;102:1225-32. 670 HT Users Interviewed Some awareness of WHI findings93% Information considered good57% Attempted to stop HT after WHI56% Considered media information good72% Perceived knowledge of WHI results No knowledge64% Unsure knowledge7% Incorrect knowledge6% Correct knowledge23% WHI 5-item quiz (4 or 5 correct)30%

27. WHI Breast Cancer Results  Results showed a small increased risk of breast cancer among women assigned to E+P  Increased risk limited to those women with prior HT use  Breast cancers among women assigned to E+P were somewhat larger and more likely to involve regional lymph nodes  Higher rate of abnormal mammograms observed in women assigned to E+P Chlebowski RT, et al. JAMA. 2003;289:3243-53. Summary

28. WHI: Considerations  Rates of discontinuation were high: –E+P group = 42% –Placebo group = 38%  A number of women initiated hormone use with their own clinicians Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.

29. WHI: Considerations continued  Clinic gynecologists were unblinded to treatment assignment at higher rate in HT group –41% unblinded in E+P –7% unblinded in placebo  Effects of unblinding in E+P group unclear; could influence patient monitoring for breast cancer and other conditions in the global index Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.

30. Section 2b: Million Women Study Postmenopausal Hormone Therapy and Risk of Cancer

31. Million Women Study  Investigators recruited 1,084,110 women in the UK, aged 50–64 years, between 1996 and 2001  Questionnaire about lifestyle, SES, medical history, and HT use sent in conjunction with invitation from NHSBSP for screening mammography  Mean age, 56 years; 9364 cases of invasive breast cancer and 637 breast cancer deaths identified during follow-up  Analysis of HT and breast cancer risk restricted to postmenopausal women (n = 828,923)  50% were ever-users of HT; 33% were current users; mean duration of use was 5.8 years SES = socioeconomic status; NHSBSP = National Health Service Breast Screening Programme. Million Women Study Collaborators. Lancet. 2003;362:419-27.

32. Incident Invasive Breast Cancer in Relation to Recency and Type of HT Used FCI = floated CI. *Relative to never-users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, body mass index, region, and deprivation index. Million Women Study Collaborators. Lancet. 2003;362:419-27. HT Use at Baseline Relative Risk (95% FCI)* All never-users1.00 (0.96–1.04) All past users1.01 (0.95–1.08) Current users E-only1.30 (1.22–1.38) E+P2.00 (1.91–2.09) Tibolone1.45 (1.25–1.67) Other/unknown types1.44 (1.17–1.76)

33. Incidence of Breast Cancer According to Recency and Type of HT Used HT Use at Baseline Cases/ Population Population Affected (%) All never-users2894/392,7570.74 All past users1044/150,1790.70 Current users E-only991/115,3830.85 E+P1934/142,8701.35 Tibolone184/18,1861.01 Other/unknown types93/95481.00 Million Women Study Collaborators. Lancet. 2003;362:419-27.

34. Incident Invasive Breast Cancer in Relation to Recency and Type of HT Used FCI = floated CI. *Relative to never-users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, BMI, region, and deprivation index. Million Women Study Collaborators. Lancet. 2003;362:419-27. Total Duration of HT Use by Type of HT Used at Baseline Relative Risk (95% FCI)* Never-users of HT1.00 0.96–1.04 Past users of HT <1 year0.94 (0.84–1.05) 1–4 years1.01 (0.92–1.12) 5–9 years1.14 (1.00–1.30) ≥10 years1.05 (0.84–1.30) Current users of E alone <1 year0.81 (0.55–1.20) 1–4 years1.25 (1.10–1.41) 5–9 years1.32 (1.20–1.46) ≥10 years1.37 (1.22–1.54) Current users of E+P <1 year1.45 (1.19–1.78) 1–4 years1.74 (1.60–1.89) 5–9 years2.17 (2.03–2.33) ≥10 years2.31 (2.08–2.56)

35. Incident Invasive Breast Cancer in Current Users of E-only Preparations Dotted line represents overall relative risk for current users of estrogen-only preparations compared with never-users at baseline. *Relative to never-users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, BMI, region, and deprivation index. Million Women Study Collaborators. Lancet. 2003;362:419-27. E-only Formulation Relative Risk (95% CI)* All E-only formulations1.30 (1.21–1.40) By constituent and dose All equine estrogen1.29 (1.16–1.43) ≤0.625 mg1.25 (1.11–1.41) >0.625 mg1.36 (1.14–1.61) All 17  -estradiol 1.24 (1.12–1.37) ≤1 mg1.25 (1.12–1.40) >1 mg1.19 (0.89–1.58) By formulation Oral1.32 (1.21–1.45) Transdermal1.24 (1.11–1.39) Implanted1.65 (1.26–2.16)

36. Incident Invasive Breast Cancer in Current Users of E+P Preparations Dotted line represents overall relative risk for current users of estrogen-progestin preparations compared with never-users at baseline. *Relative to never-users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, BMI, region, and deprivation index. Million Women Study Collaborators. Lancet. 2003;362:419-27. Duration of Use, <5 Years E+P Formulation Relative Risk (95% CI)* All E+P formulations1.70 (1.56–1.86) By progestin constituent Medroxyprogesterone acetate1.60 (1.33–1.93) Norethisterone1.53 (1.35–1.75) Norgestrel/levonorgestrel1.97 (1.74–2.33) By type of regimen Sequential1.77 (1.59–1.97) Continuous1.57 (1.37–1.79)

37. Dotted line represents overall relative risk for current users of estrogen-progestin preparations compared with never-users at baseline. *Relative to never-users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, BMI, region, and deprivation index. Million Women Study Collaborators. Lancet. 2003;362:419-27. Duration of Use,  5 Years Incident Invasive Breast Cancer in Current Users of E+P Preparations E+P Formulation Relative Risk (95% CI)* All E+P formulations2.21 (2.06–2.36) By progestin constituent Medroxyprogesterone acetate2.42 (2.10–2.80) Norethisterone2.10 (1.89–2.34) Norgestrel/levonorgestrel2.23 (2.04–2.44) By type of regimen Sequential2.12 (1.95–2.30) Continuous2.40 (2.15–2.67)

38. NA = not available. *Relative to never-users, stratified by age, time since menopause, parity and age at first birth, family history of breast cancer, body mass index, region, and deprivation index. Million Women Study Collaborators. Lancet. 2003;362:419-27. Relative Risk of Fatal Breast Cancer in Relation to Use of HT at Baseline HT Use at Baseline Breast Cancer Deaths/ Population RR (95% FCI)* Mortality Rate (%) Never-users238/392,7571.00 (0.88–1.14) 0.060 Current users191/285,9871.22 (1.05–1.41) 0.066 Past users88/150,1791.05 (0.85–1.29) 0.058 Total breast cancer deaths517/828,923NA0.062

39. Breast Cancer Mortality Rates in the Million Women Study Million Women Study Collaborators. Lancet. 2003;362:419-27. HT Use at Baseline Breast Cancer Deaths/Breast Cancer Cases Mortality Rate (%) Never-users238/28948.2 Current users191/32025.9 Past users88/10448.4 Total breast cancer deaths517/69617.1

40. Results for Breast Cancer Mortality With HT Use Show Consistency Relative Risk of Mortality (95% CI) 0.10.51.010.02.0 Hunt et al, 1990 Henderson et al, 1991 Willis et al, 1996 Grodstein et al, 1997 Current Use Past Use Sellers et al, 1997 Rodriguez et al, 2001 Current Use Past Use

41. Million Women Study: Considerations  Of the >1,000,000 patients, validity of self-reported HT use was assessed by comparing to prescription records in only 570 women in 2 general practices 1  Mortality results were based on a total of 517 breast cancer deaths 2  Inconsistencies in reported statistics and number of participants in various subgroups not addressed  Breast cancers were diagnosed on average 1.2 years after recruitment 2  The average time between diagnosis and death was 1.7 years 2 —implies advanced disease at time of diagnosis 1 Banks E, et al. J Epidemiol Biostat. 2001;6:357-63. 2 Million Women Study Collaborators. Lancet. 2003;362:419-27.

42. Million Women Study: Considerations  Average period of follow-up was 2.6 years for analysis of cancer incidence and 4.1 years for analysis of mortality 1  British Menopause Society 2 stated that it was not possible to draw any firm conclusions about the risk of death from breast cancer being influenced by HT use because –Number of deaths was small –Follow-up was too short (just over 4 years) –Statistical significance was borderline 1 Million Women Study Collaborators. Lancet. 2003;362:419-27. 2 British Menopause Society. Available at http://www.the-bms.org/news.htm

43. Section 2c: Additional Studies of Breast Cancer and HT Postmenopausal Hormone Therapy and Risk of Cancer

44. Breast Cancer Risk Among E+P Users in Recent Randomized Controlled Trials Chlebowski RT, et al. JAMA. 2003;289:3243-53. Hulley S, et al. JAMA. 2002;288:58-66. WHI HERS HERS II Relative Hazard (95% CI) 0.51.0102.0

45. Breast Cancer Risk and HT: WHI Results Compare With Previous Studies  Risk estimate from WHI is similar to results from earlier observational studies  Overall risk estimates have been consistently close to 1.0

46. Review of Observational Studies Published From 1975-2000 *Percents do not total 100% because 1 study did not report confidence intervals; NS = not significant. Bush TL, et al. Obstet Gynecol. 2001;98:498-508. E Alone (n = 45)*E+P (n = 20)

47. Risk Estimates for Incident Breast Cancer: pre-1990 Ever-users compared with never-users of unopposed estrogen Mack et al, 1975 Hoover et al, 1976 Casagrande et al, 1976 Wynder et al, 1978 Jick et al, 1980 Ross et al, 1980 Hoover et al, 1981 Kelsey et al, 1981 Thomas et al, 1982 Hulka et al, 1982 Gambrell et al, 1983 Sherman et al, 1983 Kaufman et al, 1984 Horwitz & Stewart, 1984 Hiatt et al, 1984 Nomura et al, 1986 McDonald et al, 1986 Wingo et al, 1987 Hunt et al, 1987 Ewertz, 1988 Rohan and McMichael, 1988 Mills et al, 1989 Bergkvist et al, 1989 Reprinted from Bush TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol. 2001;98:498-508, ©2001, with permission from the American College of Obstetricians and Gynecologists.

48. Kaufman et al, 1991 Palmer et al, 1991 Harris et al, 1992 Yang et al, 1992 Weinstein et al, 1993 Risch & Howe, 1994 Colditz et al, 1995 La Vecchia et al, 1995 Lipworth et al, 1995 Newcomb et al, 1995 Stanford et al, 1995 Persson et al, 1997 Brinton et al, 1998 Henrich et al, 1998 Sourander et al, 1998 Dupont et al, 1999 Magnusson et al, 1999 Persson et al, 1999 Lando et al, 1999 Schairer et al, 2000 Ross et al, 2000 Moorman et al, 2000 Risk Estimates for Incident Breast Cancer: post-1990 Reprinted from Bush TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol. 2001;98:498-508, ©2001, with permission from the American College of Obstetricians and Gynecologists. Ever-users compared with never-users of unopposed estrogen

49. 0.51.02.0 Ever-Use of HT and Breast Cancer Risk Relative Risk (95% CI) Armstrong, 1988 Dupont and Page, 1991 Steinberg et al, 1991 Sillero-Arenas et al, 1992 Colditz et al, 1993 Grady et al, 1992 Meta-Analyses

50. Collaborative Group Reanalysis: Risk of Breast Cancer With HT Similar to WHI Results *P <.01 vs never-user. † Average duration of use was 11 years. RR = relative risk. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997;350:1047-59. HT UseRR Ever use1.14* Current use1.21* Current use,  5 years † 1.35* Past use1.07

51. Risk of Breast Cancer Changes With a Woman’s Age American Cancer Society, Surveillance Research, 2001. Breast Cancer Facts and Figures 2001–2002. Available at: http//www.cancer.org/downloads/STT/BrCaFF2001.pdf. Age (years) Probability of Developing Breast Cancer Within 10 Years 200.05% (1 in 2044) 300.40% (1 in 249) 401.49% (1 in 67) 502.77% (1 in 36) 603.45% (1 in 29) 704.16% 1 in 24)

52. Absolute Risk of Breast Cancer in the General Population  Each 50-year-old woman has approximately a 2.8% chance of developing breast cancer by age 60 years  This translates to an absolute risk of 2.8 per 100 women All Women Aged 50 Years in the General Population— Risk for Breast Cancer by Age 60 Years In 100 women, 2.8 are at risk American Cancer Society, Surveillance Research, 2001. Breast Cancer Facts and Figures 2001–2002. Available at: http//www.cancer.org/downloads/STT/BrCaFF2001.pdf.

53. Absolute Risk of Breast Cancer After 5 Years of HT  WHI results indicate an HR for breast cancer of 1.24 after 5 years of HT use (a 24% increase in risk) 1  This translates into an absolute risk of 3.5 per 100 users Risk of Breast Cancer by Age 60 Years After 5 Years of HT Use (Assuming a 24% Increase in Risk) 1 Chlebowski RT, et al. JAMA. 2003;289:3243-53. 3.5 of 100 women who are HT users are at risk (<1 additional woman over baseline risk)

54. DurationCases/ControlRR and 99% FCI <1 Year1154/25461.09 1–4 Years1660/39991.05 5–9 Years813/19121.19 10–14 Years386/8671.09  15 Years 337/5841.58 Increase in risk per year = 1.023. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet. 1997;350:1047-59. Reprinted with permission from Elsevier Science. Collaborative Group Reanalysis: Breast Cancer Risk by Duration of HT Use 0.1 1.0 0.5 2.0

55. Duration of HT Use and Breast Cancer Risk *Odds adjusted for age, age at first full-term pregnancy, and family history of breast cancer. Stanford JL, et al. JAMA. 1995;274:137-42. E Alone 1–3 mos 4 mos–2.9 y 3 y–4.9 y 5 y–7.9 y 8 y–11.9 y 12 y–14.9 y 15 y–19.9 y  20 y E+P 1–3 mos 4 mos–2.9 y 3 y–4.9 y 5 y–7.9 y  8 y Relative Odds* (95% CI) 0.10.51.010.02.0

56. Breast Cancer Risk With HT Use in Women With a Family History Relative Risk (95% CI) HT Use Past Users  5 Years  5 Years Current Users  5 Years  5 Years Sellers TA, et al. Ann Intern Med. 1997;127:973-80. 0.10.51.0102.0 0.51.02.05.0

57. Relative Risk (95% CI) 0.51.05.02.010.0 * * * HT Use and Breast Cancer in Women With a History of Benign Breast Disease HT Users Without Proliferative Disease (PD; hyperplasia) *P = NS between groups Dupont WD, et al. Cancer. 1999;85:1277-83. HT Users Nonusers All PD HT Users Nonusers PD Without Atypia HT Users Nonusers Atypical Hyperplasia

58. Previous Studies Reported Smaller Tumors in HT Users *P <.05 vs nonusers. Used with permission from Holli K, et al. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol. 1998 Sep;16(9):3115-3120. Patients (%) Primary Tumor Size (cm) <2 or In Situ 22 * * (n = 176) (n = 126) (n = 116) (n = 39)

59. *P <.05 vs nonusers. Bilimoria MM, et al. Ann Surg Oncol. 1999;6:200-7. Patients (%) * * Previous Studies Reported Lower-Grade Tumors in HT Users

60. Previous Studies Reported Tumors With More Favorable Prognostic Indicators in E+P Users *P <.05 vs nonusers. Cheek J, et al. Arch Surg. 2002;137:1015-21. Patients (%) * * *

61. Breast Cancer Stage at Diagnosis P-value vs all nonusers =.27; vs age-adjusted cohort =.03. Pappo I, et al. Ann Surg Oncol. 2003;11:52-8. HT Users vs Nonusers Stage HT Nonusers (%) HT users (%) DCIS17.120.0 I41.745.5 II26.230.9 III13.43.6 IV1.60.0

62. Section 2d: Can Estrogen Be Used Safely in Breast Cancer Survivors? Postmenopausal Hormone Therapy and Risk of Cancer

63. Survival Rates for Breast Cancer Patients HT Users HT Nonusers P =.003 HT Users Compared With Nonusers Used with permission from DiSaia PJ, et al. Breast cancer survival and hormone replacement therapy: a cohort analysis. Am J Clin Oncol. 2000 Dec;23(6):541-545.

64. Postmenopausal Hormone Therapy and Risk of Cancer Cumulation Proportion Surviving Time (Years) HT Group Control Group Log-rank Test = 2.324 P =.020 Decker DA, et al. Menopause. 2003;10:277-85.

65. Effect of HT on Breast Cancer Recurrence and Mortality Breast Cancer Recurrence Breast Cancer Mortality Total Mortality O'Meara ES, et al. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst. 2001;93(10):754-62, by permission of Oxford University Press. 0.1 1.0 0.5 2.0

66. HT in Breast Cancer Survivors n = 56 HT users. Average duration of follow-up was 12.8 years (range, 4.7 to 38.9 years). Average duration of HT use was 6.4 years (range, 1 to 20.9 years). Peters GN, et al. Ann Surg Oncol. 2001;8:828-32. Outcome Number of Patients Local recurrence1 Contralateral cancer1 Regional/distant recurrence0 Breast cancer death0

67. HT After Breast Cancer Retrospective Observational Study, 1964-1999  n = 1122  286 HT users: duration of use, 1–26 years (median = 1.8 years)  Follow-up: 0–36 years (median = 6.1 years ) CCHT = continuous-combined HT. *Types of HT included estrogen/progestin (48%), oral progestin (27%), vaginal estrogen (11%), vaginal estrogen/oral progestin (7%), and oral or transdermal estrogen (6%). Durna EM, et al. Med J Australia. 2002;177:347-51. Any HT,* RR (95% CI) CCHT Only, RR (95% CI) Breast cancer recurrence 0.62 (0.43–0.87)0.81 (0.52–1.27) Breast cancer mortality 0.40 (0.22–0.72)0.32 (0.12–0.88) All-cause mortality0.34 (0.19–0.59)0.27 (0.10–0.73)

68. Hormonal Replacement Therapy After Breast Cancer—Is It Safe? (HABITS) Trial  Trial terminated in December 2003; safety analyses reported in research letter published in Lancet  Women with a previously treated breast cancer randomized to either –HT –Best treatment without hormones  Treatment was not blinded  Type of HT or best treatment determined by local physician  434 women were randomized; 345 (80%) had at least one follow-up report  Primary endpoint was any new breast cancer Holmberg L, Anderson H. Lancet. 2004;363:453-5.

69. HABITS: Baseline Characteristics In Women With Follow-Up Data Holmberg L, Anderson H. Lancet. 2004;363:453-5. CharacteristicHTNo HT Number of women randomized219215 Number of women with follow-up174171 Median follow-up, years2.1 Median time between primary treatment and randomization, years 2.62.7 Median number of follow-up reports33 Mean age, years55.555.0 Node-positive, %2621 Hormone receptor status unknown, %2722 Breast preserved, %6257 Receiving HT before diagnosis, %5256 Receiving adjuvant tamoxifen, %21

70. HABITS: Risk of New Breast Cancer in HT Versus Non-HT Group 0.11.010.0 Relative Hazard (95% CI) 0.540.0 All Women Receptor Positive Receptor Negative Tamoxifen No Tamoxifen HT Before Diagnosis No HT Before Diagnosis Events/Total # in Subset 33/345 14/159 6/72 4/72 29/273 14/177 19/168 Holmberg L, Anderson H. Lancet. 2004;363:453-5.

71. Summary: Breast Cancer Risk  The WHI reported a small, increased risk of invasive breast cancer with an average of 5.6 years of E+P use  Most observational studies do not show an increased risk of breast cancer with HT use; some suggest a small increased risk with long-term HT use  Risk estimates from prospective, randomized trials and observational studies are similar  In the WHI, breast cancers in women assigned to E+P were somewhat larger and more likely to involve regional lymph nodes; other studies show that HT users have less aggressive, smaller tumors

72. Summary: Breast Cancer Risk continued  Positive family history of breast cancer is not a contraindication for HT  In observational studies, breast cancer survival rates are better in HT users –True for Million Women Study if breast cancer mortality rate is calculated as in other studies (ie, breast cancer deaths/breast cancer cases)  In breast cancer survivors, HT use has not been shown to worsen mortality or recurrence

73. Section 3: HT and Colorectal Cancer Risk Postmenopausal Hormone Therapy and Risk of Cancer

74. Facts and Figures About Colorectal Cancer  Third most common cancer in US women, and third most common cause of cancer death in women  An individual’s lifetime risk of developing colorectal cancer is 6%, with 90% of cases occurring after age 50 years  2003 estimates: 74,700 new cases and 29,000 new deaths in women  10-year survival for colorectal cancer is 55% American Cancer Society. Cancer Facts and Figures 2003. Available at: www.cancer.org/docroot/STT/stt_0.asp.

75. HT Use May Be Associated With Decreased Risk of Colorectal Cancer Relative Risk (95% CI) *Statistic refers to colon cancer risk only. † Multivariate risk analysis. ‡ Risk assessment adjusted for age only. § Meta-analysis includes 2 studies of colorectal cancer mortality. Jacobs et al, 1994* † Newcomb and Storer, 1995* † Folsom et al, 1995* † Troisi et al, 1997 ‡ Kampman et al, 1997 † Grodstein et al, 1998 † Paganini-Hill, 1999 ‡ Hully et al, 2002 † Chlebowski et al, 2004 † Meta-analysis: Nanda et al, 1999* † Meta-analysis: Grodstein et al, 1999 ‡§

76. WHI Results: Effect of HT on Risk of Colorectal Cancer HR = 0.56 95% nCI = 0.38–0.81 95% aCI = 0.33–0.94 Placebo E+P Kaplan-Meier Estimate Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004.

77. Absolute Risk of Colorectal Cancer After 5 Years of E+P  Each 50-year-old woman has approximately a 0.5% chance of developing colorectal cancer by age 60 years 1 –This translates to an absolute risk of 5.0 cases per 1000 women  WHI results indicate an HR for colorectal cancer of 0.56 after 5 years of E+P use (a 44% decrease in risk) 2 –This translates into an absolute risk of 2.8 cases per 1000 users 1 Feuer EJ, Wun LM. Available at: http://srab.cancer.gov/devcan/canques.html. Accessed 1/24/04. 2 Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004.

78. Mortality Outcomes for Colorectal Cancer Patients: Ever-Users of HT Calle et al, 1995 Sturgeon et al, 1995 Persson et al, 1996 Meta-analysis: Nanda et al, 1999 Relative Risk (95% CI) 0.51.0102.0

79. Risk for Colorectal Cancer Does Not Appear Associated With Duration of Use Paganini-Hill et al, 1999  4 years  4 years Troisi et al, 1997  5 years  5 years Grodstein et al, 1998  5 years  5 years *Age-adjusted RR compared with never-users Relative Risk* (95% CI) 0.10.51.010.02.0

80. Summary: Colorectal Cancer Risk  In the WHI, colorectal cancer risk in E+P group was lower than in placebo group  WHI results corroborate other studies that show a protective effect of HT in colorectal cancer  Finding of greater proportion of advanced cancers in E+P users requires further study –Possible role of vaginal bleeding in delaying care suggests need for expanded colorectal screening in postmenopausal women

81. Section 4: HT and Ovarian Cancer Risk Postmenopausal Hormone Therapy and Risk of Cancer

82. Ovarian Cancer: Background  Ovarian cancer is the second leading cause of death from gynecologic cancers 1  Ovarian cancer is usually diagnosed in its advanced stage  An estimated 1 woman in 70 will develop ovarian cancer in her lifetime, and 1 in 100 will die from the disease 2  Median age of diagnosis is 63 years 2  Estimates for 2003: 25,400 new cases and 14,300 new deaths from ovarian cancer 1 1 American Cancer Society. Cancer Facts and Figures 2003. Available at: www.cancer.org/docroot/STT/stt_0.asp. 2 Schneider HP. Maturitas. 2002;43:S35-52.

83. WHI Results: Hazard Ratio for Invasive Ovarian Cancer with E+P Incidence rate of invasive ovarian cancer for the total study population was 34 cases per 100,000 person-years. Anderson GL, et al. JAMA. 2003;290:1739-48. Hazard Ratio 0.10.51.05.02.0 95% nCI 95% aCI E+P Placebo

84. Ovarian Cancer Incidence: Meta-Analyses Relative Risk (95% CI) Garg et al, 1998 Coughlin et al, 2000 Garg PP, et al. Obstet Gynecol. 1998;92:472-479. Coughlin SS, et al. J Clin Epidemiol. 2000;53:367-375.

85. Centers for Disease Control Meta-Analysis Relative Risk (95% CI) European/Australian Case-Control Studies Hospital/Clinic Controls Booth et al, 1998 La Vecchia et al, 1982 Parazzini et al,1994 Polchronopolou et al, 1993 Tzonou et al, 1984 Community Controls Purdie et al, 1995 US/Canadian Case-Control Studies Hospital/Clinic Controls Annegers et al, 1979 Hartge et al, 1988 Hempling et al, 1997 Hildreth et al, 1981 Kaufman et al, 1989 Community Controls Cramer et al, 1983 Lee et al, 1986 Risch, 1996 Weiss et al, 1982 Schneider HP. Maturitas. 2002;43:S35-S52. ©2002 Elsevier Ireland, Ltd. Used with permission. 0.40.61.01.41.82.22.63.04.05.0

86. Risk of Ovarian Cancer With HT  Nationwide case-control trial—Sweden  655 cases and 3899 controls, 1993–1995 Risk assessment expressed as odds ratio compared with never-users. Riman T, et al. J Natl Cancer Inst. 2002;94:497-504. UseE aloneSequential E+P Continuous E+P Ever1.43 (1.02–2.0)1.54 (1.15–2.05)1.02 (0.73–1.43) <1 year1.4 (NS)1.88 (1.11–3.17)1.28 (NS) 1 to <2 Years1.07 (NS)1.47 (NS)0.84 (NS) 2 to <5 Years0.99 (NS)1.3 (NS)0.91 (NS) 5 to <10 Years1.8 (NS)1.07 (NS)0.91 (NS)  10 Years 2.4 (1.03–4.46)2.1 (NS)1.8 (NS)

87. Effect of HT on Ovarian Cancer Risk: Data From the BCDDP Follow-up Nonuser E Alone,  4 Years E Alone, 4–9 Years E Alone, 10–19 Years E Alone,  20 Years E+P,  2 Years E+P,  2 Years Relative Hazard (95% CI) *BCDDP = Breast Cancer Detection Demonstration Project. Lacey JV Jr, et al. JAMA. 2002;288:334-41.

88. American Cancer Society Cancer Prevention Study II  Prospective, cohort study enrolled 676,306 women in 1982  Two-thirds of enrollees were excluded from analysis (211,581 used for analysis)  Main outcome measure: ovarian cancer mortality  Estrogen use assessed by questionnaire in 1982  46,000 women were hormone users (current or former) at baseline Rodriguez C, et al. JAMA. 2001;285:1460-5.

89. Results From ACS Prevention Study II Rodriguez C, et al. JAMA. 2001;285:1460-5. Number of Deaths Rate Ratio (95% CI) Ever-use2551.23 (1.06–1.43) 10 or more years of use (baseline)312.20 (1.53–3.17)

90. ACS Prevention Study II: Considerations  Did not include exposure information after 1982  Due to exclusion criteria, analyses did not include 61% of the subjects who died of ovarian cancer  Estimate of mortality with long-term use based on 31 deaths

91. Summary: Ovarian Cancer Risk  Data on the association between the use of HT and the risk for ovarian cancer are inconsistent

92. Section 5: HT and Endometrial Cancer Risk Postmenopausal Hormone Therapy and Risk of Cancer

93. Risk of Endometrial Cancer Is Decreased With E+P Regimens Results From Meta-analyses Nelson HD, et al. JAMA. 2002;288:872-81. Grady D, et al. Obstet Gynecol. 1995;85:304-13. Relative Risk95% CI No HT1.0— E only2.32.1–2.5 E+P0.80.6–1.2

94. WHI Results: Hazard Ratio for Endometrial Cancer with E+P Incidence rate of endometrial cancer for the total study population was 62 cases per 100,000 person-years. Anderson GL, et al. JAMA. 2003;290:1739-48. Hazard Ratio E+P 0.10.51.05.02.0 95% nCI 95% aCI Placebo

95. Endometrial Hyperplasia Rates With Lower Doses of NETA Hyperplasia Rate After 12 Months (%) n = 1176. E 2 = estradiol; NETA = norethindrone acetate. P <.001 for all continuous-combined groups vs unopposed E 2. Kurman RJ, et al. Obstet Gynecol. 2000;96:373-9. E 2 1 mgE 2 1 mg/NETA 0.1 mg E 2 1 mg/NETA 0.25 mg E 2 1 mg/NETA 0.5 mg

96. Women’s HOPE = Women’s Health, Osteoporosis, Progestin, Estrogen; CEE = conjugated equine estrogens; MPA = medroxyprogesterone. Pickar JH, et al. Fertil Steril. 2003;80:1234-40. Women’s HOPE Study Endometrial Hyperplasia Rates After 1 and 2 Years of Low-Dose E+P Hyperplasia Rate (%) 0.625 mg0.625/ 2.5 mg 0.45 mg0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg0.3/ 1.5 mg Placebo CEECEE/MPA 0.00 Year 1 Year 2

97. Summary: Endometrial Cancer Risk  Historically, estrogen in combination with a progestin has been shown to be protective against endometrial cancer in women with intact uteri –Progestin use must be for >10 days per month  Results from the WHI did not find a protective effect of HT on endometrial cancer risk –May be due to high BMI of participants

98. Section 6: Recommendations for Patient Education Postmenopausal Hormone Therapy and Risk of Cancer

99. Recommendations for Patient Education  Discuss menopause and HT prior to the onset of symptoms  Ask patients to make short-term, annual decisions about HT  Discuss information about HT that is known with good certainty  Acknowledge questions that remain under investigation  Give patients a recommendation about treatment