Postmenopausal Hormone Therapy and Risk of Cancer

Postmenopausal Hormone Therapy and Risk of Cancer A CME Slide Library From the Council on Hormone Education 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 Postmenopausal Hormone Therapy and Risk of Cancer Section 1: Evaluation of Cancer Risk in the WHI 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. WHI: Preliminary Cancer Outcomes Placebo Invasive breast cancers, E+P users Colorectal cancers, E+P users Endometrial cancer, E+P users All cancer, E+P users 0.1 0.5 1.0 95% nCI 95% aCI 2.0 5.0 Hazard Ratio 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. Overview of E+P Component of WHI 373,092 Women Initiated Screening Exclusion Criteria Included: • Moderate-to-severe menopausal symptoms • Dementia 18,845 Provided Consent and Reported No Hysterectomy 16,608 Randomized 8506 Assigned to Receive Estrogen + Progestin 8102 Assigned to Receive Placebo The Women’s Health Initiative Study Group. Control Clin Trials. 1998;19:61-109. WHI: Primary Outcomes  Primary outcome adverse outcome – CHD (nonfatal MI, CHD death)  Primary – 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. 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 Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33. 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. WHI: Baseline Characteristics Characteristic Age at screening, years* Prior hormone use, % E+P n = 8506 63.2 (7.1) 26.1 Placebo n = 8102 63.3 (7.1) 25.6 Body mass index, kg/m2* Never smokers, % Diabetes, % Hypertension, % Statin use at baseline, % 28.5 (5.8) 49.6 4.4 35.7 6.9 28.5 (5.9) 50.0 4.4 36.4 6.8 History of MI, %† History of CABG/PTCA, %† Family history of breast cancer, % 1.6 1.1 16.0 1.9 1.5‡ 15.3 *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. 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. 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. 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. Data and Safety Monitoring Board (DSMB)  The DSMB’s decision to stop E+P arm early was based on a monitoring boundary for breast cancer that was designated before study began1 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 use2 – Small increased risk of stroke   – No increased risk of breast cancer 1Writing 2NIH Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33. News. Available at: http://www.nhlbi.nih.gov/new/press/04-03-02.htm. Postmenopausal Hormone Therapy and Risk of Cancer Section 2: HT and Breast Cancer Risk Postmenopausal Hormone Therapy and Risk of Cancer Section 2a: WHI Breast Cancer Results WHI: Effect of E+P on Risk of Invasive Breast Cancer 0.04 Cumulative Proportion E+P Placebo 0.03 Unweighted HR = 1.24 (95% CI, 1.01–1.54) 0.02 0.01 0 0 1 2 3 4 5 6 7 Time (years) Chlebowski RT, et al. JAMA. 2003;289:3243-53. WHI: Effect of E+P on Risk of In Situ Breast Cancer 0.04 Cumulative Proportion E+P Placebo 0.03 Unweighted HR = 1.18 (95% CI, 0.77–1.82) 0.02 0.01 0 0 1 2 3 4 5 6 7 Time (years) Chlebowski RT, et al. JAMA. 2003;289:3243-53. WHI: Risk of Invasive Breast Cancer in Women With and Without Prior HT Use Prior HT Use None <5 Years 5 Years Overall % of WHI Population 74.0 14.8 11.2 100 0.1 0.5 1.0 2.0 4.0 6.0 Hazard Ratio (95% CI) Chlebowski RT, et al. JAMA. 2003;289:3243-53. WHI: Characteristics of Invasive Breast Cancers E+P (n = 199) Tumor size, mean ± SD (cm) Positive lymph nodes, % 1.7 ± 1.1 25.9 74.6 24.4 1.0 25.0 43.3 31.7 Placebo (n = 150) 1.5 ± 0.9 15.8 82.7 14.0 2.0 20.3 47.7 32.0 .61 .048 P-Value .04 .03 SEER stage, % Localized Regional Metastatic Morphology, grade, % Well differentiated Moderately differentiated Poorly differentiated/anaplastic SEER = Surveillance, Epidemiology, and End Results. Chlebowski RT, et al. JAMA. 2003;289:3243-53. WHI: Characteristics of Invasive Breast Cancers (continued) E+P (n = 199) ER status, % Positive 86.8 88.2 .72 Placebo (n = 150) P-Value Negative PR status, % Positive Negative 13.2 75.0 25.0 4 (2.0) 11.8 69.9 30.0 4 (2.7) — .33 Deaths attributed to breast cancer, n (%) ER = estrogen receptor; PR = progesterone receptor. Chlebowski RT, et al. JAMA. 2003;289:3243-53. WHI: Mammography Results % Abnormal* E+P Placebo Year 1 9.4 5.4† Overall 31.5 21.2† *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. 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/m2, increased benefit with increased levels of current exercise Less benefit from current exercise in women with BMI 24.14–28.44 kg/m2; no benefit if BMI 28.44 kg/m2 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. 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/m2 at study enrollment compared with BMI 22.6 kg/m2 (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. Risk of Postmenopausal Breast Cancer Summary From WHI Observational Study  Body weight and BMI were highly correlated with postmenopausal breast cancer risk1,2 HT use did not change risk in women of average size or less who exercised regularly1   In non-lean women (BMI 28.4 kg/m2), exercise did not decrease risk, but risk was not increased with HT use1 1McTiernan 2Morimoto A, et al. JAMA. 2003; 290:1331-6. LM, et al. Cancer Causes and Control. 2003;13:741-51 Perception and Knowledge of WHI Results 670 HT Users Interviewed Some awareness of WHI findings Information considered good 93% 57% Attempted to stop HT after WHI Considered media information good Perceived knowledge of WHI results No knowledge Unsure knowledge Incorrect knowledge Correct knowledge WHI 5-item quiz (4 or 5 correct) Ettinger B, et al. Obstet Gynecol. 2003;102:1225-32. 56% 72% 64% 7% 6% 23% 30% WHI Breast Cancer Results Summary  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. 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. 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. Postmenopausal Hormone Therapy and Risk of Cancer Section 2b: Million Women Study 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. Incident Invasive Breast Cancer in Relation to Recency and Type of HT Used HT Use at Baseline All never-users All past users Current users E-only E+P Tibolone Other/unknown types 1.30 (1.22–1.38) 2.00 (1.91–2.09) 1.45 (1.25–1.67) 1.44 (1.17–1.76) Relative Risk (95% FCI)* 1.00 (0.96–1.04) 1.01 (0.95–1.08) 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. 0.5 1.0 1.5 2.0 2.5 Incidence of Breast Cancer According to Recency and Type of HT Used HT Use at Baseline All never-users All past users Current users E-only E+P Tibolone Other/unknown types 991/115,383 1934/142,870 184/18,186 93/9548 0.85 1.35 1.01 1.00 Cases/ Population 2894/392,757 1044/150,179 Population Affected (%) 0.74 0.70 Million Women Study Collaborators. Lancet. 2003;362:419-27. Incident Invasive Breast Cancer in Relation to Recency and Type of HT Used Total Duration of HT Use by Type of HT Used at Baseline Never-users of HT Past users of HT <1 year 1–4 years 5–9 years ≥10 years Current users of E alone <1 year 1–4 years 5–9 years ≥10 years Current users of E+P <1 year 1–4 years 5–9 years ≥10 years Relative Risk (95% FCI)* 1.00 0.96–1.04 0.94 (0.84–1.05) 1.01 (0.92–1.12) 1.14 (1.00–1.30) 1.05 (0.84–1.30) 0.81 (0.55–1.20) 1.25 (1.10–1.41) 1.32 (1.20–1.46) 1.37 (1.22–1.54) 1.45 (1.19–1.78) 1.74 (1.60–1.89) 2.17 (2.03–2.33) 2.31 (2.08–2.56) 0.0 1.0 2.0 3.0 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. Incident Invasive Breast Cancer in Current Users of E-only Preparations E-only Formulation All E-only formulations By constituent and dose All equine estrogen ≤0.625 mg >0.625 mg All 17-estradiol ≤1 mg >1 mg By formulation Oral Transdermal Implanted 1.32 (1.21–1.45) 1.24 (1.11–1.39) 1.65 (1.26–2.16) 1.29 (1.16–1.43) 1.25 (1.11–1.41) 1.36 (1.14–1.61) 1.24 (1.12–1.37) 1.25 (1.12–1.40) 1.19 (0.89–1.58) Relative Risk (95% CI)* 1.30 (1.21–1.40) 0.5 1.0 1.5 2.0 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. Incident Invasive Breast Cancer in Current Users of E+P Preparations Duration of Use, <5 Years E+P Formulation Relative Risk (95% CI)* All E+P formulations By progestin constituent Medroxyprogesterone acetate Norethisterone 1.70 (1.56–1.86) 1.60 (1.33–1.93) 1.53 (1.35–1.75) Norgestrel/levonorgestrel By type of regimen Sequential Continuous 1.97 (1.74–2.33) 1.77 (1.59–1.97) 1.57 (1.37–1.79) 0.0 1.0 2.0 3.0 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. Incident Invasive Breast Cancer in Current Users of E+P Preparations Duration of Use, 5 Years Relative Risk (95% CI)* E+P Formulation All E+P formulations By progestin constituent Medroxyprogesterone acetate Norethisterone 2.21 (2.06–2.36) 2.42 (2.10–2.80) 2.10 (1.89–2.34) Norgestrel/levonorgestrel By type of regimen Sequential Continuous 2.23 (2.04–2.44) 2.12 (1.95–2.30) 2.40 (2.15–2.67) 0.0 1.0 2.0 3.0 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. Relative Risk of Fatal Breast Cancer in Relation to Use of HT at Baseline Breast Cancer Deaths/ Population 238/392,757 191/285,987 88/150,179 517/828,923 HT Use at Baseline Never-users Current users Past users Total breast cancer deaths RR (95% FCI)* 1.00 (0.88–1.14) 1.22 (1.05–1.41) 1.05 (0.85–1.29) NA Mortality Rate (%) 0.060 0.066 0.058 0.062 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. Breast Cancer Mortality Rates in the Million Women Study Breast Cancer Deaths/Breast Cancer Cases 238/2894 191/3202 88/1044 517/6961 HT Use at Baseline Never-users Current users Past users Total breast cancer deaths Mortality Rate (%) 8.2 5.9 8.4 7.1 Million Women Study Collaborators. Lancet. 2003;362:419-27. Results for Breast Cancer Mortality With HT Use Show Consistency 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 0.1 0.5 1.0 2.0 10.0 Relative Risk of Mortality (95% CI) 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 practices1 Mortality results were based on a total of 517 breast cancer deaths2 Inconsistencies in reported statistics and number of participants in various subgroups not addressed Breast cancers were diagnosed on average 1.2 years after recruitment2 The average time between diagnosis and death was 1.7 years2—implies advanced disease at time of diagnosis E, et al. J Epidemiol Biostat. 2001;6:357-63. Women Study Collaborators. Lancet. 2003;362:419-27.     1Banks 2Million 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 mortality1 British Menopause Society2 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  1Million 2British Women Study Collaborators. Lancet. 2003;362:419-27. Menopause Society. Available at http://www.the-bms.org/news.htm Postmenopausal Hormone Therapy and Risk of Cancer Section 2c: Additional Studies of Breast Cancer and HT Breast Cancer Risk Among E+P Users in Recent Randomized Controlled Trials WHI HERS HERS II 0.5 1.0 2.0 10 Relative Hazard (95% CI) Chlebowski RT, et al. JAMA. 2003;289:3243-53. Hulley S, et al. JAMA. 2002;288:58-66. 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  Review of Observational Studies Published From 1975-2000 100 E Alone (n = 45)* 82% E+P (n = 20) 80% Studies (%) 80 60 40 20 2% 0 <1.0 NS from 1.0 >1.0 <1.0 NS from 1.0 >1.0 13% 10% 10% Risk Estimates *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. 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 Reprinted from Bush TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Bergkvist et al, 1989 Obstet Gynecol. 2001;98:498-508, ©2001, with permission from the American College of Obstetricians and Gynecologists. 0.1 1 10 Risk Estimates for Incident Breast Cancer: post-1990 Ever-users compared with never-users of unopposed estrogen 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 Reprinted from Bush TL, Whiteman M, Flaws JA. Hormone replacement therapy and breast cancer: a qualitative review. Moorman et al, 2000 Obstet Gynecol. 2001;98:498-508, ©2001, with permission from the American College of Obstetricians and Gynecologists. 0.1 1 10 Ever-Use of HT and Breast Cancer Risk Meta-Analyses Armstrong, 1988 Dupont and Page, 1991 Steinberg et al, 1991 Sillero-Arenas et al, 1992 Colditz et al, 1993 Grady et al, 1992 0.5 1.0 2.0 Relative Risk (95% CI) Collaborative Group Reanalysis: Risk of Breast Cancer With HT Similar to WHI Results HT Use Ever use RR 1.14* Current use Current use, 5 years† Past use *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. 1.21* 1.35* 1.07 Risk of Breast Cancer Changes With a Woman’s Age Age (years) 20 30 40 Probability of Developing Breast Cancer Within 10 Years 0.05% (1 in 2044) 0.40% (1 in 249) 1.49% (1 in 67) 50 60 70 2.77% (1 in 36) 3.45% (1 in 29) 4.16% 1 in 24) American Cancer Society, Surveillance Research, 2001. Breast Cancer Facts and Figures 2001–2002. Available at: http//www.cancer.org/downloads/STT/BrCaFF2001.pdf. 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. 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) 3.5 of 100 women who are HT users are at risk (<1 additional woman over baseline risk) 1Chlebowski RT, et al. JAMA. 2003;289:3243-53. Collaborative Group Reanalysis: Breast Cancer Risk by Duration of HT Use Duration Cases/Control RR and 99% FCI <1 Year 1–4 Years 1154/2546 1660/3999 1.09 1.05 5–9 Years 10–14 Years 813/1912 386/867 1.19 1.09 15 Years 337/584 0.1 1.58 0.5 1.0 2.0 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. Duration of HT Use and Breast Cancer Risk 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 0.1 *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. 0.5 1.0 2.0 10.0 Relative Odds* (95% CI) Breast Cancer Risk With HT Use in Women With a Family History HT Use Past Users 5 Years >5 Years Current Users 5 Years >5 Years 0.1 Sellers TA, et al. Ann Intern Med. 1997;127:973-80. 0.5 1.0 2.0 5.0 10 Relative Risk (95% CI) HT Use and Breast Cancer in Women With a History of Benign Breast Disease HT Users Without Proliferative Disease (PD; hyperplasia) All PD HT Users Nonusers HT Users Nonusers HT Users Nonusers * * * 0.5 1.0 2.0 5.0 10.0 PD Without Atypia Atypical Hyperplasia Relative Risk (95% CI) *P = NS between groups Dupont WD, et al. Cancer. 1999;85:1277-83. Previous Studies Reported Smaller Tumors in HT Users 100 80 (n = 126) (n = 176) * HT No HT Patients (%) 60 (n = 116) 40 20 0 (n = 39) * <2 or In Situ 2 *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. Primary Tumor Size (cm) Previous Studies Reported Lower-Grade Tumors in HT Users Current HT Use (n = 140) No HT Use (n = 202) 50 40 30 20 10 0 * Patients (%) * Grade I *P < .05 vs nonusers. Bilimoria MM, et al. Ann Surg Oncol. 1999;6:200-7. Grade II Grade III Previous Studies Reported Tumors With More Favorable Prognostic Indicators in E+P Users 100 E+P Users (n = 144) Nonusers (n = 148) Patients (%) 80 * * * 60 40 20 0 T1 Lesions Stage 1 Node Negative *P < .05 vs nonusers. Cheek J, et al. Arch Surg. 2002;137:1015-21. Breast Cancer Stage at Diagnosis HT Users vs Nonusers Stage DCIS I II III IV HT Nonusers (%) 17.1 41.7 26.2 13.4 1.6 HT users (%) 20.0 45.5 30.9 3.6 0.0 P-value vs all nonusers = .27; vs age-adjusted cohort = .03. Pappo I, et al. Ann Surg Oncol. 2003;11:52-8. Postmenopausal Hormone Therapy and Risk of Cancer Section 2d: Can Estrogen Be Used Safely in Breast Cancer Survivors? Survival Rates for Breast Cancer Patients HT Users Compared With Nonusers 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 HT Users Survival Fraction HT Nonusers P = .003 30 60 90 120 Months of Follow-up 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. Postmenopausal Hormone Therapy and Risk of Cancer Cumulation Proportion Surviving 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 Log-rank Test = 2.324 P = .020 HT Group Control Group Time (Years) Decker DA, et al. Menopause. 2003;10:277-85. Effect of HT on Breast Cancer Recurrence and Mortality Breast Cancer Recurrence Breast Cancer Mortality Total Mortality 0.1 0.5 1.0 2.0 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. HT in Breast Cancer Survivors Outcome Local recurrence Contralateral cancer Regional/distant recurrence Breast cancer death 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. Number of Patients 1 1 0 0 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 ) Any HT,* RR (95% CI) CCHT Only, RR (95% CI) 0.81 (0.52–1.27) 0.32 (0.12–0.88) 0.27 (0.10–0.73) Breast cancer recurrence Breast cancer mortality All-cause mortality 0.62 (0.43–0.87) 0.40 (0.22–0.72) 0.34 (0.19–0.59) 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. 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. HABITS: Baseline Characteristics In Women With Follow-Up Data Characteristic Number of women randomized HT 219 No HT 215 Number of women with follow-up Median follow-up, years Median time between primary treatment and randomization, years Median number of follow-up reports Mean age, years Node-positive, % Hormone receptor status unknown, % Breast preserved, % 174 2.1 2.6 3 55.5 26 27 62 171 2.1 2.7 3 55.0 21 22 57 Receiving HT before diagnosis, % Receiving adjuvant tamoxifen, % Holmberg L, Anderson H. Lancet. 2004;363:453-5. 52 21 56 21 HABITS: Risk of New Breast Cancer in HT Versus Non-HT Group Events/Total # in Subset All Women Receptor Positive Receptor Negative Tamoxifen No Tamoxifen HT Before Diagnosis No HT Before Diagnosis 33/345 14/159 6/72 4/72 29/273 14/177 19/168 0.1 0.5 1.0 10.0 40.0 Relative Hazard (95% CI) Holmberg L, Anderson H. Lancet. 2004;363:453-5. 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  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 Postmenopausal Hormone Therapy and Risk of Cancer Section 3: HT and Colorectal Cancer Risk Facts and Figures About Colorectal Cancer  Third most common cancer in US women, and third most common cause of cancer death in women individual’s lifetime risk of developing colorectal cancer is 6%, with 90% of cases occurring after age 50 years estimates: 74,700 new cases and 29,000 new deaths in women  An  2003  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. HT Use May Be Associated With Decreased Risk of Colorectal Cancer 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‡§ 0.0 0.2 0.4 *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. 0.6 0.8 1.0 1.2 Relative Risk (95% CI) 1.4 WHI Results: Effect of HT on Risk of Colorectal Cancer Kaplan-Meier Estimate 0.015 Cumulative Hazard for Colorectal Cancer HR = 0.56 95% nCI = 0.38–0.81 95% aCI = 0.33–0.94 Placebo 0.010 0.005 E+P 0.000 0 1 2 3 4 5 6 7 Time (year) Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004. 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 years1 – 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 1Feuer 2Chlebowski EJ, Wun LM. Available at: http://srab.cancer.gov/devcan/canques.html. Accessed 1/24/04. RT, et al. N Engl J Med. 2004;350:991-1004. 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 0.5 1.0 2.0 10 Relative Risk (95% CI) 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 0.1 0.5 1.0 2.0 10.0 Relative Risk* (95% CI) *Age-adjusted RR compared with never-users 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 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  Finding Postmenopausal Hormone Therapy and Risk of Cancer Section 4: HT and Ovarian Cancer Risk Ovarian Cancer: Background  Ovarian cancer is the second leading cause of death from gynecologic cancers1 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 disease2     Median age of diagnosis is 63 years2 Estimates for 2003: 25,400 new cases and 14,300 new deaths from ovarian cancer1 Cancer Society. Cancer Facts and Figures 2003. Available at: www.cancer.org/docroot/STT/stt_0.asp. HP. Maturitas. 2002;43:S35-52. 1American 2Schneider WHI Results: Hazard Ratio for Invasive Ovarian Cancer with E+P Placebo E+P 95% nCI 95% aCI 0.1 0.5 1.0 2.0 5.0 Hazard Ratio 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. Ovarian Cancer Incidence: Meta-Analyses Garg et al, 1998 Coughlin et al, 2000 0.0 1.0 2.0 3.0 Relative Risk (95% CI) Garg PP, et al. Obstet Gynecol. 1998;92:472-479. Coughlin SS, et al. J Clin Epidemiol. 2000;53:367-375. Centers for Disease Control Meta-Analysis 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 0.4 0.6 1.0 1.4 1.8 2.2 2.6 3.0 4.0 5.0 Schneider HP. Maturitas. 2002;43:S35-S52. ©2002 Elsevier Ireland, Ltd. Used with permission. Relative Risk (95% CI) Risk of Ovarian Cancer With HT   Nationwide case-control trial—Sweden 655 cases and 3899 controls, 1993–1995 E alone 1.43 (1.02–2.0) Continuous E+P 1.02 (0.73–1.43) Use Ever Sequential E+P 1.54 (1.15–2.05) <1 year 1 to <2 Years 2 to <5 Years 5 to <10 Years 10 Years 1.4 (NS) 1.07 (NS) 0.99 (NS) 1.8 (NS) 2.4 (1.03–4.46) 1.88 (1.11–3.17) 1.47 (NS) 1.3 (NS) 1.07 (NS) 2.1 (NS) 1.28 (NS) 0.84 (NS) 0.91 (NS) 0.91 (NS) 1.8 (NS) Risk assessment expressed as odds ratio compared with never-users. Riman T, et al. J Natl Cancer Inst. 2002;94:497-504. 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 0.1 *BCDDP = Breast Cancer Detection Demonstration Project. Lacey JV Jr, et al. JAMA. 2002;288:334-41. 1 10 Relative Hazard (95% CI) 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. Results From ACS Prevention Study II Rate Ratio (95% CI) 1.23 (1.06–1.43) Ever-use 10 or more years of use (baseline) Number of Deaths 255 31 2.20 (1.53–3.17) Rodriguez C, et al. JAMA. 2001;285:1460-5. ACS Prevention Study II: Considerations  Did not include exposure information after 1982 to exclusion criteria, analyses did not include 61% of the subjects who died of ovarian cancer  Due  Estimate of mortality with long-term use based on 31 deaths Summary: Ovarian Cancer Risk  Data on the association between the use of HT and the risk for ovarian cancer are inconsistent Postmenopausal Hormone Therapy and Risk of Cancer Section 5: HT and Endometrial Cancer Risk Risk of Endometrial Cancer Is Decreased With E+P Regimens Results From Meta-analyses Relative Risk No HT E only E+P 1.0 2.3 0.8 95% CI — 2.1–2.5 0.6–1.2 Nelson HD, et al. JAMA. 2002;288:872-81. Grady D, et al. Obstet Gynecol. 1995;85:304-13. WHI Results: Hazard Ratio for Endometrial Cancer with E+P Placebo E+P 95% nCI 95% aCI 0.1 0.5 1.0 2.0 5.0 Hazard Ratio 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. Endometrial Hyperplasia Rates With Lower Doses of NETA 16 Hyperplasia Rate After 12 Months (%) 14 12 10 8 6 4 2 0 E2 1 mg E2 1 mg/NETA 0.1 mg E2 1 mg/NETA 0.25 mg E2 1 mg/NETA 0.5 mg n = 1176. E2 = estradiol; NETA = norethindrone acetate. P < .001 for all continuous-combined groups vs unopposed E2. Kurman RJ, et al. Obstet Gynecol. 2000;96:373-9. Endometrial Hyperplasia Rates After 1 and 2 Years of Low-Dose E+P Women’s HOPE Study 30 Hyperplasia Rate (%) 25 20 15 10 5 0.00 0.00 0.625/ 2.5 mg Year 1 Year 2 0.00 0.45/ 2.5 mg 0.00 0.45/ 1.5 mg 0.00 0.3/ 1.5 mg 0.00 0 0.625 mg 0.45 mg 0.3 mg Placebo CEE CEE/MPA 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. 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 Postmenopausal Hormone Therapy and Risk of Cancer Section 6: Recommendations for Patient Education 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