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 Risk2a. WHI Breast Cancer Results2b. Million Women Study2c. Additional Studies of Breast Cancer and HT2d. 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
Section 1:
Evaluation of Cancer
Risk in the WHI
Postmenopausal Hormone Therapy and Risk of Cancer
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
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
0.1 0.5 1.0 5.02.0
95% nCI
95% aCI
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
18,845 Provided 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
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.
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
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
*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.
CharacteristicE+P
n = 8506Placebon = 8102
Age at screening, years* 63.2 (7.1) 63.3 (7.1)
Prior hormone use, % 26.1 25.6
Body mass index, kg/m2* 28.5 (5.8) 28.5 (5.9)
Never smokers, % 49.6 50.0
Diabetes, % 4.4 4.4
Hypertension, % 35.7 36.4
Statin use at baseline, % 6.9 6.8
History of MI, %† 1.6 1.9
History of CABG/PTCA, %† 1.1 1.5‡
Family history of breast cancer, % 16.0 15.3
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.
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 Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.2NIH News. Available at: http://www.nhlbi.nih.gov/new/press/04-03-02.htm.
Data and Safety Monitoring Board (DSMB)
Section 2:
HT and Breast Cancer Risk
Postmenopausal Hormone Therapy and Risk of Cancer
Section 2a:
WHI Breast Cancer Results
Postmenopausal Hormone Therapy and Risk of Cancer
0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7
WHI: Effect of E+P on Risk of Invasive Breast Cancer
Cu
mu
lati
ve P
rop
ort
ion
Time (years)
Unweighted HR = 1.24(95% CI, 1.01–1.54)
Chlebowski RT, et al. JAMA. 2003;289:3243-53.
E+P
Placebo
0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7
WHI: Effect of E+P on Risk of In Situ Breast Cancer
Cu
mu
lati
ve P
rop
ort
ion
Time (years)
E+P
Placebo
Chlebowski RT, et al. JAMA. 2003;289:3243-53.
Unweighted HR = 1.18(95% CI, 0.77–1.82)
WHI: Risk of Invasive Breast Cancer in Women With and Without Prior HT Use
Hazard Ratio (95% CI)
0.1 0.5 1.0 4.02.0
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.
E+P (n = 199)
Placebo (n = 150) P-Value
Tumor size, mean ± SD (cm) 1.7 ± 1.1 1.5 ± 0.9 .04
Positive lymph nodes, % 25.9 15.8 .03
SEER stage, %
Localized 74.6 82.7
Regional 24.4 14.0 .048
Metastatic 1.0 2.0
Morphology, grade, %
Well differentiated 25.0 20.3
Moderately differentiated 43.3 47.7 .61
Poorly differentiated/anaplastic 31.7 32.0
WHI: Characteristics of Invasive Breast Cancers
SEER = Surveillance, Epidemiology, and End Results.Chlebowski RT, et al. JAMA. 2003;289:3243-53.
E+P (n = 199)
Placebo (n = 150) P-Value
ER status, %
Positive 86.8 88.2 .72
Negative 13.2 11.8
PR status, %
Positive 75.0 69.9 .33
Negative 25.0 30.0
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)
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†
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
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 A, et al. JAMA. 2003; 290:1331-6.2Morimoto LM, et al. Cancer Causes and Control. 2003;13:741-51
Summary From WHI Observational Study
Perception and Knowledge of WHI Results
Ettinger B, et al. Obstet Gynecol. 2003;102:1225-32.
670 HT Users InterviewedSome awareness of WHI findings 93%
Information considered good 57%
Attempted to stop HT after WHI 56%
Considered media information good 72%
Perceived knowledge of WHI results
No knowledge 64%
Unsure knowledge 7%
Incorrect knowledge 6%
Correct knowledge 23%
WHI 5-item quiz (4 or 5 correct) 30%
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
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.
Section 2b:
Million Women Study
Postmenopausal Hormone Therapy and Risk of Cancer
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
0.5 1.0 1.5 2.0 2.5FCI = 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 BaselineRelative Risk
(95% FCI)*
All never-users 1.00 (0.96–1.04)
All past users 1.01 (0.95–1.08)
Current users
E-only 1.30 (1.22–1.38)
E+P 2.00 (1.91–2.09)
Tibolone 1.45 (1.25–1.67)
Other/unknown types 1.44 (1.17–1.76)
Incidence of Breast Cancer According to Recency and Type of HT Used
HT Use at BaselineCases/
PopulationPopulation Affected (%)
All never-users 2894/392,757 0.74
All past users 1044/150,179 0.70
Current users
E-only 991/115,383 0.85
E+P 1934/142,870 1.35
Tibolone 184/18,186 1.01
Other/unknown types 93/9548 1.00
Million Women Study Collaborators. Lancet. 2003;362:419-27.
Incident Invasive Breast Cancer in Relation to Recency and Type of HT Used
0.0 1.0 2.0 3.0FCI = 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 HT 1.00 0.96–1.04Past users of HT
<1 year 0.94 (0.84–1.05)1–4 years 1.01 (0.92–1.12)5–9 years 1.14 (1.00–1.30)≥10 years 1.05 (0.84–1.30)
Current users of E alone
<1 year 0.81 (0.55–1.20)1–4 years 1.25 (1.10–1.41)5–9 years 1.32 (1.20–1.46)≥10 years 1.37 (1.22–1.54)
Current users of E+P
<1 year 1.45 (1.19–1.78)1–4 years 1.74 (1.60–1.89)5–9 years 2.17 (2.03–2.33)≥10 years 2.31 (2.08–2.56)
Incident Invasive Breast Cancer in Current Users of E-only Preparations
0.5 1.0 1.5 2.0Dotted 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 breastcancer, BMI, region, and deprivation index.Million Women Study Collaborators. Lancet. 2003;362:419-27.
E-only FormulationRelative Risk
(95% CI)*All E-only formulations 1.30 (1.21–1.40)
By constituent and dose
All equine estrogen 1.29 (1.16–1.43)
≤0.625 mg 1.25 (1.11–1.41)
>0.625 mg 1.36 (1.14–1.61)
All 17-estradiol 1.24 (1.12–1.37)
≤1 mg 1.25 (1.12–1.40)
>1 mg 1.19 (0.89–1.58)
By formulation
Oral 1.32 (1.21–1.45)
Transdermal 1.24 (1.11–1.39)
Implanted 1.65 (1.26–2.16)
Incident Invasive Breast Cancer in Current Users of E+P Preparations
0.0 1.0 2.0 3.0Dotted 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 breastcancer, BMI, region, and deprivation index.Million Women Study Collaborators. Lancet. 2003;362:419-27.
Duration of Use, <5 Years
E+P FormulationRelative Risk
(95% CI)*
All E+P formulations 1.70 (1.56–1.86)
By progestin constituent
Medroxyprogesterone acetate 1.60 (1.33–1.93)
Norethisterone 1.53 (1.35–1.75)
Norgestrel/levonorgestrel 1.97 (1.74–2.33)
By type of regimen
Sequential 1.77 (1.59–1.97)
Continuous 1.57 (1.37–1.79)
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 breastcancer, 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
0.0 1.0 2.0 3.0
E+P FormulationRelative Risk
(95% CI)*
All E+P formulations 2.21 (2.06–2.36)
By progestin constituent
Medroxyprogesterone acetate 2.42 (2.10–2.80)
Norethisterone 2.10 (1.89–2.34)
Norgestrel/levonorgestrel 2.23 (2.04–2.44)
By type of regimen
Sequential 2.12 (1.95–2.30)
Continuous 2.40 (2.15–2.67)
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/
PopulationRR
(95% FCI)*Mortality Rate (%)
Never-users 238/392,757 1.00 (0.88–1.14)
0.060
Current users 191/285,987 1.22 (1.05–1.41)
0.066
Past users 88/150,179 1.05 (0.85–1.29)
0.058
Total breast cancer deaths 517/828,923 NA 0.062
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-users 238/2894 8.2
Current users 191/3202 5.9
Past users 88/1044 8.4
Total breast cancer deaths 517/6961 7.1
Results for Breast Cancer Mortality With HT Use Show Consistency
Relative Risk of Mortality (95% CI)
0.1 0.5 1.0 10.02.0
Hunt et al, 1990
Henderson et al, 1991
Willis et al, 1996
Grodstein et al, 1997Current Use
Past Use
Sellers et al, 1997
Rodriguez et al, 2001Current Use
Past Use
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
1Banks E, et al. J Epidemiol Biostat. 2001;6:357-63.2Million Women Study Collaborators. Lancet. 2003;362:419-27.
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 Women Study Collaborators. Lancet. 2003;362:419-27.2British Menopause Society. Available at http://www.the-bms.org/news.htm
Section 2c:
Additional Studies of
Breast Cancer and HT
Postmenopausal Hormone Therapy and Risk of Cancer
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)
0.5 1.0 102.0
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
10%
80%
10%13%
82%
2%0
20
40
60
80
100
<1.0 NS from1.0
>1.0 <1.0 NS from1.0
>1.0
Risk Estimates
Stu
die
s (%
)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)
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
0.1 1 10
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.
0.1 1 10
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
0.5 1.0 2.0
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
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 Use RR
Ever use 1.14*
Current use 1.21*
Current use, 5 years† 1.35*
Past use 1.07
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
20 0.05% (1 in 2044)
30 0.40% (1 in 249)
40 1.49% (1 in 67)
50 2.77% (1 in 36)
60 3.45% (1 in 29)
70 4.16% 1 in 24)
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 womenAll Women Aged 50 Years in the General Population—
Risk for Breast Cancer by Age 60 Years
In 100 women, 2.8 are at riskIn 100 women, 2.8 are at riskAmerican 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)
1Chlebowski 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)
3.5 of 100 women who are HT users are at risk (<1 additional woman over baseline risk)
Duration Cases/Control RR and 99% FCI
<1 Year 1154/2546 1.09
1–4 Years 1660/3999 1.05
5–9 Years 813/1912 1.19
10–14 Years 386/867 1.09
15 Years 337/584 1.58
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 1.00.5 2.0
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 Alone1–3 mos4 mos–2.9 y3 y–4.9 y5 y–7.9 y8 y–11.9 y12 y–14.9 y15 y–19.9 y20 y
E+P1–3 mos4 mos–2.9 y3 y–4.9 y5 y–7.9 y8 y
Relative Odds* (95% CI)
0.1 0.5 1.0 10.02.0
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.
0.1 0.5 1.0 102.00.5 1.0 2.0 5.0
Relative Risk (95% CI)
0.5 1.0 5.02.0 10.0
*
*
*
HT Use and Breast Cancer in Women With a History of Benign Breast Disease
HT Users Without Proliferative Disease (PD; hyperplasia)
*P = NS between groupsDupont WD, et al. Cancer. 1999;85:1277-83.
HT UsersNonusersAll PD
HT UsersNonusersPD Without Atypia
HT UsersNonusersAtypical Hyperplasia
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.
Pat
ien
ts (
%)
0
20
40
60
80
100
HT No HT
Primary Tumor Size (cm)
<2 or In Situ 2
*
*
(n = 176)
(n = 126)
(n = 116)
(n = 39)
0
10
20
30
40
50
Grade I Grade II Grade III
Current HT Use (n = 140) No HT Use (n = 202)
*P < .05 vs nonusers.Bilimoria MM, et al. Ann Surg Oncol. 1999;6:200-7.
Pat
ien
ts (
%)
*
*
Previous Studies Reported Lower-Grade Tumors in HT Users
0
20
40
60
80
100
T1 Lesions Stage 1 Node Negative
E+P Users (n = 144) Nonusers (n = 148)
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.
Pat
ien
ts (
%)
*
**
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
StageHT Nonusers
(%)HT users
(%)
DCIS 17.1 20.0
I 41.7 45.5
II 26.2 30.9
III 13.4 3.6
IV 1.6 0.0
Section 2d:
Can Estrogen Be Used Safely
in Breast Cancer Survivors?
Postmenopausal Hormone Therapy and Risk of Cancer
Survival Rates for Breast Cancer Patients
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 30 60 90 120
Months of Follow-up
Su
rviv
al F
ract
ion
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.
Postmenopausal Hormone Therapy and Risk of Cancer
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25 30 35
Cu
mu
lati
on
Pro
po
rtio
n S
urv
ivin
g
Time (Years)
HT Group
Control Group
Log-rank Test = 2.324P = .020
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
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 1.00.5 2.0
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.
OutcomeNumber of Patients
Local recurrence 1
Contralateral cancer 1
Regional/distant recurrence 0
Breast cancer death 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 )
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 mortality 0.34 (0.19–0.59) 0.27 (0.10–0.73)
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 CharacteristicsIn Women With Follow-Up DataIn Women With Follow-Up Data
Holmberg L, Anderson H. Lancet. 2004;363:453-5.
Characteristic HT No HT
Number of women randomized 219 215
Number of women with follow-up 174 171
Median follow-up, years 2.1 2.1
Median time between primary treatment and randomization, years
2.6 2.7
Median number of follow-up reports 3 3
Mean age, years 55.5 55.0
Node-positive, % 26 21
Hormone receptor status unknown, % 27 22
Breast preserved, % 62 57
Receiving HT before diagnosis, % 52 56
Receiving adjuvant tamoxifen, % 21 21
HABITS: Risk of New Breast Cancer in HT Versus Non-HT Group
0.1 1.0 10.0
Relative Hazard (95% CI)
0.5 40.0
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.
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 Riskcontinued
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
Section 3:
HT and Colorectal
Cancer Risk
Postmenopausal Hormone Therapy and Risk of Cancer
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.
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
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‡§
0.000
0.005
0.010
0.015
0 1 2 3 4 5 6 7
Time (year)
Cu
mu
lati
ve H
aza
rd
for
Co
lore
cta
l C
an
ce
r
WHI Results: Effect of HT on Risk of Colorectal Cancer
HR = 0.5695% nCI = 0.38–0.8195% aCI = 0.33–0.94 Placebo
E+P
Kaplan-Meier Estimate
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 EJ, Wun LM. Available at: http://srab.cancer.gov/devcan/canques.html. Accessed 1/24/04.2Chlebowski 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
Relative Risk (95% CI)
0.5 1.0 102.0
Risk for Colorectal Cancer Does Not Appear Associated With Duration of Use
Paganini-Hill et al, 19994 years4 years
Troisi et al, 19975 years5 years
Grodstein et al, 19985 years5 years
*Age-adjusted RR compared with never-users
Relative Risk* (95% CI)
0.1 0.5 1.0 10.02.0
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
Section 4:
HT and Ovarian Cancer Risk
Postmenopausal Hormone Therapy and Risk of Cancer
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
1American Cancer Society. Cancer Facts and Figures 2003. Available at: www.cancer.org/docroot/STT/stt_0.asp.2Schneider HP. Maturitas. 2002;43:S35-52.
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
0.1 0.5 1.0 5.02.0
95% nCI
95% aCI
E+P
Placebo
0.0 1.0 2.0 3.0
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.
Centers for Disease Control Meta-Analysis
Relative Risk (95% CI)
European/Australian Case-Control StudiesHospital/Clinic Controls
Booth et al, 1998La Vecchia et al, 1982Parazzini et al,1994Polchronopolou et al, 1993Tzonou et al, 1984
Community ControlsPurdie et al, 1995
US/Canadian Case-Control StudiesHospital/Clinic Controls
Annegers et al, 1979Hartge et al, 1988Hempling et al, 1997Hildreth et al, 1981Kaufman et al, 1989
Community ControlsCramer et al, 1983Lee et al, 1986Risch, 1996Weiss et al, 1982
Schneider HP. Maturitas. 2002;43:S35-S52. ©2002 ElsevierIreland, Ltd. Used with permission.
0.4 0.6 1.0 1.4 1.8 2.2 2.6 3.0 4.0 5.0
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.
Use E alone Sequential E+PContinuous
E+P
Ever 1.43 (1.02–2.0) 1.54 (1.15–2.05) 1.02 (0.73–1.43)
<1 year 1.4 (NS) 1.88 (1.11–3.17) 1.28 (NS)
1 to <2 Years 1.07 (NS) 1.47 (NS) 0.84 (NS)
2 to <5 Years 0.99 (NS) 1.3 (NS) 0.91 (NS)
5 to <10 Years 1.8 (NS) 1.07 (NS) 0.91 (NS)
10 Years 2.4 (1.03–4.46) 2.1 (NS) 1.8 (NS)
Effect of HT on Ovarian Cancer Risk: Data From the BCDDP Follow-up
0.1 1 10
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.
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
Rodriguez C, et al. JAMA. 2001;285:1460-5.
Number of DeathsRate Ratio
(95% CI)
Ever-use 255 1.23 (1.06–1.43)
10 or more years of use (baseline) 31 2.20 (1.53–3.17)
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
Summary: Ovarian Cancer Risk
Data on the association between the use of HT and the risk for ovarian cancer are inconsistent
Section 5:
HT and Endometrial
Cancer Risk
Postmenopausal Hormone Therapy and Risk of Cancer
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 Risk 95% CI
No HT 1.0 —
E only 2.3 2.1–2.5
E+P 0.8 0.6–1.2
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
0.1 0.5 1.0 5.02.0
95% nCI
95% aCI
Placebo
Endometrial Hyperplasia Rates With Lower Doses of NETA
0
2
4
6
8
10
12
14
16
Hy
per
pla
sia
Ra
te A
fter
1
2 M
on
ths
(%
)
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.
E2 1 mg E2 1 mg/NETA0.1 mg
E2 1 mg/NETA0.25 mg
E2 1 mg/NETA0.5 mg
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
0
5
10
15
20
25
30
Hy
per
pla
sia
Ra
te (
%)
0.625 mg 0.625/2.5 mg
0.45 mg 0.45/2.5 mg
0.45/1.5 mg
0.3 mg 0.3/1.5 mg
Placebo
CEE CEE/MPA
0.000.000.000.000.000.00
Year 1
Year 2
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
Section 6:
Recommendations for
Patient Education
Postmenopausal Hormone Therapy and Risk of Cancer
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