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

Postmenopausal Hormone Therapy and Risk of Cancer

A CME Slide Library From the

Council on Hormone Education


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


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

maybe a flow chart of the entire whi would be helpful here. observational study, ert and hrt.

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


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



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


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.


Section 2:

HT and Breast Cancer Risk


Section 2a:

WHI Breast Cancer Results


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


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


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


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


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


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

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


Current users of E+P


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


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


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


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?


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.


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


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


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


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


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


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


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


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


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


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

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

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