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Breast Cancer in the Women’s Health Initiative Trial of Estrogen Plus Progestin. For the WHI Investigators Rowan T Chlebowski, MD., Ph.D. Menopausal Hormone Therapy and Breast Cancer (Background).

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Breast cancer in the women s health initiative trial of estrogen plus progestin l.jpg
Breast Cancer in the Women’s Health Initiative Trial of Estrogen Plus Progestin

For the WHI Investigators

Rowan T Chlebowski, MD., Ph.D.


Menopausal hormone therapy and breast cancer background l.jpg
Menopausal Hormone Therapy and Breast Cancer (Background) Initiative Trial of Estrogen Plus Progestin

Preponderance of observational studies suggest long duration estrogen plus progestin increases breast cancers which have:

- Low stage and favorable prognosis

- Receptor positive preponderance

- More lobular histology

Holli J Clin Oncol 1998; 16: 3115 Gapstur JAMA 1999; 281: 2021

Delgado Maturitas 2001; 38: 147 Lower Breast Cancer Res Treat 1999; 58: 205

Chen, JAMA 287: 734, 2002 Coldity Am JEpid 147 (5): 645, 1998


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Descriptive Characteristics in WHI Participants Initiative Trial of Estrogen Plus Progestin

Age Age at menarche Relatives with breast ca (n)

Ethnicity Term pregnancies (n) Benign breast disease

Education Age at first birth Prior estrogen (E) alone use

Gail Risk Children breastfed (n) Prior E + progestin (P) use

BMI Oral Contraceptive use NSAID use

Alcohol Use % Energy from fat Physical Activity

None of these characteristics differed significantly between treatment groups


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Descriptive Characteristics By Treatment Group Initiative Trial of Estrogen Plus Progestin

“Current” users required three month washout


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WHI Estrogen+Progestin Trial Initiative Trial of Estrogen Plus ProgestinBreast Safety

  • Baseline mammogram and clinical breast exams required for eligibility

  • Annual mammograms and clinical breast exams required when on study

  • Study medications withheld if safety procedures not performed


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Breast Cancers by Category and Treatment Group Initiative Trial of Estrogen Plus Progestin

1 Hazard ratios (HR) from unweighted Cox proportional hazards regression models

2 P values from weighted Cox proportional hazards regression models


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Invasive Breast Cancer By Group Initiative Trial of Estrogen Plus Progestin

Hazard ratios (HR) from unweighted Cox proportional hazards regressions models

Z Statistics and p values from weighted Cox proportional hazards regression models


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Sensitivity Analysis of Adherent Participants Invasive Breast Cancers by Group

Participants were censored 6 months after becoming non-adherent (taking < 80% study meds or taking non-protocol hormones)

Hazard ratios (HR) from unweighted Cox proportional hazards regressions models

Z Statistics and p values form weighted Cox proportional hazards regression models


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Breast Cancers (Annualized Percentage) by Age Breast Cancers by Group

P-value tests interactions of E+P and age


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Breast Cancer (Annualized Percentage) by BMI Breast Cancers by Group

P-value tests for interaction of E+P with BMI


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Breast Cancers (Annualized Percentage) by Prior Menopausal Hormone Therapy (MHT) Use

More breast cancers on E+P in both groups

Non-significant trend, no interaction

Ever users at somewhat lower risk

Cumulative exposure versus selection bias

1 P value tests for interaction with E+P and prior MHT



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Breast Cancer Characteristics by Group Assignment

1 P value tests association with treatment groups

Similar histology and grade on E+P and placebo


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1 AssignmentThe first P value tests association with treatment groups

2 P-value for “missing” rows test the association of % missing with treatment group

Both receptor positive and negative breast cancers greater on E+P


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Breast Cancer Characteristics by Group Assignment

1 mean (SD) for tumor with known tumor size

2 P-values from weighted Cox proportional hazards models

More advanced stage on E+P


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Year 1 Mammogram Findings by Group Assignment

1 p < .0001 comparing E+P versus placebo

Increased abnormal mammograms after 1 year on E+P


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Summary AssignmentMammogram Findings by Group and Time

1 % of women due for visit with mammogram in study period who had mammogram

2 % of women with any category of abnormal mammogram

3 p < 0.0001 E+P versus placebo


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Abnormal Mammograms: Associated with Short Duration E+P Use Assignment

4 % absolute increase in abnormal mammograms after one year on E+P

10% absolute increase in abnormal mammograms after about 5 years on E+P


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Recent Results from the UK Million Women Study

National Health Service Breast Cancer Screening Program

Inform Interpretation of WHI Results


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Million Women Study Women Study

  • NHSBSP in the UK invites women 50-69 for mammography screening q 3 years by letters

  • A questionnaire regarding HT use was added to the screening invitation letter

  • HT use data was linked to NHS central registries for breast cancer and death outcomes

  • 1,084,110 women flagged

  • 9,364 incident invasive breast cancers seen

Lancet 2003; 362: 419-27.


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Relative Risk of Fatal Breast Cancer by HT Use at Baseline in the Million Women Study Based on 517 deaths after 4.1 years

* P = 0.05 for current versus never Lancet 2003; 362; 419-27.

HT associated with increased breast cancer mortality in “short term” users


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Relative Risk of Breast Cancer in the Million Women Study By E+P Duration

E+P associated with increased breast cancers in < 1 year



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Conclusions Hormone Type

Combined E+P use increases breast Ca,

diagnosed at more advanced stage and

increases abnormal mammograms

These results suggest: Use of E+P may

stimulate breast cancer growth and hinder

breast cancer diagnosis


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