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) 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: 3115Gapstur JAMA 1999; 281: 2021 Delgado Maturitas 2001; 38: 147Lower Breast Cancer Res Treat 1999; 58: 205 Chen, JAMA 287: 734, 2002Coldity Am JEpid 147 (5): 645, 1998

Descriptive Characteristics in WHI Participants AgeAge at menarcheRelatives with breast ca (n) EthnicityTerm pregnancies (n)Benign breast disease EducationAge at first birthPrior estrogen (E) alone use Gail RiskChildren breastfed (n) Prior E + progestin (P) use BMIOral Contraceptive useNSAID use Alcohol Use% Energy from fatPhysical Activity None of these characteristics differed significantly between treatment groups

Descriptive Characteristics By Treatment Group Prior Menopausal Hormone Use E+P (n, %) Placebo Never6280 (73.9)6024 (74.4) Prior1674 (19.7)1588 (19.6) Current548 (6.4)487 (6.0) “Current” users required three month washout

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 WHI Estrogen+Progestin Trial Breast Safety

Breast Cancers by Category and Treatment Group Breast CaE+PPlacebo HR (95% CI) 1 P-Value 2 Total ( ) Invasive (1.01–1.54) In situ ( ) Hazard ratios (HR) from unweighted Cox proportional hazards regression models 2 P values from weighted Cox proportional hazards regression models

Hazard ratios (HR) from unweighted Cox proportional hazards regressions models Z Statistics and p values from weighted Cox proportional hazards regression models Invasive Breast Cancer By Group

Sensitivity Analysis of Adherent Participants Invasive Breast Cancers by Group Hazard ratios (HR) from unweighted Cox proportional hazards regressions models Z Statistics and p values form weighted Cox proportional hazards regression models Participants were censored 6 months after becoming non-adherent (taking < 80% study meds or taking non-protocol hormones)

Breast Cancers (Annualized Percentage) by Age AgeE+PPlaceboHRP-value y52 (0.31)40 (0.26)1.20 ( ) y94 (0.44)72 (0.31)1.22 ( ) y53 (0.54)38 (0.41)1.34 ( ) P-value tests interactions of E+P and age

Breast Cancer (Annualized Percentage) by BMI BMIE+PPlaceboHRP-value 2545 (0.31)32 (0.23)1.35 ( ) (0.42)49 (0.31)1.40 ( ).12 > 3082 (0.50)68 (0.45)1.08 ( ) P-value tests for interaction of E+P with BMI

Breast Cancers (Annualized Percentage) by Prior Menopausal Hormone Therapy (MHT) Use Prior MHT E+PPlaceboHR (95% CI) P value None141 (0.40)121 (0.36)1.09 ( ).10 Ever58 (0.46)29 (0.25)1.86 ( ) 1 P value tests for interaction with E+P and prior MHT 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

Breast Cancer Incidence by Prior MHT Use and Randomization Assignment No prior MHTPrior MHT YearE+PPlaceboHRE+PPlaceboHR Z for trend

Breast Cancer Characteristics by Group E+PPlaceboP-Value Histology Ductal67.8 %67.3 % Lobular11.1 %10.3 %0.885 Ductal + Lobular7.5 %5.3 % Grade Well25.0 %20.3 % Moderately43.3 %47.7 %0.609 Poor31.7 %32.0 % Similar histology and grade on E+P and placebo 1 P value tests association with treatment groups

Receptor StatusE+PPlaceboP-Value 1, 2 Estrogen receptor Positive158 (86.8)112 (88.2)0.720 Negative24 (13.2)15 (11.8) Missing17 (8.5)23 (15.4)0.049 Progesterone receptor Positive135 (75.0)86 (69.9)0.328 Negative45 (25.0)37 (30.0) Missing19 (9.5)27 (18.0)0.021 Both receptor positive and negative breast cancers greater on E+P 1 The first P value tests association with treatment groups 2 P-value for “missing” rows test the association of % missing with treatment group

Breast Cancer Characteristics by Group E+PPlaceboP-Value Tumor size, cm (1.1)1.5 (0.9) Nodes Positive %15.8%0.033 SEER Stage Regional / Mets 25.4%16.0% mean (SD) for tumor with known tumor size 2 P-values from weighted Cox proportional hazards models More advanced stage on E+P

Year 1 Mammogram Findings by Group Mammogram Findings E+P (n, %)Placebo Negative / Benign finding 6940 (90.7)6912 (94.6) Abnormal (total)716 (9.4)398 (5.4) 1 Short interval f/u 625 (8.2)332 (4.5) Suspicious abnormality 85 (1.1)59 (0.8) Highly suggestive 6 (0.1)7 ( 0.1) 1 p <.0001 comparing E+P versus placebo Increased abnormal mammograms after 1 year on E+P

Summary Mammogram Findings by Group and Time BaselineYear 1Cumulative E+PPlaceboE+P Placebo E+P Placebo Mammogram Performed 1 100% 90.3%90.5%97.3%97.8% Mammogram Abnormal (total) 2 5.2%5.0%9.4% 1 5.4%31.5% % 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 < E+P versus placebo

Abnormal Mammograms: Associated with Short Duration E+P Use 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

Recent Results from the UK Million Women Study National Health Service Breast Cancer Screening Program Inform Interpretation of WHI Results

Million Women Study NHSBSP in the UK invites women 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:

Relative Risk of Fatal Breast Cancer by HT Use at Baseline in the Million Women Study Based on 517 deaths after 4.1 years HT useRR (95% CI) Never1.00 ( ) Current1.22 ( )* * P = 0.05 for current versus neverLancet 2003; 362; HT associated with increased breast cancer mortality in “short term” users

Relative Risk of Breast Cancer in the Million Women Study By E+P Duration DurationCases/PopulationRR (95% CI) < 1 yr97/ ( ) 1-4 yr582/ ( ) 5-9 yr850/ ( ) > 10 yr362/ ( ) E+P associated with increased breast cancers in < 1 year

Relative Risk of Breast Cancer in the Million Women Study By Hormone Type Hormone TypeRR (95% CI) Estrogen only1.30 ( ) Equine Estrogens1.29 ( ) Ethinyloestradiol1.24 ( ) Estrogen + Progestin2.00 ( ) Medroxyprogesterone1.60 ( ) Norethisterone1.53 ( )

Conclusions 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