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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)
  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
      Descriptive Characteristics in WHI Participants

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
   Descriptive Characteristics By Treatment Group

Prior Menopausal      E+P (n, %)    Placebo
Hormone Use


  Never               6280 (73.9)     6024 (74.4)

  Prior               1674 (19.7)     1588 (19.6)

 Current               548 (6.4)       487 (6.0)



 “Current” users required three month washout
    WHI Estrogen+Progestin Trial
           Breast 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
  Breast Cancers by Category and Treatment Group

Breast Ca E+P           Placebo HR (95% CI)1            P-Value2
  Total           245       185             1.24             0.0004
                                        (1.02-1.50)
  Invasive        199       150            1.24               0.003
                                       (1.01–1.54)
  In situ         47         37             1.18              0.086
                                        (0.77-1.82)
1 Hazard ratios
              (HR) from unweighted Cox proportional hazards
regression models
2Pvalues from weighted Cox proportional hazards regression
models
         Invasive Breast Cancer By Group




Hazard ratios (HR) from unweighted Cox proportional hazards regressions models
Z Statistics and p values from weighted Cox proportional hazards regression models
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) f rom unweighted Cox proportional hazards regressions models
        Z Statistics and p values f orm weighted Cox proportional hazards regression models
Breast Cancers (Annualized Percentage) by Age

Age        E+P         Placebo        HR         P-value

 50-59 y   52 (0.31)   40 (0.26)       1.20
                                   (0.80-1.82)


 60-69 y   94 (0.44)   72 (0.31)       1.22        .20
                                   (0.90-1.66)


 70-79 y   53 (0.54)   38 (0.41)       1.34
                                   (0.88-2.04)


  P-value tests interactions of E+P and age
   Breast Cancer (Annualized Percentage) by BMI

 BMI             E+P           Placebo             HR         P-value

       25         45 (0.31)     32 (0.23)           1.35
                                                (0.86-2.13)


     25-30        72 (0.42)     49 (0.31)           1.40        .12
                                                (0.97-2.01)


     > 30         82 (0.50)     68 (0.45)           1.08
                                                (0.78-1.49)


P-value tests for interaction of E+P with BMI
    Breast Cancers (Annualized Percentage) by Prior
       Menopausal Hormone Therapy (MHT) Use
Prior MHT               E+P         Placebo   HR                  P
                                           (95% CI)             value
    None            141 (0.40) 121 (0.36)     1.09
                                          (0.86-1.39)
                                                                 .10
     Ever            58 (0.46)      29 (0.25)         1.86
                                                  (1.19-2.91)
          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
Breast Cancer Incidence by Prior MHT Use
     and Randomization Assignment

                    No prior MHT                Prior MHT
Year          E+P      Placebo     HR     E+P    Placebo    HR
        1      7         14        .48     5        5       .90
        2     15         22        .65    11        10      1.1
        3     19         19        .96    10        3       3.09
        4     35         23        1.45    9        4       2.16
        5     28         17        1.61   15        4       3.56
       6+     37         26        1.24    8        3       1.99
Z for trend                        2.31                     1.62
      Breast Cancer Characteristics by Group

                                             E+P      Placebo   P-Value
Histology
      Ductal                               67.8 %     67.3 %
      Lobular                               11.1 %    10.3 %     0.885
      Ductal + Lobular                      7.5 %      5.3 %
Grade
      Well                                 25.0 %     20.3 %
      Moderately                           43.3 %     47.7 %     0.609
      Poor                                 31.7 %     32.0 %
1
    P value tests association with treatment groups


Similar histology and grade on E+P and placebo
Receptor Status                                                  E+P                     Placebo      P-Value1, 2
Estrogen receptor
        Positive                                                 158 (86.8)              112 (88.2)      0.720
        Negative                                                 24 (13.2)               15 (11.8)
        Missing                                                    17 (8.5)              23 (15.4)       0.049
Progesterone receptor
        Positive                                                 135 (75.0)              86 (69.9)       0.328
        Negative                                                 45 (25.0)               37 (30.0)
        Missing                                                    19 (9.5)              27 (18.0)       0.021
1 The   f irst P value tests association with treatment groups
2 P-value   f or “missing” rows test the association of % missing with treatment group




   Both receptor positive and negative breast
            cancers greater on E+P
        Breast Cancer Characteristics by Group
                                       E+P              Placebo     P-Value
    Tumor size, cm1                 1.7 (1.1)           1.5 (0.9)   0.0382

    Nodes Positive2                  25.9 %              15.8%       0.033

    SEER Stage                       25.4%               16.0%       0.041
    Regional / Mets

1 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)

1p   < .0001 comparing E+P versus placebo

        Increased abnormal mammograms
               after 1 year on E+P
                   Summary
       Mammogram Findings by Group and Time

                             Baseline                    Year 1             Cumulative
                           E+P      Placebo         E+P       Placebo       E+P   Placebo

Mammogram                100%       100%          90.3% 90.5%             97.3%   97.8%
Performed1


Mammogram                5.2%       5.0%          9.4%1       5.4%        31.5%1 21.2%
Abnormal
(total)2
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
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 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.
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 use                            RR
                                         (95% CI)
            Never                     1.00 (0.88-1.14)

           Current                    1.22 (1.05-1.41)*

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


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
   Duration    Cases/Population         RR
                                     (95% CI)
    < 1 yr         97/9771        1.45 (1.19-1.78)

    1-4 yr        582/49240       1.74 (1.60-1.89)

    5-9 yr        850/56912       2.17 (2.03-2.33)

    > 10 yr       362/23673       2.31 (2.08-2.56)


E+P associated with increased breast
        cancers in < 1 year
Relative Risk of Breast Cancer in the Million
     Women Study By Hormone Type
      Hormone Type          RR (95% CI)
Estrogen only               1.30 (1.21-1.40)
Equine Estrogens            1.29 (1.16-1.43)
Ethinyloestradiol           1.24 (1.12-1.40)


Estrogen + Progestin        2.00 (1.88-2.12)
 Medroxyprogesterone        1.60 (1.33-1.93)
 Norethisterone             1.53 (1.35-1.75)
             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

				
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