breast cancer in the women’s health initiative trial of estrogen plus progestin for the whi...
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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 histologyHolli 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
Hormone Use
E+P (n, %) Placebo
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
• 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 TrialBreast Safety
Breast Cancers by Category and Treatment Group
Breast Ca E+P Placebo HR (95% CI)1 P-Value2
Total 245 185 1.24 (1.02-1.50)
0.0004
Invasive 199 150 1.24 (1.01–1.54)
0.003
In situ 47 37 1.18 (0.77-1.82)
0.086
1 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
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 (0.90-1.66)
.20
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 (0.97-2.01)
.12
> 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 (95% CI)
P 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)
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 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-ValueHistology
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 %
Similar histology and grade on E+P and placebo
1 P value tests association with treatment groups
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
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+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
Regional / Mets
25.4% 16.0% 0.041
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)
1 p < .0001 comparing E+P versus placebo
Increased abnormal mammograms after 1 year on E+P
SummaryMammogram Findings by Group and Time
Baseline Year 1 CumulativeE+P Placebo E+P Placebo E+P Placebo
Mammogram Performed1
100% 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 21.2%
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