Effects of Estrogen Plus Progestin in Healthy Menopausal Women: Implications for Clinical Practice Risk of Cancer
Principal Results of the Women’s Health Initiative Randomized Controlled Trial
Menopausal Hormone Therapy and Breast Cancer (Background)
Preponderance of observational studies suggests an association of especially long duration estrogen plus progestin with increased breast cancer risk However, the issue has remained controversial in scientific and practice communities Randomized prospective clinical trial evidence lacking in healthy postmenopausal women
Chen, JAMA 287: 734, 2002 Collaborative Lancet 350: 1047, 1997 Coldity Am JEpid 147 (5): 645, 1998 Genazzani Climacteric 4: 181, 2001 Whiteman J Women Health 10: 571, 2001 Nananda AJOG 186: 325, 2002
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
• Development of breast cancer resulted is permanent discontinuation of study medications • All randomized participants continued to be followed after discontinuation of study medications
WHI Estrogen+Progestin Trial Cancer Outcomes
All cancers confirmed by pathology reports when available (98%).
To date, agreement between local and central adjudication is 98% for invasive breast cancer, 98% for colorectal cancer, 96% for endometrial cancer, and 92% for other cancers.
Baseline Characteristics of E+P Participants (N=16,608) by Randomization Assignment
Estrogen+Progestin Placebo N % N %
P-value
Female relative had breast cancer Gail Model 5-year risk of breast cancer <1% 1 - <2% 2 - <5% >5%
1286 16.0
1175 15.3
0.28 0.64
1290 15.2 5384 63.3 1751 20.6 81 1.0
1271 15.7 5139 63.4 1621 20.0 71 0.9
Breast Cancer Outcome Monitoring
At the 10th interim analysis on May 31, 2002 the design-specified weighted log-rank test statistic for breast cancer crossed the designated O’Brien-Fleming boundary and was highly significant
Kaplan-Meier Estimates of Cumulative Hazards for Breast Cancer
The number of women at risk are presented below the horizontal axis for each treatment arm.
0.05
Invasive Breast Cancer
HR 1.26 nCI (1.00, 1.59) aCI (0.83, 1.92)
0.03
0.04
E+P Placebo
0.0
0.01
0.02
Time (years)
0 1
8378 8001
2
8277 7891
3
8150 7772
4
7000 6619
5
4234 3922
6
2064 1740
7
801 523
E+P Placebo
8506 8102
Invasive Breast Cancer (Annualized Percentage) by Randomization Assignment
Estrogen+Progestin Placebo Ratio Year 1 Year 2 Year 3 11 (0.13%) 26 (0.31%) 28 (0.34%) 17 (0.21%) 30 (0.38%) 23 (0.29%) 0.62 0.83 1.16
Year 4
Year 5 Year 6
40 (0.50%)
34 (0.57%) 27 (0.53%)
22 (0.29%)
12 (0.22%) 20 (0.47%)
1.73
2.64 1.12
Z-value for trend 2.56
Breast Cancer Outcome (Annualized Percentages) by Prior Menopausal Hormone Use
Years of Prior Use Estrogen + Progestin Placebo 95% Hazard Ratio Nominal CI
Never used <5
114(0.35%) 102(0.33%) 32(0.39%) 15(0.20%)
1.06 (0.81,1.38) 2.13 (1.15,3.94)
5 - <10
>10
11(0.49%)
9(0.69%)
2(0.11%)
5(0.40%)
4.61(1.01,21.02)
1.81 (0.60,5.43)
Test for trend, p=0.03
Breast Cancer Outcome (Annualized Percentage) by Age Group at Screening
Age Estrogen + Progestin Placebo Ratio
50-59 60-69 70-79
45 (0.29%)
34 (0.24%) 1.23 62 (0.34%) 1.22 28 (0.29%) 1.42
81 (0.41%)
40 (0.45%)
Sensitivity Analysis of Breast Cancer Outcome: Censored 6 months After Becoming Non-Adherent*
Hazard Ratio 95% Nominal CI
Breast Cancer (Invasive)
1.49
(1.10, 2.02)
* Using < 80 percent or stopping pills
Potential Strategy
Why not Identify Individual Women at Increased Breast Cancer Risk Using Risk Assessment Models Prior to Estrogen and Progestin?
Limitations of Current Breast Ca Risk Models Based on Family/Reproductive History
55,301 Women (941 Cases) Sensitivity Specificity 0.46% 0.66%
Sensitivity = % Women who develop breast ca in 5 yrs with the Gail Risk > 1.67% Specificity = % Women who don’t develop breast ca in 5 yrs with Gail Risk < 1.67%
Rockhill JNCI 93: 358, 2001
Non-Invasive Breast Cancer
No significant differences were observed in estrogen + progestin group compared to placebo for non-invasive breast cancer incidence
Forthcoming Analyses
Adjustment for Potential Correlates of Breast Cancer Risk Tumor Characteristics on E plus P vs. Placebo Histology (Ductal, Lobular, etc) Size (Mammographic Density) Grade Stage (Prognosis) Receptor Status
Relation to Body Mass Index Analyses of prior hormone use: Estrogen alone, Estrogen Plus Progestin, Prior Birth Control Pill Use
Menopausal Hormone Therapy and Colorectal Cancer (Background)
Emerging Information from pre-clinical and observational studies suggest that estrogen and/or estrogen plus progestin, perhaps involving hormone receptors, may have a favorable influence on colorectal cancer risk
Randomized prospective clinical trial evidence lacking in healthy menopausal women
Nanda Obstet Gyn 93: 880, 1999 Slattery Cancer Res 61: 126, 2001 Raigoso Int J Biol Mark 16: 262, 2001
Kaplan-Meier Estimates of Cumulative Hazards for Colorectal Cancer
The number of women at risk are presented below the horizontal axis for each treatment arm.
0.05
Colorectal Cancer
HR 0.63 nCI (0.43, 0.92) aCI (0.32, 1.24)
0.03
0.04
E+P Placebo
0.0
0.01
0.02
Time (years)
0
8506 8102
E+P Placebo
1
8379 8003
2
8297 7916
3
8194 7814
4
7073 6660
5
4305 3958
6
2111 1756
7
825 522
Colorectal Cancer Outcome (Annualized Percentage) by Age Group at Screening
Age Estrogen + Progestin Placebo Ratio
50-59
7 (0.05%)
23 (0.12%) 15 (0.17%)
7 (0.05%)
0.93
60-69
70-79
36 (0.20%)
24 (0.13%)
0.59
0.63
Fewer Colorectal Cancers with estrogen + progestin in women > 60 years
Endometrical Cancer Outcome (Annualized Percentages) by Randomized Assessment
Estrogen + Progestin Placebo Hazard Ratio 95% Nominal CI
Endomet Cancers
22(0.05%)
25(0.06%)
0.83
(0.47-1.47)
No increase in endometrical cancer with the estrogen + progestin combination
Ovarian Cancer and The WHI
Recent observational study found E alone (but not E plus P) associated with ↑ Ovarian Ca risk* Issue specifically reviewed by WHI DSMB (with access to E+P and E alone data) per NHLBI request Determination: Appropriate to continue E alone trial
Priority analyses of ovarian cancer in the E plus P trial underway
* Lancey JAMA 288: 334, 2002
Cancer Outcomes Summary (Annualized Percentage) by Randomization Assignment
Estrogen+Progestin Placebo Hazard Ratio 95% CI Nominal
Invasive breast cancer 166
124
1.26
(1.00,1.59)
Endometrial cancer
22
25
0.83
(0.47,1.47)
Colorectal cancer
45
67
0.63
(0.43,0.92)
Total cancer
502
458
1.03
(0.90,1.17)