Effects of Estrogen Plus Progestin in Healthy Menopausal Women: Implications for Clinical Practice R

1
Effects of Estrogen Plus Progestin in Healthy
Menopausal Women Implications for Clinical
Practice Risk of Cancer

• Principal Results of the Womens Health
  Initiative Randomized Controlled Trial

2
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
Genazzani Climacteric 4 181, 2001 Whiteman J
Women Health 10 571, 2001 Nananda AJOG 186
325, 2002
Chen, JAMA 287 734, 2002 Collaborative Lancet
350 1047, 1997 Coldity Am JEpid 147 (5) 645,
1998
3
WHI EstrogenProgestin TrialBreast 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

4
WHI EstrogenProgestin 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.
5
Baseline Characteristics of EP Participants
(N16,608) by Randomization Assignment
EstrogenProgestin Placebo
P-value
N N
Female relative had
1286 16.0 1175 15.3 0.28 breast cancer Gail Model
5-year 0.64 risk of breast cancer lt1
1290 15.2 1271 15.7
1 - lt2
5384 63.3 5139 63.4 2 - lt5
1751 20.6 1621 20.0 gt5 81 1.0 71 0.9
6
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 OBrien-Fleming boundary and was
  highly significant

7
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.
8
Invasive Breast Cancer (Annualized Percentage)
by Randomization Assignment
EstrogenProgestin Placebo Ratio
Year 1 11 (0.13) 17 (0.21) 0.62 Year
2 26 (0.31) 30 (0.38) 0.83 Year
3 28 (0.34) 23 (0.29) 1.16 Year
4 40 (0.50) 22 (0.29) 1.73 Year
5 34 (0.57) 12 (0.22) 2.64 Year
6 27 (0.53) 20 (0.47) 1.12 Z-value for trend
2.56
9
Breast Cancer Outcome (Annualized Percentages) by
Prior Menopausal Hormone Use

95 Years of Prior Use
Estrogen Progestin Placebo
Hazard Ratio Nominal CI
Never used 114 (0.35) 102 (0.33) 1.06 (0.81,1.
38) lt5 32 (0.39) 15 (0.20)
2.13 (1.15,3.94) 5 - lt10 11 (0.49)
2 (0.11) 4.61 (1.01,21.02) gt10 9 (0.6
9) 5 (0.40) 1.81 (0.60,5.43)
Test for trend, p0.03
10
Breast Cancer Outcome (Annualized Percentage)
by
Age Group at Screening
Age Estrogen Progestin Placebo
Ratio
50-59 60-69 70-79
34 (0.24) 62 (0.34) 28 (0.29)
1.23 1.22 1.42
45 (0.29) 81 (0.41) 40 (0.45)
11
Sensitivity Analysis of Breast Cancer Outcome
Censored 6 months After Becoming Non-Adherent
Hazard Ratio 95 Nominal
CI
Breast Cancer 1.49 (1.10,
2.02) (Invasive)

Using lt 80 percent or stopping pills
12
Potential Strategy

• Why not Identify Individual Women at Increased
  Breast Cancer Risk Using Risk Assessment Models
  Prior to Estrogen and Progestin?

13
Limitations of Current Breast Ca Risk Models
Based on Family/Reproductive History

• 55,301 Women (941 Cases)
• Sensitivity 0.46
• Specificity 0.66
• Sensitivity Women who develop breast ca in
  5 yrs with the Gail Risk gt 1.67
• Specificity Women who dont develop breast ca
  in 5 yrs with Gail Risk lt 1.67

Rockhill JNCI 93 358, 2001
14
Non-Invasive Breast Cancer

• No significant differences were observed in
  estrogen progestin group compared to placebo
  for non-invasive breast cancer incidence

15
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
16
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

17
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.
HR 0.63
nCI (0.43, 0.92)
aCI (0.32, 1.24)
EP
Placebo
EP
8379
8297
8194
7073
4305
2111
825
8506
Placebo
8102
8003
7916
7814
6660
3958
1756
522
18
Colorectal Cancer Outcome (Annualized
Percentage)
by Age Group at Screening
Age Estrogen Progestin Placebo
Ratio
7 (0.05) 36 (0.20) 24 (0.13)
0.93 0.59 0.63
7 (0.05) 23 (0.12) 15 (0.17)
50-59 60-69 70-79
Fewer Colorectal Cancers with estrogen
progestin in women gt 60 years
19
Endometrical Cancer Outcome
(Annualized Percentages) by Randomized
Assessment

95
Estrogen Progestin
Placebo Hazard Ratio Nominal CI
Endomet 22(0.05) 25(0.06)
0.83 (0.47-1.47)
Cancers
No increase in endometrical cancer
with the estrogen progestin
combination
20
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 EP 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
21
Cancer Outcomes Summary (Annualized Percentage)
by Randomization Assignment

95 CI
EstrogenProgestin Placebo Hazard Ratio
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)