# Presentation: 667099

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

**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

## 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

- 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 TrialBreast Safety

## All cancers confirmed by pathology reports when available (98%).

- WHI Estrogen+Progestin Trial Cancer Outcomes

-   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

- Female relative had	               1286	16.0	1175	15.3	0.28
- breast cancer
- Gail Model 5-year					0.64
- risk of breast cancer
- 	<1%	                                    1290	15.2	1271	15.7
- 	1 - <2%	                               5384	63.3	5139	63.4
- 	2 - <5%	                               1751	20.6	1621	20.0
- 	_>_5%	81	1.0	71	0.9

**	****Estrogen+Progestin****	****Placebo**

**P-value**

**	****N****	****%****	****N****	****%**

**Baseline Characteristics of E+P Participants (N=16,608) ****by Randomization Assignment**

## 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.

## Invasive Breast Cancer (Annualized Percentage) by

- 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**

**	****Estrogen+Progestin****	****Placebo****	****Ratio**

**Invasive Breast Cancer (Annualized Percentage) by**
**Randomization Assignment**

## Breast Cancer Outcome (Annualized Percentages) by Prior Menopausal Hormone Use 

- 	Never used	114	(0.35%)	102	(0.33%)	1.06	(0.81,1.38)
- 	<5                     32	(0.39%)	15	(0.20%)	2.13	(1.15,3.94)
- 	5 - <10              11	(0.49%)      2	(0.11%)	      4.61	(1.01,21.02)
- 	_>_10	9	(0.69%)	5	(0.40%)	1.81	(0.60,5.43)

**Test for trend, p=0.03**

**	****	****                                                               ****95%**** Years of Prior Use        Estrogen + Progestin          Placebo         ****	****Hazard Ratio****	****Nominal CI**

## 50-59

**Age****	****    Estrogen + Progestin           Placebo         Ratio**

- 60-69
- 70-79

-  45 (0.29%)
-  81 (0.41%)
-  40 (0.45%)

-  34 (0.24%)
-  62 (0.34%)
-  28 (0.29%)

- 1.23
- 1.22
- 1.42

## Sensitivity Analysis of Breast Cancer Outcome: Censored 6 months After Becoming Non-Adherent*

- Breast Cancer          1.49               (1.10, 2.02)               (Invasive)

**	****             ****Hazard Ratio            95% Nominal CI**

- * 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			0.46%
- Specificity			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

-     Tumor Characteristics on E plus P vs. Placebo

- Histology (Ductal, Lobular, etc)
- Size (Mammographic Density)
- Grade
- Stage (Prognosis)
- Receptor Status

-     Adjustment for Potential Correlates of Breast Cancer Risk

- Analyses of prior hormone use: Estrogen alone, Estrogen                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      Plus Progestin, Prior Birth Control Pill Use

- Relation to Body Mass Index

## 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.

- E+P

- Placebo

-  E+P

- 8506

- 8379

- 8297

- 8194

- 7073

- 4305

- 2111

- 825

-  Placebo

- 8102

- 8003

- 7916

- 7814

- 6660

- 3958

- 1756

- 522

-  HR   0.63

-  nCI  (0.43, 0.92)

- aCI  (0.32, 1.24)

## 50-59

- Age	    Estrogen + Progestin           Placebo         Ratio

- 60-69
- 70-79

-   7  (0.05%)
-  23 (0.12%)
-  15 (0.17%)

-   7  (0.05%)
-  36 (0.20%)
-  24 (0.13%)

- 0.93
- 0.59
- 0.63

**Fewer Colorectal Cancers with estrogen + progestin in women **_**>**_** 60 years**

## No increase in endometrical cancer                               with the estrogen + progestin combination

**   ****Endomet          22(0.05%)          25(0.06%)     0.83    (0.47-1.47)                                            Cancers                     **

**	****	****                                                                         ****95%****                                     Estrogen + Progestin             Placebo        Hazard Ratio        Nominal CI**

## 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**

**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)

**	****	****	****                                                 ****95% CI****                                Estrogen+Progestin    Placebo****	****    Hazard Ratio****	****        Nominal****	****	**