# Presentation: 378438

## Part I:  Statistical issues in WHIPart II:  Further analyses of prior hormone therapy on breast cancer The WHI Estrogen + Progestin Trial

- Garnet Anderson
- WHI Clinical Coordinating Center
- Fred Hutchinson Cancer Research Center
- October 7, 2003

## Statistical methods

- Design and primary analyses based on weighted logrank statistic
- T =  w (O-E)
- Weights
- Specified for each disease endpoint
- Defined as time since randomization
- Used to increase efficiency

## Weights by time since randomization for the logrank statistic

##     Evidence of CHD benefit
Statistical rules based on O’Brien-Fleming (OBF) procedures using a 0.025-level, one-sided test
AND
    Global index supportive of benefit
Statistical rules based on OBF procedures using a 0.05-level, one-sided test

- Statistical rules based on O’Brien-Fleming (OBF) procedures using a 0.025-level, one-sided test
- AND
-     Global index supportive of benefit
- Statistical rules based on OBF procedures using a 0.05-level, one-sided test

**O’Brien PC, Fleming TR.  Biometrics. 1979;35:549-556.**

- Trial monitoring: Early stopping for benefit required

**Freedman, et al.  Control Clin Trials.  1996;17:509-525.**** **

## Evidence of increase in breast cancer
OBF procedure using a 0.05-level one-sided weighted logrank test.  
OR
Evidence of increase in CHD, stroke, PE, hip fracture, colorectal cancer, endometrial cancer, or death from other causes 
OBF procedure using a 0.05-level one-sided (weighted/unweighted) logrank test, with Bonferroni correction.  
AND
Global index supportive of overall harm (Z< -1.0)

- OBF procedure using a 0.05-level one-sided weighted logrank test.
- _OR_
- Evidence of increase in CHD, stroke, PE, hip fracture, colorectal cancer, endometrial cancer, or death from other causes
- OBF procedure using a 0.05-level one-sided (weighted/unweighted) logrank test, with Bonferroni correction.
- _AND_
- Global index supportive of overall harm (Z< -1.0)

**Freedman, et al.  Control Clin Trials. 1996;17:509-525.****  **

- Trial monitoring:  Early stopping for adverse effects required

## Statistical approaches in reporting

- Intention-to-treat
- Unweighted hazard ratios
- Nominal and adjusted 95% confidence intervals from unweighted analyses
- Primary and designated safety endpoints adjusted for multiple interim analyses
- Designated secondary endpoints adjusted for multiple endpoints and interim analyses
- P-values may be shown from weighted analyses

## Statistical approaches in reporting subgroup analyses

- Inference based primarily on tests for interaction
- No adjustment for multiple testing required
- Considered hypothesis generating
- Must state
- Number of interactions tested
- Number expected to be significant by chance alone

## Prior hormone use and breast cancer

- More detailed analysis of prior exposure
- Type of prior hormone use
- Duration of prior hormone use
- Recency of prior hormone use
- Extent of disease comparisons by prior hormone use
- Mammography performance

## Breast cancer risk with E+P by prior hormone use

|  | E + P |  |  | Placebo |  |  | Hazard | Unwt | Wtd |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | N |  | % | N |  | % | Ratio | Z | Z |
| No prior PHT use |  |  |  |  |  |  |  |  |  |
|     Total Breast Cancer | 177 | 0.50 |  | 151 | 0.45 |  | 
1.10 | 
-0.83 | 
-2.28 |
|     Invasive | 141 | 0.40 |  | 121 | 0.36 |  | 1.09 | -0.72 | -1.68 |
| Any prior PHT use |  |  |  |  |  |  |  |  |  |
|     Total Breast Cancer | 68 | 0.53 |  | 34 | 0.29 |  | 
1.85 | 
-2.92 | 
-3.09 |
|     Invasive | 58 | 0.46 |  | 29 | 0.25 |  | 1.86 | -2.70 | -3.01 |

- Unweighted p for interaction = .04; Weighted p = .10

## Breast cancer incidence by prior PHT use

- Unweighted p = .04,  Weighted p = .10

- Not to be reproduced or distributed without permission from WHI

## Breast cancer risk by type of prior PHT use

|  | E+P |  | Placebo |  | HR | Unwtd | Wtd |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | N | % | N | % | (95% CI) | P | P |
| No prior use | 141 | 0.40 | 121 | 0.36 | 1.09 
(0.86-1.39) |  |  |
| Prior E-alone use only | 22 | 0.54 | 14 | 0.37 | 1.47
(0.75-2.89) |    .08 | .17 |
| Any prior E+P use | 36 | 0.42 | 15 | 0.19 | 2.19 
(1.19-4.01) |  |  |

- P-values from test for interaction with type of prior use

- Not to be reproduced or distributed without permission from WHI

## Breast cancer incidence among prior users of E-alone and combined hormones

- Unweighted p = .08;   Weighted p = .17

- Not to be reproduced or distributed without permission from WHI

## Breast cancer risk by duration of prior hormone use

|  | E+P |  | Placebo |  | HR | Unwtd | Wtd |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | N | % | N | % | (95% CI) | P | P |
| No prior use | 141 | 0.40 | 121 | 0.36 | 1.09 
(0.86-1.39) |  |  |
| < 2 years | 23 | 0.43 | 11 | 0.22 | 1.94
(0.94-4.02) |        .09 |       .15 |
| 2-4 yrs | 12 | 0.45 | 7 | 0.27 | 1.87   (0.73-4.76) |  |  |
| 4+ yrs | 23 | 0.49 | 11 | 0.27 | 1.85 
(0.90-3.80) |  |  |

- P-values from test for interaction with duration of prior use

- Not to be reproduced or distributed without permission from WHI

## Breast cancer incidence by duration of prior hormone use

- Unweighted p = .09; Weighted p = .15

- Not to be reproduced or distributed without permission from WHI

## Breast cancer risk by recency of prior hormone use

|  | E+P |  | Placebo |  | HR | Unwtd | Wtd |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Last PHT use | N | % | N | % | (95% CI) | P | P |
| At initial screen | 13 | 0.41 | 4 | 0.15 | 2.86   (0.91-8.97) |  |  |
| < 5 years ago | 17 | 0.40 | 8 | 0.21 | 2.02   (0.87-4.69) |            .59 |           .65 |
| 5-10 years ago | 10 | 0.53 | 5 | 0.28 | 2.49   (0.82-7.55) |  |  |
| 10+ yrs ago | 18 | 0.52 | 12 | 0.36 | 1.43   (0.69-2.99) |  |  |

- P-values from test for interaction with recency of use

- Not to be reproduced or distributed without permission from WHI

## Breast cancer incidence by recency of prior hormone use

- Unweighted p = .59, Weighted p=.65

- PHT use at enrollment

- PHT use within last 5 years

- Not to be reproduced or distributed without permission from WHI

## Breast cancer incidence by recency of prior hormone use, continued

- Unweighted p = .59, Weighted p=.65

- Last PHT use 5-10 years ago

- Last PHT use 10+ years ago

- Not to be reproduced or distributed without permission from WHI

## Breast cancer risk by prior hormone use and body mass index

|  | E+P |  | Placebo |  | HR | Unwtd | Wtd |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | N | % | N | % | (95% CI) | P | P |
| No prior use; BMI < 30 | 83 | 0.37 | 67 | 0.31 | 1.18   (0.86-1.64) |  |  |
| No prior use; BMI 30+ | 58 | 0.46 | 54 | 0.46 | 0.96   (0.66-1.40) |            .11 |       .12 |
| Prior use; BMI < 30 | 34 | 0.37 | 14 | 0.17 | 2.30   (1.23-4.30) |  |  |
| Prior use; BMI 30+ | 24 | 0.68 | 14 | 0.42 | 1.62   (0.83-3.16) |  |  |

- P-values from test for interaction with prior use and BMI

- Not to be reproduced or distributed without permission from WHI

## Breast cancer

- Unweighted p = .11
- Weighted   p = .12

- No prior hormone use

- Prior hormone use

- BMI < 30

- BMI 30+

- Not to be reproduced or distributed without permission from WHI

## Characteristics of prior hormone users

- Younger, leaner
- More frequently
- White
- Have at least a high school education
- Former smokers
- Drink alcohol
- Exercise
- Have used oral contraceptives
- Have vasomotor symptoms
- Have parental history of fracture after age 40
- Had a mammogram in previous 2 years
- Have different pregnancy history

## Duration of prior use by type

|  | 
E-alone |  | Combined hormone use |  | Any prior 
use |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | N | % | N | % | N | % |
| Ever | 1768 | 10.6 | 2912 | 17.5 | 4311 | 26.0 |
| Duration of prior use |  |  |  |  |  |  |
| < 5 yrs | 1337 | 75.6 | 2047 | 70.3 | 3010 | 69.8 |
| 5-10 yrs | 243 | 13.7 | 573 | 19.7 | 783 | 18.2 |
| 10+ yrs | 188 | 10.6 | 292 | 10.0 | 518 | 12.0 |

- Not to be reproduced or distributed without permission from WHI

## Recency of prior use by type

|  | 
E-alone |  | Combined hormone use |  | Any prior 
use |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | N | % | N | % | N | % |
| Recency of use |  |  |  |  |  |  |
| Baseline use | 102 | 5.8 | 943 | 32.4 | 1045 | 24.2 |
| < 5 yrs | 296 | 16.7 | 1205 | 41.4 | 1406 | 32.6 |
| 5-10 yrs | 339 | 19.2 | 552 | 17.9 | 723 | 16.8 |
| 10+ yrs | 1024 | 57.9 | 239 | 8.2 | 1130 | 26.2 |

- Not to be reproduced or distributed without permission from WHI

## Estimated effects of E+P in multivariate models*

|  | E+P 
Hazard Ratio | 
95% CI |
| --- | --- | --- |
| Controlling for multiple confounders | 1.20 | 0.94-1.53 |
| In women with no prior hormone exposure | 1.02 | 0.77-1.36 |
| In women with prior hormone exposure | 1.96 | 1.17-3.27 |

- Unweighted p = .03;  Weighted p <.0001

- *Controlling for differential characteristics of prior hormone users and other breast cancer risk factors and main effect of prior hormone use

- Not to be reproduced or distributed without permission from WHI

## Estimated effects of E+P in multivariate models

| 

In women with . . . | E+P 
Hazard Ratio | 
95% CI |
| --- | --- | --- |
| No prior hormone exposure | 1.02 | 0.77-1.36 |
| E-alone exposure only | 1.36 | 0.60-3.07 |
| Any prior combined hormone exposure | 2.46 | 1.26-4.81 |

- Unweighted p = .05;  Weighted p =.64

- Not to be reproduced or distributed without permission from WHI

## Estimated effects of E+P in multivariate models

| 

In women with . . . | E+P 
Hazard Ratio | 
95% CI |
| --- | --- | --- |
| No prior hormone exposure | 1.02 | 0.77-1.36 |
| < 5 yrs prior hormone use | 1.81 | 1.03-3.17 |
| 5-10 years prior hormone use | 2.14 | 0.98-4.66 |
| 10+ years of prior hormone use | 2.53 | 1.07-5.95 |

- Unweighted p = .08;  Weighted p <.0001

- Not to be reproduced or distributed without permission from WHI

## Estimated effects of E+P in multivariate models

| 

In women with . . | E+P 
Hazard Ratio | 
95% CI |
| --- | --- | --- |
| No prior hormone exposure | 1.02 | 0.77-1.36 |
| Hormone use at initial screen | 1.94 | 0.91-4.13 |
| Hormone use in last 5 years | 2.02 | 1.03-3.94 |
| Last hormone use 5-10 years ago | 2.67 | 1.26-5.67 |
| Last hormone use 10+ years ago | 1.52 | 0.71-3.23 |

- Unweighted p = .17;  Weighted p <.0001

- Not to be reproduced or distributed without permission from WHI

## Estimated effects of E+P in multivariate models

| 

In women with . . | E+P 
Hazard Ratio | 
95% CI |
| --- | --- | --- |
| No prior use; BMI < 30 | 1.14 | 0.79-1.64 |
| No prior use; BMI 30+ | 0.88 | 0.56-1.37 |
| Prior use; BMI < 30 | 2.29 | 1.09-4.78 |
| Prior use; BMI 30+ | 1.72 | 0.84-3.52 |

- Unweighted p = .05;  Weighted p <.0001

- Not to be reproduced or distributed without permission from WHI

## Extent of disease by prior use and randomization assignment

|  | No prior PHT |  |  | Prior PHT |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | E+P
N=141 | Placebo n=121 | P | E+P  n=58 | Placebo  n=29 | P |
| Tumor size, cm3 | 1.7(1.1) | 1.5(1.0) | .09 | 1.7(1.3) | 1.4(0.9) | .20 |
| Positive nodes,% | 26 | 17 | .15 | 26 | 9 | .12 |
| Advanced stage,% | 25 | 18 | .15 | 27 | 11 | .09 |

- Not to be reproduced or distributed without permission from WHI

## Breast cancer incidence post-intervention(diagnoses from 7/8/02 – 8/31/03)

|  | E+P |  | Placebo |  | Hazard
Ratio | Unwtd
Z |
| --- | --- | --- | --- | --- | --- | --- |
|  | N | % | N | % |  |  |
| Total | 27 | 0.40 | 22 | 0.34 | 1.17 | -0.56 |
|   Invasive | 21 | 0.31 | 18 | 0.28 | 1.13 | -0.37 |
|   In situ | 6 | 0.09 | 4 | 0.06 | 1.38 | -0.50 |

- Not to be reproduced or distributed without permission from WHI

## Cumulative breast cancer incidence, including post-intervention diagnoses*

|  | E+P |  | Placebo |  | Hazard
Ratio | Unwtd
Z | Wtd
Z |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | N | % | N | % |  |  |  |
| Total | 282 | 0.51 | 210 | 0.41 | 1.27 | -2.61 | -3.91 |
|   Invasive | 227 | 0.41 | 170 | 0.33 | 1.26 | -2.31 | -3.19 |
|   In situ | 56 | 0.10 | 42 | 0.08 | 1.25 | -1.08 | -2.14 |

- *Data through August 31, 2003

- Not to be reproduced or distributed without permission from WHI

## Summary—Breast cancer

- Suggestion of greater E+P hazard ratios in women with prior hormone exposure
- Potential confounding by differential characteristics of prior users
- Potential delay in diagnosis not taken into account
- More extensive modeling suggests
- Prior combined hormone use has a stronger effect than prior E-alone use
- Increasing duration of prior exposure is associated with greater risk
- Recency of exposure an unclear factor
- Modest evidence for interaction of E+P with prior use and BMI

## Summary—Breast cancer, continued

- Data too sparse to jointly examine
- Type
- Duration
- Recency
- Difference in extent of disease by randomization status consistent across prior use groups
- Some hints of differential effects by prior use
- Data on post-intervention comparisons are limited

## Frequency of ‘abnormal’ mammograms

- Not to be reproduced or distributed without permission from WHI

## Summary—Mammography

- E+P increases rates of abnormal mammograms
- Among women who never had a breast cancer diagnosis, the proportions with abnormal mammograms were
- 32% for E+P
- 22% for placebo
- Role of prior hormone use on mammography performance is small

## Slide 35