Estrogen plus progestin (E+P) and breast cancer incidence and mortality

Reporter: Gita Suneja, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 4, 2012

Presenter: Rowan T. Chlebowski
Presenter's Affiliation: Women's Health Initiative, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA


  • The Women's Health Initiative (WHI) was a major research program launched in 1991 to address the most common causes of death, disability and poor quality of life in postmenopausal women - cardiovascular disease, cancer, and osteoporosis. The study consisted of consisted of a set of clinical trials and an observational study, which together involved 161,608 postmenopausal women.
  • The initial results of the primary prevention trial comparing E+P vs. placebo demonstrated unacceptable risk in the development of breast cancer, and the trial was stopped early. Data was published with 5.2 years of follow-up (Rossouw, JAMA, 2002).
  • With longer follow-up, estrogen plus progestin (E+P) was found to increase breast cancer incidence, with higher percentage of node positive cancer, and increase breast cancer mortality (Chlebowski, JAMA, 2010).
  • However, breast cancers associated with E+P use in most observational studies have had a more favorable prognosis with lower stage and longer survival in hormone therapy users.
  • To address these differences, a cohort of the WHI Observational Study participants with characteristics similar to the eligibility criteria for the WHI clinical trial was identified to examine E+P association with invasive breast cancer incidence and outcome.

Materials and Methods

  • The study cohort included 41,449 postmenopausal women ages 50-70 years with no prior hysterectomy and mammogram negative for breast cancer < 2 years before enrollment who either were not hormone users (25,328) or were using E+P (16,121).
  • Breast cancers were verified by centralized medical record review.
  • Adjusted Cox proportional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI).
  • Additional analyses adjusted for breast cancer screening, censoring participants for incidence analyses who had a > 2 year interval without a mammogram.
  • Primary outcomes included incidence of invasive BC and breast cancer mortality from date of diagnosis.
  • Sensitivity analysis were performed.


  • E+P users were younger, and more likely to be white, college-educated, have lower BMI, and lower Gayle risk assessment.
  • After a mean follow-up 11.3 years, 2,236 breast cancers were diagnosed.
  • Mean duration of hormone therapy use prior to cohort entry was 5.3 years.
  • Breast cancer incidence was higher in E+P users (0.60% vs 0.42%, annualized rate, respectively: HR 1.55, 95% CI 1.41-1.70, P<0.001).
  • Screening adjusted analyses had stronger breast cancer association (0.63% vs 0.39%, HR 1.72, 95% CI 1.54-1.93; P<0.001).
  • Characteristics of breast cancer for E+P users were similar to non-users, although E+P users had more ER/PR positive and less triple negative breast cancers.
  • A "time from menopause gap" was observed - women who started E+P closer to the time of menopause had a higher risk of developing breast cancer
  • Overall survival following breast cancer, measured from diagnosis date, was similar in E+P users and non-users (HR 0.95, 95% CI 0.74-1.23).
  • The rate of adjusted deaths after breast cancer diagnosis was significantly higher for E+P users, HR 2.21, 95% CI 1.66-2.94; P<0.001.

Author's Conclusions

  • Consistent with the results of the WHI randomized clinical trial, E+P use is associated with increased breast cancer incidence.
  • As breast cancer prognosis following diagnosis on E+P is similar to that of nonusers, the higher incidence with E+P leads to increased breast cancer mortality.

Clinical Implications

  • Hormone replacement therapy has been used for many years to reduce symptoms of menopause.
  • Although the WHI highlighted the adverse effects of hormone replacement therapy on breast cancer incidence and mortality, observational studies have demonstrated a more favorable profile of breast cancer in women using E+P.
  • The current study represents a major undertaking to study the excess risk of E+P on breast cancer incidence and mortality in a large observational cohort.
  • The study findings of increased incidence of breast cancer and there a higher mortality from breast cancer. Breast cancer prognosis among E+P users and non-users was similar.
  • The discrepancy between previous observational studies and the present study may be related to confounding in observational studies. Studies that begin analyses at the time of breast cancer diagnosis and adjust for stage may "adjust away"the unfavorable effects of E+P use. Furthermore, E+P users are more likely to have regular mammograms, and most observational studies do no control for mammography screening. Screening typically detects more favorable breast cancers (slow growing, hormone receptor positive, identified at earlier stage).
  • However, a striking difference is noted between hormone replacement therapy with E alone as compared to E+P . In the WHI study, E alone was found to decrease the incidence of breast cancer, however has other unfavorable side effects (LaCroix, JAMA, 2011).
  • Furthermore, the WHI clinical trial of E+P found prognosis of breast cancer to be worse among users vs. non-users, while this observational cohort found prognosis of breast cancer to be similar among both groups. Reasons for this disparity are unclear.
  • Nonetheless, this study represents a major contribution to understanding the influence of E+P hormone replacement therapy on the incidence of and mortality from breast cancer.