Incidence and Mortality Data from the Women's Health Initiative

Abstract & Commentary

By Jeffrey T. Jensen, MD, MPH, Editor, Leon Speroff, Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: New results from the WHI show that women exposed to combined conjugated estrogens and medroxyprogesterone acetate HRT have an increase in both breast cancer diagnosis and mortality.

Source: Chlebowski RT, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010;304:1684-1692.

The authors investigated invasive breast cancer incidence and mortality after a total follow-up of 11 years among the 16,608 postmenopausal women aged 50-79 years with no prior hysterectomy who were randomized to combined oral conjugated equine estrogens (0.625 mg/day) plus medroxyprogesterone acetate (2.5 mg/day) or placebo in the Women's Health Initiative (WHI) HRT study. In the initial reports from the WHI HRT study, breast cancer incidence was increased (hazard rate [HR], 1.26; 95% confidence interval [CI], 1.00-1.59). After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence, and was obtained from 12,788 (83%) of the surviving participants, with roughly equal participation in the treated and placebo cohorts.

The authors used an intention-to-treat analysis that included all randomized participants, censoring those not consenting to additional follow-up. Compared to the placebo cohort, women that used HRT had more invasive breast cancers (385 cases [0.42% per year] vs 293 cases [0.34% per year]; HR, 1.25; 95% CI, 1.07-1.46). While breast cancers in the HRT estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group, they were slightly more likely to be node-positive (24% vs 16%; HR, 1.78; 95% CI, 1.23-2.58). Overall, there were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04) as well as more deaths from all causes occurring after a breast cancer diagnosis among women in the HRT group. The authors concluded that combined estrogen plus progestin HRT was associated with greater incidence of breast cancer, and that the cancers that occur are more commonly node-positive and associated with higher mortality.

Commentary

The Women's Health Initiative study continues to produce headlines (and calls from patients), but the results from this study are not shocking. First, to recap the original WHI publications, an increase in the incidence of breast cancer was noted in the combined (Prempro®) HRT group, but not in the estrogen-only (Premarin®) study. However, the increase in breast cancer incidence in the original combined HRT study was not statistically significant after adjustment for multiple comparisons (HR, 1.26; 95% CI, 0.83-1.92).1 Since the present study did not focus on multiple outcomes, an adjusted HR was not calculated. The 25% increase in breast cancer diagnosis seen with HRT comes as no surprise as this is a consistent number seen across multiple studies, including the large Nurses Health Study in the United States and the Million Women's Study in the United Kingdom.

The new information about mortality reported in this paper is important to consider. First, most observational studies have suggested that breast cancers associated with combined hormone therapy use generally have more favorable histology and receptor status, lower stage, and longer survival than those diagnosed in non-users of HRT.2-4 Since the WHI findings come from a prospective randomized study, they suggest that the optimistic findings from observational studies may have resulted from screening bias. However, it is important to note that the results of an RCT with restrictive inclusion/exclusion criteria may also not be generalizable to the entire population at risk. Most notably, the WHI enrolled an asymptomatic group that was overall older, more obese, and more high-risk than most healthy young menopausal women that initiate hormone therapy shortly after the onset of symptoms.

The findings of the new report support that the risk of breast cancer is slightly increased among women that used combined oral HRT, and that the risk of mortality from breast cancer was also higher. This will reinforce the entrenched position of some providers who have adopted a "do no harm" approach to the management of menopause. In my opinion this overlooks the possibility of "doing good" for our patients, and does not fulfill our obligation to balance potential risks with potential benefits.

First, let's run the numbers. While the risk of death was almost two-fold higher among users of Prempro (HR, 1.96; 95% CI, 1.0-4.04) this translates to absolute risks of 2.6 vs 1.3 deaths per 10,000 women per year in the HRT and placebo groups, respectively. According to the American Cancer Society, the overall mortality rate for breast cancer for women of all ages in 2006 was about 2.3/10,000.5,6 This suggests that the unusual findings of the original and subsequent WHI results are not the slightly higher incidence and mortality figures for breast cancer among the HRT cohort, but the unusually low rates in the placebo group. While we expect that a large randomized study will be free of bias, recall that with adjustment, the breast cancer increase in the original publication was no longer statistically significant. Although the authors of the present study performed a number of subgroup analyses that demonstrated that the trend toward increased mortality was the same regardless of age, BMI, risk factors, prior HRT use, or years from menopause, this is not the same as performing a multivariant adjustment that simultaneously corrects the for the effect of multiple confounders. Moreover, since this study required reconsent, the resulting analysis group effectively becomes a cohort study unprotected by the magic touch of randomization. Therefore, adjusting the hazard ratios for important baseline confounders would have been appropriate.

Even if we accept the results as presented, we should understand the limitations and communicate the absolute risks rather than relative risks to patients. The data demonstrate that there will be about 1 additional breast cancer death per year among 10,000 women meeting the inclusion/exclusion criteria of WHI treated with oral conjugated estrogens and medroxyprogesterone acetate. Obviously in caring for our individual patients we recognize that the numbers don't matter if you are the one facing a diagnosis of breast cancer, but they put this risk into perspective. Early diagnosis and aggressive treatment remain our most important allies in reducing breast cancer mortality. As previously discussed in OB/GYN Clinical Alert (see January 2010 issue), the 2009 U.S. Preventive Services Task Force released revised recommendations on breast cancer screening. The panel recommended against routine mammography for women in their 40s to prevent unnecessary morbidity due to screening. However, starting annual mammograms at age 40 instead of age 50 and continued to age 69 will prevent 1 additional cancer death (8.3 vs 7.3) for every 1000 women screened at the expense of 63 unnecessary biopsies. Reducing the screening interval to every other year results in 70 fewer biopsies/1000 women, but 2 additional women will die from breast cancer.7 This is excess mortality of 10-20/10,000 women screened.

I continue to believe that the positive health aspects of ERT/HRT outweigh potential risks among young otherwise healthy menopausal women. The WHI demonstrates that starting therapy in asymptomatic women remote from menopause is associated with more risks and fewer benefits. The risk of breast cancer mortality may be one consideration. While we need to counsel our patients that the present study suggests that breast cancer prognosis is not better among women that develop disease while using HRT, otherwise healthy young menopausal women looking to prevent future problems due to hormone deficiency will still benefit from treatment that is initiated shortly after the onset of menopause. And while on HRT, women should receive mammograms every year.

References

  1. Rossouw JE, et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
  2. Rosenberg LU, et al. Menopausal hormone therapy in relation to breast cancer characteristics and prognosis: A cohort study. Breast Cancer Res 2008;10:R78.
  3. Newcomb PA, et al. Prediagnostic use of hormone therapy and mortality after breast cancer. Cancer Epidemiol Biomarkers Prev 2008;17:864-871.
  4. Holli K, et al. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol 1998;16:3115-3120.
  5. American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta, GA: American Cancer Society, Inc.; 2009.
  6. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999-2005 Incidence and Mortality Web-based Report. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2009. Available at: http://www.cdc.gov/uscs.
  7. Mandelblatt JS, et al. Effects of mammography screening under different screening schedules: Model estimates of potential benefits and harms. Ann Intern Med 2009;151:738-747.