By Jeffrey T. Jensen, MD, MPH, Editor

SYNOPSIS: An individual-participant meta-analysis of prospective studies found menopausal hormone therapy associated with an elevation in the risk of breast cancer, with the highest risks associated with daily combined therapy.

SOURCE: Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: Individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019;394:1159-1168.

The Collaborative Group on Hormonal Factors in Breast Cancer, a United Kingdom-based research group, was established in 1992 with the goal of bringing together published and unpublished epidemiologic studies on breast cancer risk associated with the use of menopausal hormonal therapy (MHT). For this report, the group identified and analyzed anonymized information on individual participants from 58 studies (24 prospective, 34 retrospective) of postmenopausal women that included 143,887 cases of invasive breast cancer and 424,972 controls without breast cancer published between 1992 and 2018. They categorized MHT use as estrogen-only (ET) or combined estrogen-progestogen (EPT) and evaluated the effect of age at first use, duration of use, time since last use, and preparation last used. Breast cancers were classified as estrogen-receptor positive or negative (ER+ or ER-); ductal or lobular; and localized or spread beyond the breast (e.g., metastatic). The meta-analysis results showed that every MHT type (except vaginal estrogen) increased the risk of breast cancer. The risk estimates increased with longer duration of use and were greater for EPT than ET (years 1-4: EPT relative risk [RR], 1.60; 95% confidence interval [CI], 1.52-1.69), ET RR, 1.17; 95% CI, 1.10-1.26; years 5-14: EPT RR, 2.08; 95% CI, 2.02-2.15; ET RR ,1.33; 95% CI, 1.28-1.37). The risk associated with continuous EPT (RR 2.3; 95% CI, 2.21-2.40) exceeded that of non-daily progestogen therapy (RR 1.93; 95% CI, 1.84-2.01). However, the types of estrogens and progestogens, and the routes of administration, did not affect risk further. After ceasing MHT, some excess risk persisted for more than 10 years. Of interest, obesity reduced the overall effect of an excess risk of MHT on breast cancer.

Putting these results together, the Collaborative Group concluded that five years of MHT, starting at age 50 years, would result in one additional breast cancer case in every 50 users of daily EPT, one in every 70 users of nondaily EPT, and one in every 200 users of ET, and that continuing the use of MHT for 10 years would double these estimates. They estimated that about 1 million of the approximately 20 million breast cancer cases diagnosed since 1990 in Western countries may have been caused by MHT use.

COMMENTARY

The publication of this large individual participant meta-analysis of breast cancer risk with MHT did not generate much news. This is somewhat surprising, given the inclusion of attributable risk data suggesting that MHT may have directly caused up to one in 20 cases of breast cancer. One explanation could be that in the post Women’s Health Initiative (WHI) world, we have fewer users of MHT and less interest by the public and clinicians. We seem more distracted by herbicides and general environmental contamination.

On a more optimistic note, the lack of interest may reflect the consensus that this report provided no new information. Prior research, including many of the publications in the meta-analysis, has documented a small increase in breast cancer risk associated with MHT, and further demonstrates the risk primarily associated with combined EPT. In fact, the American Cancer Society lists combined MHT as one of several factors with risk estimates below 2.0 in the most recent Breast Cancer Facts and Figures report. Other factors associated with this level of risk include alcohol use, physical inactivity, and obesity.

To be fair, any increase in risk associated with a modifiable factor is potentially important; the question is whether this study should influence current practice. All epidemiologic studies require careful assessment of baseline confounding factors that may influence the outcome. The long list of risk factors in Table 1 illustrates the challenge faced by most studies of breast cancer risk. In this meta-analysis, the authors adjusted for age, alcohol use, parity, and age at first birth. Commonly, missing data are imputed according to a pre-defined algorithm. Although well-intentioned, all of this affects the accuracy of the final estimate. A meta-analysis cannot correct underlying flaws in the original studies. In contrast, meta-analyses frequently magnify these errors by creating tight confidence intervals around risk estimates that exaggerate significance. As I have mentioned many times, risk estimates less than 2.0 are considered weak effects, and should be viewed with extreme caution unless obtained under the rigorous conditions of a well-designed, double-blind, randomized trial.

For this reason, the WHI still provides the best estimates of risk from MHT. In WHI, the use of combined daily EPT resulted in a significantly elevated hazard ratio (HR) for breast cancer (HR, 1.24; 95% CI, 1.01-1.54).¹ However, the magnitude of the increase is small, and statistical significance was lost in most of the subanalyses. Perhaps of greater interest is the reduction in breast cancer risk observed in the WHI ET arm. Anderson et al found that the use of estrogen only for a median of 5.9 years was associated with a significantly lower incidence of invasive breast cancer compared with placebo (HR, 0.77; 95% CI, 0.62-0.95), with no significant difference in risk reduction in those women diagnosed during the intervention phase (21% decrease) and post-intervention (25% decrease).² Even more impressively, fewer of the ET-treated women died from breast cancer (HR, 0.37; 95% CI, 0.13-0.91) or from any cause. What I find most impressive in evaluating the WHI results is that the magnitude of the effect of protection with estrogen-only therapy (~60%) is actually larger than the magnitude of widely quoted increased risk with combined estrogen-progestin therapy (~25%). The meta-analysis results also reflect practice patterns from many years ago that may no longer have relevance.

After WHI, most clinicians have moved away from combined daily MHT regimens that administer conjugated equine estrogens and medroxyprogesterone acetate. The use of transdermal or vaginal estradiol in physiologic doses prevents adverse effects on cardiovascular outcomes.^3,4 Administration of lower doses of oral natural progesterone or use of the lowest dose levonorgestrel intrauterine systems for endometrial protection may reduce the risk of breast cancer in women using combined therapy, but it will be years before these data become available.

REFERENCES

1. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative Randomized Trial. JAMA 2003;289:3243-3253.
2. Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: Extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. Lancet Oncol 2012;13:476-486.
3. Laliberté F, Dea K, Duh MS, et al. Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause 2018;25:1297-1305.
4. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: Impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation 2007;115:840-845.