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Summary

At the end of July what seems to be one of the most significant publications from the WHI-HT studies was released. After 18 years from the first publication on the effects of HT on breast cancer risk, data from long-term follow up of 27 347 postmenopausal women enrolled in the two randomized hormone therapy vs placebo clinical trials were divulged. From the data it seems that women randomized to CEE alone benefited from a statistically significantly lower breast cancer incidence that persisted for more than a decade after discontinuing use and a statistically significantly lower breast cancer mortality. In contrast, women previously randomized to CEE plus MPA had a statistically significantly higher breast cancer incidence that persisted for more than a decade after discontinuing use, but no significant difference in breast cancer mortality.

Commentary

One of the major safety issues regarding menopausal hormone therapy (MHT), which was put forward in a blast when the preliminary WHI CEE+MPA arm data were released in July 2002, was the alarming finding that this treatment significantly increased the incidence of breast cancer [1]. As a result, the previous very positive sentiment (“all women should consider HRT”) turned overnight to panic, with massive discontinuation of use and refusal by physicians to prescribe hormones even when much needed in those who had moderate to severe menopausal symptoms. Unfortunately, later on, when more detailed information was published, showing that there was no risk for women who were hormone-naive at study entry, the negative atmosphere did not change. Furthermore, the positive results from the CEE-only arm, which demonstrated some protection from breast cancer, did not have any impact on the views by both the public and most of the caregivers.

Since then, things calmed down a bit, as we all got used to the situation, accepting the fact that many women suffer from menopausal symptoms and poor quality of life because they either refused or were denied proper hormonal treatment because of the breast cancer scare. Perhaps the current publication in JAMA by the WHI investigators may end the dispute over the potential contribution of MHT to breast cancer risk [2]. These are data on women who participated in both arms of the WHI clinical trial and stopped taking therapy thereafter. There was a long-term follow-up, and breast cancer cases were recorded and analyzed.

The WHI CEE-only arm study ended after 7.2 years (median) and had pointed towards a significant 24% reduction in breast cancer incidence versus placebo [3]. After the median cumulative 16.2 years (trial+post-intervention period), the corresponding figure was a 22% reduction. Interestingly, while in the clinical phase CEE-alone was particularly beneficial for women with no prior HT use and women with gap time ≥ 5 years (time from menopause to hormone therapy initiation), these subgroup differences were attenuated and were no longer statistically significant when data for the whole cumulative period were analyzed [2].

The opposite was found in the CEE+MPA users, still in line with the previously published results of the clinical phase, which lasted 5.2 years (26% increased risk versus placebo) [1]. The increase in breast cancer incidence was higher in women with prior hormone use and women with gap time < 5 years. Post-intervention, through a median 20.7 years cumulative follow-up, CEE plus MPA continued to demonstrate a significant increase in breast cancer incidence (28% increased risk) while subgroup differences were attenuated and were no longer statistically significant [2].

In the article discussion, the authors tried to understand why the previous large observational trials did not show a reduction of risk for CEE-only users. They mention the possibility of “chance” findings, between-study variability in the rate of keeping routine, regular, periodical mammography in the community, potential WHI study limitations. In searching for a biological rationale, the known effects of CEE-only on breast tissue were also discussed in brief in the article.

Importantly, in such situations, we should address the absolute numbers of breast cancer cases rather than point at HR or percentages. The authors refer to that issue as well: “in absolute terms the reduction is modest; for every 10 000 person-years of women following prior use of CEE alone, there would be two fewer deaths as a result of breast cancer and two fewer deaths after breast cancer”.

These data should be perceived as reassuring also for the CEE+MPA arm follow-up. Study conclusions were: “decisions regarding the use of any hormone therapy regimen should consider the full range of risk and benefits, involve shared decision-making with the patient, and recognize that risk-benefit balance is altered by additional factors such as age, time from menopause, oophorectomy status and prior hysterectomy, with some outcomes persisting and some attenuating after stopping use”.

Unfortunately, there are still many gaps in knowledge with a low chance of filling them in the coming years. For example, what is the risk for long term use of other types of estrogen, progestins and hormonal combinations, including androgens, or of lower doses or transdermal preparations? If the absolute additional or fewer number of cases per 10000 patient-years is so small, then a significant statistical benefit or risk may be regarded as negligible or trifle when discussing initiation or discontinuation of therapy in the individual clinical setting.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
The Hebrew University Hadassah Medical School, Jerusalem, Israel

References

  1. Rossouw JE, Anderson GL, Prentice RL, 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; 288:321–33.
    https://pubmed.ncbi.nlm.nih.gov/12117397/
  2. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. .
    https://pubmed.ncbi.nlm.nih.gov/32721007/
  3. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712.
    https://pubmed.ncbi.nlm.nih.gov/15082697/
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