Hormone Replacement and Breast Cancer Risk: The Authors Reply

Our commentary in the July 2009 issue of ONCOLOGY concluded that the current level of evidence for safety and efficacy of “natural” hormone replacement therapy (NHRT) is not conclusive. In terms of safety, the majority of data suggests that NHRTs demonstrate risks similar to those of conventional hormone replacement therapy (HRT). Efficacy trials of NHRTs have produced mixed and sometimes contradictory results. We further suggested that the administration of hormone therapy rely on evidence-based clinical judgment; NHRT advice to women should be based on the same risk/benefit assessment that would be used when considering conventional HRT.

Drs. Creasman and DiSaia use this as a segue in their Letter to the Editor to defend the use of HRT for women, taking the position that there is really a lot of fuss about nothing with HRT, and if NHRT is the same, no problem. They argue that for breast cancer survivors, “In view of the present data, we feel it is important for women to know there are choices, and current data would suggest that there is no increased risk of recurrence with HRT.”

Debatable Defense
Their first defense of HRT is a 2002 citation by Chlebowski et al,[1] but the writers fail to mention the fact that these authors concluded, “Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.”

They go on to cite other studies including a small (n = 43) 1985 trial by Matelski et al.[2] The writers conclude from this citation that “In the 1970s and early 1980s, several prospective randomized studies compared estrogen with tamoxifen in such women. The results were similar.” Their conclusion is not shared by the evidence. Even the authors of their citation disagree, concluding that “Initial hormonal therapy with tamoxifen in postmenopausal patients with advanced breast cancer and ERP status positive or unknown is superior to primary estrogen treatment.”

The writers also comment on the HABITS trial,[3] which was stopped as a result of increased breast cancer risk in the HRT arm and the Stockholm trial.[4] They conclude “In view of the present data, we feel it is important for women to know there are choices, and current data would suggest that there is no increased risk of recurrence with HRT.” Once again, their conclusions are not consistent with the evidence or other well considered analyses.

Further Evidence
Prentice et al[5] examined the effects of daily 0.625-mg conjugated equine estrogens plus 2.5-mg medroxyprogesterone acetate in relation to both prior hormone therapy and time from menopause to first use of postmenopausal hormone therapy (“gap time”) in the Women’s Health Initiative (WHI) trial and in a corresponding subset of the WHI observational study on postmenopausal women with a uterus enrolled at 40 US clinical centers during 1993–1998. The authors found that hazard ratios agreed between the two cohorts at a specified gap time and time from hormone therapy. They determined that the “Combined trial and observational study data support an adverse effect on breast cancer risk.” They further concluded, “The WHI clinical trial and observational study each support an adverse effect of daily 0.625-mg conjugated equine estrogen plus 2.5-mg medroxyprogesterone acetate on breast cancer. Women who initiate treatment soon after menopause and continue for many years appear to be at particularly high risk.”

As if this weren’t enough, a recent review by Chlebowski et al[6] showed a significant increase in deaths (not incidence) from lung cancer for women receiving estrogen plus progestin compared to placebo controls enrolled in the WHI.

Conclusion
The writers’ argument in favor of the safety of HRT is not supported by the evidence, including their own references. Our conclusions in the July 2009 ONCOLOGY Commentary remain unchanged-namely that HRT (including NHRT) should be based on a balanced risk/benefit assessment and that high-risk patients including survivors of hormone-driven breast cancer are not appropriate candidates for HRT. As new clinical trials increase our body of knowledge, we will hopefully have more tools and flexibility when making clinical judgments, but at this time we must not lose sight of the principle of “do no harm.”

References:

1. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 289:3243-3253, 2003
2. Matelski H, Hubaman M, Zipoli T: Randomized trial of estrogen vs tamoxifen therapy for advanced breast cancer. Am J Clin Oncol 8:128-133, 1985.
3. Holmberg L, Anderson H: HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: Trial stopped. Lancet 363:453-455, 2004.
4. von Schoultz E, Rutquist LE, et al: Menopausal hormone therapy after breast cancer: The Stockholm Randomized Trial. J Natl Cancer Inst 97:533-535, 2005.
5. Prentice RL, Chlebowski RT, Stefanick ML, et al: Estrogen plus progestin therapy and breast cancer in recently postmenopausal women. Am J Epidemiol 167:1207-1216, 2008.
6. Chlebowski RT, Schwartz AG, Wakelee H, et al: Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): A post-hoc analysis of a randomised controlled trial: Lancet 374:1243-1251, 2009.