ERT for Women with a History of Breast Cancer: Is it Safe?

Abstract & Commentary

Synopsis: Investigators at MD Anderson conducted a prospective, randomized study of estrogen replacement therapy (ERT) in women with prior early stage breast cancer. Data from this study were combined with an observational series of comparable patients. ERT was associated with modest lipid and skeletal benefits but with no increase in breast cancer or compromise in disease-free survival. They conclude that larger-scale randomized studies are needed to confirm the safety of ERT for patients with a history of breast cancer.

Source: Vassilopoulou-Sellin R, et al. Cancer. 2002;95: 1817-1826.

Amid the controversy of hormone replace- ment therapy (HRT) these days, there persists a debate on whether a woman with prior breast cancer should ever receive estrogen therapy. In the current report, Vassilopoulou-Sellin and colleagues from MD Anderson Cancer Center conducted a prospective clinical trial to assess the safety and efficacy of prolonged ERT in a group of menopausal women with localized (stage I or stage II) breast carcinoma and a minimum disease-free interval of 2 years if estrogen-receptor negative (ER-) or 10 years if ER status was unknown. For 5 years, Vassilopoulou-Sellin et al followed 77 trial participants and 222 additional women with clinical and prognostic characteristics comparable to those of the trial participants who did not wish to participate in the randomized, prospective trial. Of the eligible trial participants, 34 were randomized to receive ERT and 43 were not. In the observational group, 22 received ERT and 200 did not. Patient and disease characteristics, such as tumor size, number of lymph nodes involved, menopausal status, and disease-free interval were comparable for women who had enrolled on the trial and women who were not.

ERT consisted of Premarin (conjugated estrogen, Wyeth-Ayerst Pharmaceuticals) 0.625 mg on days 1-25 of each month. Progesterone was omitted because it might have an independent influence on the development of certain cancers or on the recurrence of breast cancer.

Thus, there were 56 women on ERT, and 2 of these (3.6%) developed a contralateral, new breast carcinoma. In the group that was not on ERT, 33 of 243 (13.5%) developed new or recurrent breast cancer. ERT was associated with modest lipid and skeletal benefits.

Vassilopoulou-Sellin et al concluded from their findings that ERT did not compromise disease free survival in these patients who were treated previously for localized (stages I and II) breast cancer. However, they call for larger, randomized studies to confirm these findings.

Comment by William B. Ershler, MD

The management of breast cancer commonly involves controversial issues that take seemingly forever to resolve. An example, of course, is the decades it took to determine that modified surgical procedures produce comparable results to radical mastectomy when it comes to overall survival or local control.1 Another controversy is whether patients with prior breast cancer could or should ever receive ERT.

The merits and limitations of estrogen replacement therapy have been discussed extensively, especially in light of the recent report from the Women’s Health Initiative (WHI) study.2 In that large, prospective randomized controlled study on the benefits and risks of combined HRT, there was a small excess in cases of breast cancer, myocardial infarction, cerebrovascular accidents, and venous thromboembolism, in conjunction with a slight diminution of the number of cases of bone fracture and colon cancer. These findings have raised the level of concern about the use of HRT in general, but methodological issues have also been raises. For example, Lamay, in a recently published editorial,3 points out that the WHI study included a broad range of ages, and only one third were in the decade of 50-59 (the age typically in which HRT is prescribed for menopausal symptoms). He pointed out that except for venous thrombosis, the confidence intervals for outcomes were near the limit of statistical significance and that these disappear upon adjustment. Perhaps most importantly with regard to clinical practice (and the current report on breast cancer), the terminated WHI study involved the use of combined estrogen and progestin. Results of the ongoing WHI study on estrogen alone will be of great interest and importance.

The current report provides prospective data with a longer follow-up than previous reports on the use of ERT in patients with prior breast cancer. The findings reinforce the sense that ERT does not compromise disease-free survival in patients with previously treated early stage breast cancer. In the current climate, however, it will take a larger randomized study in prior breast cancer patients coupled with the safety data from the WHI study of estrogen (alone) before there is likely to be enthusiasm from the community and from practicing physicians with regard to ERT in this setting.

Dr. Ershler is INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, D.C.

References

1. Fisher B, et al. N Engl J Med. 2002;347:1233-1241.

2. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

3. Lamay A. J Obstet Gynacol Can. 2002;24:711-715.