Estrogens and Women With Breast Cancer

I was quite disappointed with Dr. Graham A. Colditz’s review of the literature concerning the use of estrogen replacement therapy in patients with breast cancer, which appeared in the November 1997 issue of ONCOLOGY (pp 1491-1497).

Dr. Colditz assumes that risk factors for breast cancer are prognostic. The available data do not support this supposition. For example, women with a family history of breast cancer, who themselves develop the disease have a better prognosis than do women with breast cancer and no such family history.[1] Dr. Colditz correctly notes that women diagnosed with breast cancer while taking estrogen have a better prognosis than postmenopausal women diagnosed with breast cancer who have never taken estrogen. However, he attributes this survival advantage to a “higher probability of estrogen-sensitive tumors among women taking postmenopausal hormones” or, alternatively, to the fact that “estrogen may promote slower-growing tumors....”

At our institution, we compared women diagnosed with breast cancer while taking hormones to age- and pathology-matched postmenopausal women diagnosed while not taking hormones.[2] We found that women taking hormones have smaller tumors with less nodal involvement and lower S-phase fractions than do women not taking hormones. No wonder they have a better prognosis! They are not more likely to have estrogen-receptor (ER)–positive tumors.

Estrogen and Breast Cancer Prognosis
Dr. Colditz does not mention any of the studies on the effects of estrogen on breast cancer prognosis. Several physicians have reported on small series of patients who either continued taking estrogen after being diagnosed with breast cancer or began taking hormones after the diagnosis was made. Wile et al[3] reported on 25 breast cancer patients, including one stage III patient and seven stage II patients who were taking hormone replacement therapy. With a mean follow-up of 35 months, two patients developed a recurrence, and overall survival was 96%.

Powles et al[4] observed one local recurrence at 64 months among 35 women taking both conjugated estrogens (Premarin) and tamoxifen (Nolvadex). DiSaia et al[5] et al reported on 77 breast cancer patients who used hormone replacement therapy; 42% began the therapy within 1 year of diagnosis, and the majority had ER-positive tumors. Although five patients developed recurrences, 92% were alive and free of disease at last follow-up.

Gambrell followed 256 postmenopausal women with breast cancer for a period ranging from 8 to 18 years.[6] Median survival for those who had never used estrogen was 84 months; for past users of estrogen, it was 80 months; and for current users, 143 months.

A randomized, prospective trial comparing estrogen to tamoxifen as adjuvant therapy for T1-4 N0-3 invasive cancers noted a recurrence rate of 37% in placebo-treated patients, compared to recurrence rates of 24% in those treated with tamoxifen and 18% in those using estrogen.[7] Estrogen-receptor-positive tumors had the lowest recurrence rates of the three groups, and there were no recurrences in estrogen-treated patients with ER-positive tumors.

A prospective, randomized trial comparing hormone replacement therapy to no treatment began in the United States in 1992.[8] Entry was restricted to: (1) postmenopausal women with ER-negative stage I or II breast cancer who had had no evidence of disease for at least 2 years; and (2) ER-positive patients who were disease-free for 10 years. Patients took conjugated estrogens, 0.625 mg, on days 1 to 25 of each month. After 5 years of accrual, only 100 patients have been randomized. There has been one distant metastasis in the control group who were not receiving estrogen. No recurrences have been noted in the women taking conjugated estrogens.

Finally, in the days before tamoxifen was available, estrogens were considered first-line standard therapy for postmenopausal women with advanced cancers.[9,10] In randomized trials, estrogens demonstrated activity equivalent to that of tamoxifen in terms of inducing complete and partial remissions and prolonging survival.[11] Estrogens were also commonly combined with chemotherapy, producing significantly enhanced survival over chemotherapy alone.[12]

Effects of Tamoxifen in Breast Cancer Patients
Tamoxifen is both an estrogen agonist and estrogen antagonist. It is thought to reduce mortality from breast cancer by blocking the ER, thus preventing any residual ER-positive cancer cells in the body from “seeing” low levels of estrogen produced by the adrenal glands and adipose tissues of postmenopausal women. Also, as an estrogen agonist, tamoxifen prevents osteoporosis, lowers serum cholesterol, and is associated with an increased risk of endometrial cancer—all properties of estrogen. Although the survival benefit of tamoxifen is attributed to its function as an ER antagonist, its beneficial effect may actually be due to its estrogen agonism.

Conclusions
Contrary to Dr. Colditz’s conclusions, the available data do not support withholding estrogens from women with breast cancer. There is considerable evidence that estrogens favorably affect the prognosis of women with breast cancer, while there is scant evidence demonstrating that estrogens adversely affect prognosis. Dr. Colditz concludes: “Although only large randomized trials can provide definitive answers....the feasibility and ethics of such studies hinder their implementation.” On the contrary, I know many breast cancer patients who take postmenopausal hormones whether or not a physician condones or condemns them.

We accept lumpectomy and radiation as acceptable treatment for breast cancer only because a few brave women refused to have a mastectomy and subsequently did not develop a recurrence, leading us to question the value of mastectomy. A comparable group of brave women are now questioning the absolute contraindication of postmenopausal hormone therapy in breast cancer survivors. Now is the ideal time for randomized, prospective studies.

Dr. Tartter has taken the liberty of misreading and misquoting my commentary, although we are in agreement on the need for a randomized trial. He fails to note that I quote in detail several of the studies he describes in which small numbers of women were given estrogens after being diagnosed with breast cancer. On page 1494, I state that these studies are too small to be considered meaningful.

I conclude further that “only large randomized trials can provide definitive answers to the question surrounding the use of hormones by women who have had breast cancer.” Data are currently sparse, and, I contend, insufficient to guide clinical practice. This is, therefore, an ideal time to undertake a large randomized trial.

Alhough I suggest that recruitment to such a trial may be difficult, in part due to ethical considerations, Dr. Tartter suggests that this will not be the case, as he knows of many women who are taking hormones after being diagnosed with breast cancer. The key question is, would these women agree to randomization? Our priority should be the accumulation of scientific evidence to guide clinical practice.

Graham A. Colditz, MD,Associate Professor of Medicine, Channing Laboratory, Harvard Medical School, Boston, Massachusetts

References:

1. Israeli D, Tartter PI, Brower ST, et al: The significance of family history for patients with breast cancer. J Am Coll Surg 179:29-32, 1994.

2. Squitieri R, Tartter PI, Ahmed S, et al: Breast cancers in postmenopausal hormone users and nonuser controls. J Am Coll Surg 178:167-170, 1994.

3. Wile AG, Opfell RW, Margileth DA: Hormone replacement therapy in previously treated breast cancer patients. Am J Surg 165:372-375, 1993.

4. Powles TJ, Hickish T, Casey S, et al: Hormone replacement therapy after breast cancer. The Lancet 342:60-6l, 1993.

5. DiSaia PJ, Grosen BA, Odicino F, et al: Replacement therapy for breast cancer survivors: A pilot study. Cancer 76:2075-2078, 1995.

6. Gambrell RD: Hormone replacement therapy and breast cancer risk. Arch Fam Med 5:341-348, 1996.

7. Palshof T, Mouridsen HT, Daehnfeldt JL: Adjuvant endocrine therapy of primary operable breast cancer. Report of the Copenhagen breast cancer trials. Eur J Cancer (suppl) 1:183-187, 1980.

8. Vassilopoulou-Sillen R, Theriault RL: Randomized prospective trial of estrogen-replacement therapy in women with a history of breast cancer. Monogr Natl Cancer Inst 16:153-159, 1994.

9. Stoll BA: Hypothesis: Breast cancer regression under oestrogen therapy. Br Med J 3:446-450, 1973.

10. Kaufman RJ: Advanced breast cancer: Additive hormonal therapy. Cancer 31:194-203, 1981.

11. Ingle JN, Ahmann DL, Green SJ, et al: Randomized clinical trial of diethylstilbesterol vs tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med 304:16-21, 1981.

12. Kiang DT, Gay J, Goldman A, et al: A randomized trial of chemotherapy and hormonal therapy in advanced breast cancer. N Engl J Med 313:1241-1246, 1985.