Clinical Review

Weighing HRT use after breast cancer

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HRT has long been contraindicated in women who have—or have had—breast cancer. Here, the author examines the effects estrogen has on the breast and reviews several studies that suggest HRT actually may be of benefit to these women.


 

References

Key points
  • Eighty percent of the approximately 205,000 women expected to develop breast cancer this year will be succesfully treated.
  • The data to date suggest that HRT in the patient who has had breast cancer is not detrimental. Some larger studies note fewer recurrences and breast cancer deaths, and less total mortality in HRT users.
  • The absolute risk of breast cancer in a 10-year HRT user is 0.6%.
  • Fifty-nine percent of premenopausal breast cancer patients are willing to consider eventually taking HRT.

This year, almost 50,000 women under the age of 50 will develop breast cancer. Most will undergo chemotherapy and become amennorhic. It is well known that premature surgical menopause usually results in more significant vasomotor symptoms than a natural menopause. It certainly follows that women who have had a chemotherapeutically-induced menopause will have a similar experience.

Hormone replacement therapy (HRT) has proven efficient in the treatment of vasomotor symptoms. Many women also take HRT for good urogenital health, primary cardiac protection, and to assist in the prevention of osteoporosis, colon cancer, and possibly Alzheimer’s disease. In some studies HRT has been linked to an increased risk of breast cancer due to prolonged estrogen exposure; however, the data are inconclusive.

Estrogen appears to stimulate the growth of breast cancer cells in tissue cultures at low doses, but inhibits growth at high doses.

Thankfully, 80% of the approximately 205,000 women expected to develop breast cancer this year will be successfully treated. As a result, more and more breast cancer survivors will present to their Ob/Gyns for the treatment of vasomotor symptoms or other benefits that HRT offers. For this reason, it is important to examine fully the effects of estrogen on the breast and the potential use of HRT in the breast cancer patient.

Sorting the data

Laboratory data. Volumes of research have been conducted on the association between estrogen use and breast cancer. Laboratory data have shown increased cellular activity of estrogen-receptor mammary cancer cells when estradiol is applied and decreased activity when estradiol is withdrawn or a progestin added.1 Apparently, this is not the case with estrogen-receptor-negative tumor cells. Elevated estrogen serum levels also have suggested a direct relationship to breast cancer.2 In some of these studies, only a one-time sample was available for evaluation, estradiol levels were determined only when breast cancer had been diagnosed, and the highest quintile was compared with the lowest quintile—not the mean or median levels. There have been no studies indicating whether serial serum levels are associated with breast cancer. Apparently, in the premenopausal patient, the correlation between serum estradiol levels and breast cancer has produced conflicting results.

While the actions of estrogen in established breast cancers are not entirely understood, they appear to be very complex. Estrogen appears to stimulate the growth of breast cancer cells in tissue cultures at low doses, but inhibits growth at high doses.3 Evidence also suggests that, in breast tumors, internal levels of estradiol can be maintained independent of levels outside the tumor. Therefore, endogenous and exogenous estrogens may have relatively little effect on tumor growth.4

Clinical data. These are mainly epidemiologic studies suggesting that risk factors are increased when prolonged estrogen exposure is present, i.e., early menarche, late menopause, obesity, unopposed endogenous estrogen. Late first-term pregnancy also has been suggested as a risk factor because final differentiation of the terminal duct epithelium—induced by pregnancy and lactation—was postponed by about a decade. In the last quarter-century, more than 50 epidemiological studies have investigated the effect of HRT in the breast cancer patient. These studies have produced mixed results. The Collaborative Group’s breast cancer study, which reanalyzed most of the world’s data, suggests a slightly increased risk of breast cancer in HRT users.5 Although the risk ratio (RR) is said to be 1.35 in women who take HRT for 5 years or more, the absolute risk notes an increase of 45 to 51 per 1,000 women, or 0.6% in a 10-year user. The greatest risk appears to be in thin women.

Several studies—including the Nurses’ Health Study6 and the Iowa Women’s Health Study7 —have established an association between the use of postmenopausal HRT and reduced mortality. The Iowa study evaluated the association between HRT and mortality in women with and without a family history of breast cancer. The adjusted RR for total mortality in women with a family history of breast cancer currently using HRT for more than 5 years was 0.55 (CI 0.28–1.07), which was lower than the estimated RR for women without a family history of breast cancer. Cobleigh and associates summarized data from 5 studies and found that the prognosis was better for women with breast cancer who took HRT before diagnosis than those who never took HRT. Those patients who took HRT before diagnosis had smaller tumors, with better differentiation and less cellular proliferation than women who developed breast cancer and had not taken HRT.

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