Does hormone replacement therapy increase the risk of breast cancer

Carolyn Vachani RN, MSN, AOCN
Last Modified: June 18, 2009

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Question

I have a very simple question. Does hormone replacement therapy increase the risk of breast cancer?


Answer
Carolyn Vachani RN, MSN, AOCN, OncoLink's Nurse Educator, responds:

Hormone-replacement therapy (HRT) has been an issue for women's health since its introduction in the mid-1970s. HRT's proposed benefits included menopause symptom relief, prevention of cardiovascular disease, and prevention of osteoporosis. The risk of breast cancer and endometrial (uterine) cancer was thought to be outweighed by the benefits of HRT. In the last few years, several large studies have found this to be untrue, changing the standard practice of using HRT for postmenopausal women.

The largest randomized study looking at the issue of breast cancer risk with hormone replacement therapy (HRT) is The Women's Health Initiative (WHI), a long-term (15 years) national health study sponsored by the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI). The study focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women. Over 161,000 women aged 50-79 participated in this study, which started enrolling in 1993. The study consisted of several groups (or arms); the two that pertain to this question are women taking estrogen alone (those who have had a hysterectomy), and women taking estrogen and progestin. Estrogen alone can have negative effects on uterine tissue, so any woman who still has her uterus (has not had a hysterectomy) is given progestin to counteract this estrogen effect.

The study arm that received estrogen alone was ended early (in March, 2004, after 6.8 years) because not only was there no benefit in preventing heart disease, but there was in fact an increase in blood clots and strokes. The researchers did see a trend towards fewer cases of breast cancer, but this data is uncertain and more analysis is being done. The estrogen and progestin (E+P) arm was stopped in July 2002 after 5.2 years (also earlier than planned), also because the apparent risks outweighed the benefits. Specifically, the E+P arm experienced more heart attacks, strokes, and blood clots. Furthermore, this arm had a 24% increase in cases of breast cancer (245 of the 8,506 E+P women, compared to 185 of the 8,102 women on placebo, were diagnosed with breast cancer). Although the breast cancer seen in both groups was of similar subtypes under the microscope, the E+P group had larger tumors and more advanced (later stage) breast cancers. The study will continue to follow all of the women for at least 10 more years, so more information is still to come. You can learn more about the Women's Health Initiative at http://www.nhlbi.nih.gov/whi/

In 2006, a study reported a 7% decrease in breast cancer diagnoses in 2003 (14,000 fewer cases that year) and that the decrease appeared to be due to the fact that women had stopped taking HRT after the WHI results were released. A follow up study reported that the number of cases leveled off in 2004. The decrease had been seen in women over 50 and more often in estrogen receptor positive tumors. Critics say breast cancer takes years to develop and the stopping of HRT could not be the cause. But studies have shown that a withdrawal of estrogen can actually cause estrogen receptor positive tumors to regress or shrink and may prevent undetected cancer cells from progressing. They don’t yet know if this decrease in cases will be long term or if rates will rebound several years after stopping the use of HRT.

The United Kingdom conducted a study that followed women 50-64 years of age for 5 years. These women were not randomized, but rather the researchers just observed their HRT use and health. The study was called The Million Women Study because it followed over one million women. The researchers observed a significant increase in breast cancer cases in women taking HRT, as well as an increase in deaths due to breast cancer. In 2007, this study also reported an increase in ovarian cancer among women taking HRT. They reported this risk was only while on the medication and that their risk returned to that of women who had not taken HRT when the medication was stopped. You can learn more about this study at www.millionwomenstudy.org

On a good note, a group of compounds known as Selective Estrogen Receptor Modulators (SERMS) have been studied in the prevention of breast cancer. These compounds bind to estrogen receptors (which are found in females in the tissue of the breast, uterus, brain, bone, liver, and heart). SERMS can bind to selected tissue receptors, causing either an anti-estrogen effect OR an estrogen-like effect, depending on the compound. Two commonly used SERMs are tamoxifen and raloxifene, which have an anti-estrogen effect on breast and uterine tissue but an estrogen-like effect on bone (which helps prevent osteoporosis). Both compounds have been shown in studies to decrease breast cancer risk, which led to the Study of Tamoxifen and Raloxifene (STAR) trial. This study enrolled 20,000 women at high risk for developing breast cancer.  STAR found that both medications reduced a woman’s risk of developing breast cancer by 50%. Researchers had hoped the side effects of blood clots and uterine cancer would be less with raloxifene, but the differences in uterine cancers and strokes in the participants were not statistically significant. However, there were fewer blood clots, pulmonary embolisms and cataracts in the raloxifene group, and this difference was statistically significant.

The drugs do have different side effect profiles; tamoxifen takers had more hot flashes, vaginal bleeding, leg cramps and bladder control problems and raloxifene takers had more issues with painful intercourse and joint pain. In addition, STAR found that tamoxifen may be more effective in preventing DCIS and LCIS, but the difference in this study was not statistically significant. These therapies may be an option for high risk postmenopausal women looking to reduce the risk of invasive cancer.

You can learn more about the STAR trial at http://nci.nih.gov/star

References

Chlebowski RT, et al. "Breast Cancer After Use of Estrogen plus Progestin in Postmenopausal Women." N Engl J Med 2009 Feb 5;360(6):573-587.

Ravdin, P et al. The Decrease in Breast Cancer Incidence in 2003 in the United States. The New England Journal of Medicine (2007) 356:1670-1674.

Vogel VG, Costantino JP, et al. Effects of Tamoxifen vs. Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes. Journal of the American Medical Association (2006) 295(23): 2727-2741.

Writing Group for the Women's Health Initiative Investigators. "Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women." JAMA (2002) 288:321-333.



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