Tamoxifen and other hormonal therapies for treating early stage breast cancer and preventing it


By Diana Zuckerman, Ph.D., Anna Mazzucco, Ph.D., and Brandel France de Bravo, MPH
Updated 2014

Breast cancer is the most common type of cancer in women around the world, and the second leading cause of cancer deaths among U.S. women.

Women who are diagnosed with early-stage breast cancer almost always undergo surgery to remove the cancer (either lumpectomy or mastectomy). Most will also choose at least one other treatment in addition to surgery:

1) If they have a lumpectomy, they usually undergo radiation to shrink the tumor before surgery or to kill any cancer cells in the breast that were missed during surgery;

2) About 1 in 3 women undergochemotherapy to reduce the size of the tumor before surgery or to reduce the chances of the cancer coming back after surgery.1,2 Chemotherapy is more likely for women whose tumors are larger (1 centimeter or larger), high grade, or less common or more aggressive types.

3) If their cancer is estrogen receptor positive, many women will try to take hormonal therapy for at least five years after surgery to lower the chance of cancer coming back in the future.

Types of Hormonal Therapies for Early Stage Breast Cancer

Hormonal therapy (also called hormone treatment/therapy or anti-estrogen therapy) is the opposite of the type of hormones women sometimes take to reduce the symptoms of menopause.  It lowers your estrogen levels instead of increasing them.

Hormonal therapy is recommended for most women with breast cancer, and sometimes it is taken by women who have not been diagnosed with breast cancer but are at high risk for it based on their genes or family history. When hormonal therapy is used before developing breast cancer, it is called “primary prevention” or “chemoprevention,” even though it is very different from the drugs used in chemotherapy to treat breast cancer.

Four types of hormonal therapy are FDA-approved for early-stage breast cancer treatment: tamoxifen, exemestane, letrozole, and anastrozole. Tamoxifen is also approved for preventing breast cancer in high-risk women, along with a fifth drug, raloxifene. There are other hormonal therapies that a doctor may prescribe, but they have not yet been sufficiently studied or approved by the FDA as safe and effective to either prevent breast cancer or treat early-stage breast cancer.

There are risks as well as benefits to hormonal treatment, and tamoxifen, the most widely used and studied type of hormonal treatment, is no longer considered the first choice treatment for most postmenopausal women. Some breast cancer patients experience such bad side effects from tamoxifen that they stop taking it after a few years. A study published in 2013 in the British Journal of Cancer found that 1 in 4 women didn’t complete the recommended five years of tamoxifen.3

How does Hormonal Therapy work?

Hormonal treatment for breast cancer is sometimes called “anti-estrogen therapy,” is used to starve the breast cancer cells of the hormone they thrive on, which is estrogen. Hormonal treatment is effective for women with estrogen receptor-positive breast cancer (the most common type of breast cancer) and estrogen-receptor positive ductal carcinoma in situ (DCIS), which is a type of lesion that increases a women’s risk of breast cancer. Approximately 3 out of 4 breast cancers are estrogen-receptor positive.4 Hormonal therapy is not effective for women with estrogen-receptor negative breast cancer.

There are other hormonal therapies being studied, including those for women whose cancers are fed by the hormone progesterone. These women have progesterone receptor-positive breast cancer, but most are estrogen-receptor positive as well, and can also benefit from anti-estrogen therapy.

All hormonal therapy is taken as a daily pill for a minimum of 5 years. For some types of hormonal therapy, such as tamoxifen, recent research has shown that breast cancer patients can reduce their chances of recurrence a little bit more by increasing the number of years they take the therapy.

For women with breast cancer who have already gone through menopause, hormonal therapy using aromatase inhibitors seems to be more effective than tamoxifen or raloxifene, which belong to a class of drugs known as selective estrogen receptor modulators (SERMs).  Once a woman has gone through menopause, her ovaries no longer produce estrogen but the enzyme aromatase still produces some estrogen.  Interfering with the production of estrogen is another way of starving breast cancer cells that feed off of estrogen. Since aromatase inhibitors do not block the production of estrogen from the ovaries, they are not usually used by premenopausal women. Studies are being done but it is still too early to say whether or not aromatase inhibitors should be given in addition to tamoxifen to premenopausal women with breast cancer or DCIS.5

How effective is hormonal therapy for women with early-stage breast cancer?

Tamoxifen.  A study published in 2013 in Lancet showed that taking tamoxifen for 10 years results in slightly lower recurrence rates and slightly better survival rates, compared to taking it for 5 years. This study, which followed breast cancer patients taking tamoxifen for longer than other studies, found that 25% of the women who took tamoxifen for 5 years had their cancer return within 15 years of surgery, whereas 21% of women who took tamoxifen for 10 years had a breast cancer recurrence within 15 years. Survival was also slightly better: over 81% of women who took tamoxifen for 10 years were alive 15 years after surgery compared to just under 79% of the women who took tamoxifen for only 5 years. While longer treatment with tamoxifen resulted in 2.5% more patients surviving for 15 years, it also resulted in 1.5% more women developing uterine cancer, one of the more serious risks linked to tamoxifen.6,7

Tamoxifen is the only hormonal therapy approved for use in women with DCIS. It reduces a woman’s risk of getting DCIS again or developing breast cancer in either breast.  According to a 2011 study published in the Journal of the National Cancer Institute, 10% of women treated with lumpectomy and radiation had a recurrence of DCIS or developed breast cancer in the same breast within 15 years of surgery, as compared with 8.5% in the women who also took tamoxifen. Among the women who took tamoxifen, only 7.3% developed DCIS or breast cancer in the other, previously healthy, breast whereas 10.8% of the women who didn’t take tamoxifen in addition to lumpectomy and radiation were diagnosed with DCIS or breast cancer in the other breast.8

Raloxifene. This drug was first approved to treat osteoporosis, a condition where bones become more porous and breakable, in women after menopause. In 2007, raloxifene was approved as a hormonal treatment to prevent breast cancer—not to treat it. For prevention, it works very much like tamoxifen, and is almost as effective,9 but has fewer side effects (see “Side Effects of Hormonal Therapy” below). In addition, it has the benefit of increasing bone density.

Aromatase inhibitors (exemestane, letrozole,or anastrozole). The three FDA-approved aromatase inhibitors can be used by postmenopausal women in any of the following ways: 1) they can be taken for 5 years; 2) they can be taken for 2-3 years after having taken tamoxifen for 2-3 years; or 3) they can be taken for 5 years after 5 years of tamoxifen. In general, each of the aromatase inhibitors seems to work about equally well.  Some studies have suggested that aromatase inhibitors—whether taken alone or after tamoxifen—may be more effective than tamoxifen alone at preventing cancer recurrence in postmenopausal women.  But there has not been a clear advantage for aromatase inhibitors over tamoxifen in helping breast cancer patients live longer (see below for more details).10

Aromatase inhibitors instead of tamoxifen. For example, in one study lasting almost 9 years, taking letrozole for 5 years reduced the chance of cancer recurrence more than taking tamoxifen for the same amount of time.  Of the women taking letrozole, 24% had a recurrence of breast cancer, compared to 28% of women taking tamoxifen. In addition, 85% of the women who took letrozole were alive after almost 9 years, compared to 81% of the women who took tamoxifen.11  A different study comparing another aromatase inhibitor, anastrozole, with tamoxifen also found that the aromatase inhibitor was more effective in preventing recurrence.  In that study, 30% of the women taking anastrozole had a cancer recurrence, compared to 33% of women taking tamoxifen.  However, the women who took anastrozole were not significantly more likely to be alive 9 years after surgery than the women who took tamoxifen.12

Aromatase inhibitors after tamoxifen. When used for 2-5 years after taking tamoxifen, aromatase inhibitors have been shown to prevent breast cancer recurrence more than just taking tamoxifen for 5 years.13,14 For example, 6% of women who took the aromatase inhibitor letrozole for about 30 months after 5 years of tamoxifen had a cancer recurrence, compared to 10% among women who did not take anything after tamoxifen.  Among women who took the aromatase inhibitor anastrozole for about 5 years after 5 years of tamoxifen, 8% had a cancer recurrence, compared to 12% of women who took only tamoxifen.15

However, in terms of overall survival—living longer whether or not the cancer returns—most studies have not shown a clear benefit to following tamoxifen with an aromatase inhibitor.16 Nevertheless, a few studies showed that taking both forms of hormonal therapy might help some women live longer.  For example, women with breast cancer in their lymph nodes (“lymph node-positive”) who took letrozole after taking tamoxifen reduced their chance of dying by 39% over 30 months compared to women who took tamoxifen alone.17

For now, the American Society of Clinical Oncologists advises postmenopausal women to take aromatase inhibitors, either alone or in combination with tamoxifen.18 Because some women might tolerate one drug better than another, the best treatment strategy will vary from woman to woman. This is why it is important to discuss side effects with your doctor. If side effects are making it difficult to continue taking a particular hormonal therapy, you may want to try a different one.

See the table at the end of this article for a summary of all the different hormonal therapy options.

Side effects and Risks of Hormonal Therapy

Tamoxifen increases the chances of a woman developing endometrial cancer and blood clots in legs and lungs, especially for women over 50 years of age.19,20  Women taking tamoxifen are about twice as likely to get endometrial cancer, although the overall risk is still low; about 2 women out of 1,000 taking tamoxifen will get endometrial cancer each year.21  Women taking tamoxifen are also about twice as likely to suffer blood clots; for example, in one of the longest term studies, 7% of women taking tamoxifen experienced blood clots.22  Moreover, tamoxifen therapy often causes side effects similar to those experienced in menopause, including hot flashes and irregular periods.23  In one study, 41% of women taking tamoxifen experienced hot flashes, and 10% experienced vaginal bleeding.24

 Like tamoxifen,  Raloxifene increases the risk of blood clots, but it does not increase a woman’s risk of endometrial cancer the way tamoxifen does.

Aromatase inhibitors increase the risk for osteoporosis compared with tamoxifen or taking no hormonal therapy at all.  Exemestane, a commonly used aromatase inhibitor (brand name Aromasin), also increases the risk for visual disturbances, joint pain, an allergic reaction to medication, or diarrhea.  In one of the longest term studies, almost 19% of women experienced joint pain while taking exemestane.25

In very rare cases, the side effects of hormonal therapy can be fatal or can harm a patient’s quality of life.  Close monitoring of women for symptoms, such as abnormal uterine bleeding, is needed, and women taking tamoxifen should receive annual pelvic exams.26

Different women respond differently to the various forms of hormonal therapy, which is why it is not uncommon for women to switch to different hormonal treatments after starting.

Too little of one hormone (melatonin) may interfere with hormonal therapy

Exposure to light and insufficient night time sleep lower the amount of melatonin produced, and melatonin helps prevent breast tumors from growing.  In a 2014 study on rats, scientists showed that sleep disruptions (due to poor sleep or night shift work) and exposure to light at night can make tamoxifen less effective at blocking estrogen.27  Breast cancer patients taking tamoxifen (and possibly other hormonal therapies) should avoid work and light at night when possible using light blocking curtains and/or a sleep mask (see our article on sleep masks and health here).

Hormonal therapy to prevent breast cancer in women at high risk (primary prevention)

While the oldest form of hormonal therapy, tamoxifen, and its newer cousin, raloxifene are the only drugs approved to prevent breast cancer in women who’ve never had the disease but are at high risk, early results from long-term studies suggest that aromatase inhibitors are also effective at preventing breast cancer in postmenopausal women.28 Studies are underway to see if aromatase inhibitors can be used to prevent breast cancer in premenopausal women as well, but it is likely that they would have to be used in combination with other drugs to temporarily stop ovarian function.

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