What to Know About Tamoxifen and the Risk of Uterine Cancer

Tamoxifen is a selective estrogen receptor modulator (SERM). Depending on the tissue, it can either block or stimulate estrogen receptors.

You take tamoxifen orally. It can come in the form of a tablet or as an oral solution. The brand names for tamoxifen include Nolvadex and Soltamox.

Tamoxifen is used to treat or prevent breast cancer in a variety of settings. It does this by inhibiting the hormone estrogen from binding to its receptors in breast tissue.

Tamoxifen is approved by the Food and Drug Administration (FDA) for the following uses:

• to treat metastatic breast cancer that’s estrogen receptor (ER)-positive
• to treat early ER-positive breast cancer after breast cancer surgery
• to lower the risk of breast cancer after surgery for ductal carcinoma in situ (DCIS), an early, noninvasive form of breast cancer
• to help prevent breast cancer in women who have a higher breast cancer risk

Tamoxifen is taken over a period of several years. Most people will take it for 5–10 years.

There are also several off-label uses for tamoxifen. Some examples include inducing ovulation for treating infertility and treating gynecomastia, an enlargement of the breast tissue in males.

While tamoxifen inhibits estrogen activity in breast tissue, it can stimulate estrogen receptors in other parts of the body, including the uterus.

Estrogen can prompt cells in the lining of your uterus (the endometrium) to multiply. Over time, increased estrogen activity may increase your risk of developing uterine cancer.

Various studies have estimated that tamoxifen users have a 1.5- to 6.9-fold higher risk of endometrial cancer, the most common type of uterine cancer. It also increases the risk of uterine sarcoma, a rarer kind of uterine cancer.

A 2023 review of research reports that a higher dosage and longer duration of tamoxifen use are associated with a higher endometrial cancer risk. Endometrial cancer risk may also be higher in younger tamoxifen users than in those that are older.

While taking tamoxifen can increase your risk of uterine cancer, tamoxifen-associated cancers are still uncommon. For example, the risk of developing endometrial cancer due to tamoxifen is about 1 in 500.

A recent study from 2022 that included over 78,000 premenopausal participants found that women who had taken tamoxifen to treat breast cancer had a significantly increased risk of endometrial hyperplasia, polyps, carcinoma, and other uterine cancers compared with those who were not treated with tamoxifen.

People who develop tamoxifen-associated uterine cancer can sometimes have a poorer outlook. This is because uterine cancers that are associated with tamoxifen can be more aggressive or may be diagnosed at later stages.

The duration of tamoxifen use can also play a role. Generally speaking, people who take tamoxifen for longer may not have as good an outlook if they do develop uterine cancer.

Research from 2000 found that the 3-year endometrial cancer survival was 76% for those who used tamoxifen for 5 years or more, compared with 85% for people that used it for 2–5 years and 94% for those who had never used it.

For many people, the benefits of tamoxifen far outweigh its risks. For example, the ACS notes that preventive drugs for breast cancer, such as tamoxifen, can reduce the risk of breast cancer in high risk individuals by about 40%.

Additionally, a 2013 study found that in the 5–14 years after starting tamoxifen, the risk of:

• death due to breast cancer was 15% and 12.2% in those who took the drug for 5 and 10 years, respectively
• breast cancer recurrence was 25.1% and 21.4% in individuals who took tamoxifen for 5 and 10 years, respectively
• endometrial cancer was 1.6% and 3.1% in those taking tamoxifen for 5 years and 10 years, respectively

For people with additional risk factors for developing uterine cancer, the risks of tamoxifen may not be OK for them. It’s important to discuss the risks and benefits of tamoxifen with your oncologist and healthcare team.

What are the side effects of tamoxifen?

Some of the common side effects of tamoxifen include:

• hot flashes
• vaginal discharge
• changes in mood
• irregular periods
• nausea
• fluid retention

In addition to an increased risk of uterine cancer, tamoxifen has other possible serious side effects, such as:

• deep vein thrombosis (DVT)
• pulmonary embolism (PE)
• stroke
• problems with the eyes
• problems with the liver

What are other risk factors for uterine cancer?

In addition to taking tamoxifen, other risk factors for uterine cancer include:

• older age
• a family history of uterine cancer
• a personal history of breast cancer or ovarian cancer
• endometrial hyperplasia
• other factors affecting estrogen levels, such as:
  • using estrogen-only hormone replacement therapy
  • having polycystic ovary syndrome (PCOS) or certain types of ovarian tumors
  • starting your period early or undergoing menopause later
  • never being pregnant
• health conditions like obesity and type 2 diabetes
• previous radiation therapy to the pelvic area

What’s the outlook for uterine cancer?

Your outlook can depend on many factors, such as the type of cancer, its stage, and your age and overall health.

According to the SEER database of the National Cancer Institute, the overall 5-year survival rate for uterine cancer is 81%. This means that 81% of people with uterine cancer are alive 5 years after diagnosis.

People who are taking or have taken tamoxifen are at a higher risk for developing uterine cancer. These cancers may be more aggressive or diagnosed at later stages than uterine cancers in someone who has never taken tamoxifen.

But generally speaking, tamoxifen-associated uterine cancers are still uncommon. The benefits of tamoxifen may outweigh its risks for some people.

If tamoxifen is part of your breast cancer treatment plan, be sure to discuss its associated risks with your oncologist.