Tamoxifen and Uterine Cancer

The widely prescribed drug tamoxifen has been extending breast cancer patient’s lives since its approval by the FDA in 1977. In this article, we’ll explore the potential risks of tamoxifen in causing uterine cancer, particularly:

• How tamoxifen may increase uterine cancer risks,
• How quickly can tamoxifen cause uterine cancer and
• Strategies to mitigate these risks.

Tamoxifen is a drug designed to mimic estrogen, a hormone that promotes the growth of certain types of breast cancer cells. It acts by blocking estrogen’s ability to promote tumor growth in the breast.

Primarily, tamoxifen is used to treat estrogen-positive breast cancer and prevent it from recurring. Now, women at high-risk of invasive breast cancer can also take tamoxifen as chemoprevention, with a goal of minimizing the risk of the development of breast cancer. By blocking estrogen, the drug helps to slow or even stop the growth of cancer cells.

Like many other drugs, tamoxifen does present certain risks and side effects.

One concern is that tamoxifen slightly increases the chance of a woman developing endometrial cancer and uterine sarcoma, two subtypes of uterine cancer. This risk comes from tamoxifen’s estrogen-like effects on the endometrial lining as it may stimulate growth and potentially lead to malignancy, especially in postmenopausal women.

Learn more: Types of Uterine Cancer

Tamoxifen, while inhibiting breast cancer cells, activates or stimulates uterine cells. It promotes the growth of these cells, causing the endometrial lining to thicken. This increases the risk of developing benign endometrial polyps, hyperplasia and potentially, cancer.

Although benign endometrial polyps and hyperplasia are not cancerous, they are risk factors for uterine cancer. Some polyps may turn cancerous and it is more common in postmenopausal women. Overall, the risk of developing changes in the uterine wall, such as benign endometrial polyps, hyperplasia and cancer, within four years of tamoxifen use is 67%, although polyps are the most likely type of change a woman would experience.

Scientists have followed patients on tamoxifen for up to 10 years. They found that the risk is slightly higher in those who have been taking the drugs for extended periods. In the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, researchers studied women who continued tamoxifen for an extra five years beyond the standard five-year course.

For postmenopausal women taking tamoxifen for five years, their risk of developing uterine cancer over 15 years is only about 2–3%; however, the chance of dying from this cancer is extremely low because it is typically caught early and treated effectively.

Extending the use of tamoxifen to ten years increases the risk a bit more, by another 2% over 15 years. Still, the chance of dying from it remains very small.

Women who have not gone through menopause face little to no risk of developing uterine cancer from tamoxifen. They also face fewer side effects from it. Women who have undergone a hysterectomy will not have these risks.

Tamoxifen is effective for those with ER-positive breast cancer, significantly reducing both the rates of recurrence and death. Scientists have estimated that the drug can lower the risk of death from ER-positive breast cancer by as much as 50%.

The ATLAS study highlights the benefits of prolonged tamoxifen use. The extra years of tamoxifen provide even more protection against breast cancer. For many, the benefits of tamoxifen indeed outweigh its potential risks.

Although it may elevate the risks of uterine cancer among these individuals, there are ways to manage these risks. Importantly, the added risk associated with tamoxifen use goes back to normal within a few years after stopping the drug.

During the decision-making process, the American College of Obstetrician and Gynecologists (ACOG) offers the following recommendations for doctors regarding tamoxifen’s risks for uterine cancer:

1. Inform all women taking tamoxifen about the slight risk of developing uterine cancer, including the precancerous form (endometrial hyperplasia), endometrial cancer and uterine sarcomas.
2. Encourage them to promptly report any unusual vaginal symptoms like bloody discharge, spotting or staining. Investigate these symptoms.
3. Provide routine gynecologic care without additional monitoring for premenopausal women on tamoxifen.
4. Avoid routine screenings for uterine cancer, like transvaginal ultrasounds or biopsies, for women on tamoxifen unless they are at high risk. These screenings may lead to more invasive and costly procedures.
5. Closely monitor postmenopausal women on tamoxifen for signs of endometrial hyperplasia and cancer. Alternatively, they could be treated with aromatase inhibitors.
6. Consider screening postmenopausal women for benign endometrial polyps before starting tamoxifen therapy, as these women tend to develop endometrial hyperplasia. Employ screening methods such as transvaginal ultrasound and sonohysterography.
7. If endometrial hyperplasia develops, provide appropriate gynecologic care and reassess the patient’s risks for uterine cancer. If the patient accepts the risks and decides to continue tamoxifen therapy, thoughtfully consider a hysterectomy for uterine cancer with her. After the hysterectomy, doctors may reinstitute tamoxifen in consultation with the breast care team.
8. Otherwise, extend tamoxifen treatment to 10 years, as it provides additional benefits.

Alternatively, raloxifene (EVISTA®) is another estrogen-like drug that is as effective as tamoxifen at reducing the risk of breast cancer. It triggers fewer uterine cancers. It is approved for risk reduction (chemoprevention) of invasive breast cancer in postmenopausal women.

Aromatase inhibitors are another class of breast cancer drugs for postmenopausal women. Differing from tamoxifen and raloxifene, they work by lowering the production of estrogen in the body. They are often alternatives to tamoxifen. Examples of aromatase inhibitors are anastrozole (Arimidex®), letrozole (Femara®) and exemestane (Aromasin®).