Tamoxifen for Breast Cancer Recurrence Prevention

tamoxifen pills on nightstand used for breast cancer
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Tamoxifen, also known by the brand name Nolvadex, is one of the more commonly prescribed medications used to prevent breast cancer recurrence. When used appropriately, it may reduce the risk of breast cancer coming back by roughly 50 percent. The drug may also be used to reduce the chance that certain women will develop breast cancer in the first place, or to slow the growth of metastatic breast cancer.

Tamoxifen is a medication with both anti-estrogen and estrogen-like effects, depending on the particular type of tissue it affects. It is classified as a selective estrogen receptor modulator (SERM), along with the medication Evista (raloxifene), and considered over aromatase inhibitors (AIs) in several cases.

Indications

There are three primary uses for tamoxifen:

  • In women and men diagnosed with estrogen receptor-positive early-stage breast cancer after surgery, chemotherapy, and/or radiation to reduce the risk of recurrence
  • In women and men diagnosed with hormone receptor-positive advanced stage or metastatic breast cancer
  • For primary breast cancer prevention in those at an increased risk of developing the disease (a.k.a. cancer previvors)

Tamoxifen is usually not considered beneficial for those who have estrogen- or progesterone-negative breast cancer. If your cancer is estrogen receptor- as well as HER2-positive, your doctor may recommend tamoxifen (or an aromatase inhibitor), a HER2-targeted medication such as Herceptin, or both, depending on your specific situation.

Tamoxifen comes in 10 milligram (mg) and 20 mg tablets, with the most common dose being 20 mg once daily. It is usually taken daily for five to 10 years or until a person switches over to an aromatase inhibitor.

Benefits

Tamoxifen was approved in 1998 and has since been found effective in treating breast cancer for millions of people. It is still considered an excellent option if you are premenopausal or are postmenopausal and cannot take an aromatase inhibitor.

When used after primary treatment (e.g., surgery), it may reduce your risk of breast cancer recurrence by half if your tumor was estrogen receptor-positive. The drug continues to have this benefit even after you stop taking it.

It can also reduce your risk of developing another cancer in the same breast or a new cancer in your other breast by up to 50 percent.

In contrast to its anti-estrogen effects on breast tissue, tamoxifen has estrogen-like effects on bone. Therefore tamoxifen (as well as Evista) may help slow or stop bone loss. Tamoxifen may also lower cholesterol levels, specifically LDL cholesterol.

How It Works

Estrogen receptor-positive breast cancer cells are fed by estrogen. Estrogen in the body binds to proteins on the surface of these cells (estrogen receptors) to signal the cell to divide and grow. Tamoxifen binds to this receptor, essentially starving the cancer cells.

Tamoxifen is broken down into a metabolite called endoxifen by the cytochrome P450 enzyme CYP2D6. (There are also other enzymes such as CYP3A4, but CYP2D6 is likely most significant.) Endoxifen is 30 to 100 times more effective in suppressing estrogen-related cell growth than tamoxifen, and is the principal compound responsible for its effects. You may hear tamoxifen referred to as a "pro-drug" for this reason.

Anything that reduces the activity of CYP2D6 can result in a reduced amount of the active metabolite. Reduced activity of the enzyme may occur if you are taking other medications or if you have particular genetic variations that make the enzyme less active.

The Impact of Your Genetics

There is a spectrum of activity of the CYP2D6 enzyme, and this results in differences in the metabolism of drugs. A review of studies found that extensive metabolizers appear to have better outcomes than poor metabolizers. Overall, roughly 20 percent of people have reduced activity of this enzyme.

There are commercial genotyping kit tests available for the genotyping of CYP2D6, but this testing is not ordinarily done for women on tamoxifen therapy for estrogen receptor-positive breast cancer. In other words, you probably won't know if this issue applies to you.

This is an area of controversy as well, and some researchers believe that the presence of another enzyme, CYP3A4*22, might compensate for the reduction of endoxifen concentrations related to low CYP2D6 activity.

A 2019 study published in the Journal of Clinical Oncology may be reassuring to those who wonder if they are poor metabolizers. In this study, the researchers found no association between CYP2D6 genotypes or endoxifen concentrations and the clinical outcomes of people with early-stage breast cancer who were treated with tamoxifen.

It's worth noting that the activity of CYP2D6 tends to be higher in the summer months (it's dependent on vitamin D to some degree), and vitamin D testing is important for women living with breast cancer.

Tamoxifen vs. Aromatase Inhibitors

Aromatase inhibitors are also used to prevent breast cancer recurrence. Drugs in this class include Aromasin (exemestane), Arimidex (anastrozole), and Femara (letrozole). There are several differences between these drugs and tamoxifen, which dictate who can benefit from them and what risks they carry.

Effectiveness in Premenopausal Women

In premenopausal women, the majority of estrogen in the body is produced by the ovaries. After menopause, the conversion of androgens (produced in the adrenal glands) to estrogen is the primary source of estrogen. Aromatase inhibitors work by blocking this conversion, hence reducing estrogen levels.

Since aromatase inhibitors do not address estrogen produced by the ovaries, they are ineffective before menopause unless a woman has received ovarian suppression therapy. This, however, is not the case with tamoxifen.

Risk of Recurrence

For women who are postmenopausal or those who are premenopausal and have received ovarian suppression therapy, an aromatase inhibitor may offer greater benefits in reducing the risk of recurrence. This is one reason why oncologists may recommend switching to an aromatase inhibitor when you reach menopause, or treating you with ovarian suppression therapy to induce menopause.

Bone Loss

Aromatase inhibitors also cause menopausal symptoms but can accelerate bone loss rather than reduce it like tamoxifen. Bone and joint pain can occur with either class of drugs, but are much more common with aromatase inhibitors.

Cost

With respect to cost, tamoxifen therapy is usually much less expensive than any of the aromatase inhibitors.

Side Effects

Many of the common side effects of tamoxifen are essentially the same as those that occur during menopause, when there is a reduced amount of estrogen in the body.

Common side effects of tamoxifen include:

  • Hot flashes
  • Night sweats
  • Vaginal dryness
  • Vaginal discharge
  • Reduced libido

Hot flashes are actually linked with better survival from breast cancer.

Risks

Tamoxifen's actions on endometrial tissue can raise the risk of uterine cancer. This risk is dependent on the length of time you are on the drug. The risk is highest for women over the age of 50, but is still less than 1 percent.

Tamoxifen can also increase your risk of developing blood clots either in your legs (deep vein thrombosis) or lungs (pulmonary embolism). It's not certain at this time, but tamoxifen may also increase the risk of heart attack or stroke.

It's important to call your doctor if you have any symptoms you are concerned about, especially:

  • Abnormal vaginal bleeding
  • Pain in your pelvis
  • Leg pain and/or swelling
  • Chest pain
  • Shortness of breath
  • Weakness, numbness, or tingling
  • Vision problems


Interactions and Contraindications

As with many medications, there are situations in which tamoxifen should not be used or where caution is needed.

Due to the way in which it is metabolized, tamoxifen may interact with both some common prescription and over-the-counter medications. Talk to your doctor about any other medications you use and make sure your pharmacist is aware as well. In particular, several antidepressants, as well as over-the-counter allergy medications, may reduce the effectiveness of tamoxifen.

Due to a relatively high rate of birth defects, tamoxifen should not be used in pregnancy, and the drug should be stopped at least two months before trying to get pregnant.

How Long You Should Take It

Based on clear evidence from two large randomized phase III clinical studies (ATLAS and aTTom), a 10-year rather than a 5-year adjuvant treatment with tamoxifen is associated with a smaller risk of recurrence and a reduction in breast cancer mortality.

This reduction in breast cancer recurrence must be weighed against potential side effects for each person. For example, if your cancer has a relatively high risk of recurrence (such as if lymph nodes are positive), the benefit of longer treatment may clearly outweigh the risk. In contrast, if your tumor has a very low risk of recurrence, the potential adverse effects of tamoxifen (such as blood clots) may outweigh the potential benefit.

A Word From Verywell

Tamoxifen can be a lifesaver for some women with breast cancer. As with all medications, however, there are potential risks and side effects. Working closely with your doctor while you are on this drug will ensure you catch any problems that may arise.

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