Letrozole (Femara) for Breast Cancer: Why It’s Recommended, How It Works, and What to Expect

By Sarah Friend, MD

If you’ve been diagnosed with estrogen receptor-positive (ER+) breast cancer or ductal carcinoma in situ (DCIS), there’s a good chance you’ll hear your oncologist talk about endocrine therapy, also called hormone-blocking or hormone therapy.

Letrozole, also known by the brand name Femara, is one of these medications. Letrozole belongs to a class of hormone-blocking medications called aromatase inhibitors (AIs). Other commonly used aromatase inhibitors include anastrozole (Arimidex) and exemestane (Aromasin).

Unlike chemotherapy, letrozole does not directly attack rapidly dividing cells. Instead, it dramatically lowers the amount of estrogen available to stimulate ER+ breast cancer cells.

Aromatase inhibitors are used across the spectrum of ER+ breast disease, from DCIS (stage 0) through early-stage invasive breast cancer and metastatic breast cancer. However, the reason for taking hormone-blocking therapy differs depending on the stage of disease.

Why Is Letrozole Recommended?

ER+ breast cancer cells use estrogen as a growth signal. By lowering estrogen levels, letrozole essentially takes away one of the cancer cell’s major sources of fuel.

Stage 0 (DCIS): Reducing the Risk of a Future Breast Cancer Event

Ductal carcinoma in situ (DCIS) is considered stage 0 because the abnormal cells remain contained within the breast ducts and have not invaded the surrounding breast tissue.

For postmenopausal patients with ER+ DCIS, hormone-blocking (endocrine) therapy with an aromatase inhibitor may be recommended after treatment to reduce the chance of having another breast cancer event.

Importantly, hormone-blocking therapy for DCIS has not been shown to improve survival, since survival after DCIS is already excellent.

Instead, the benefit is primarily about risk reduction.

Endocrine therapy can lower the chance of the DCIS returning in the treated breast. A recurrence could occur as another area of DCIS or as invasive breast cancer. It can also lower the risk of developing a new ER+ DCIS or invasive breast cancer in the opposite breast.

This distinction is important because the decision to take hormone-blocking therapy after DCIS is different from the decision after invasive breast cancer. With DCIS, you and your doctor are weighing a reduction in the risk of future breast cancer events against the potential side effects of taking the medication.

Stages I–III: Reducing the Risk of Recurrence

For people who have been treated for stages I–III ER+ invasive breast cancer, letrozole is most commonly given as adjuvant endocrine (hormone-blocking) therapy. “Adjuvant” simply means treatment given after surgery. The goal is to lower the chance that breast cancer will return in the future.

Less commonly, an aromatase inhibitor such as letrozole may be used as neoadjuvant endocrine therapy. “Neoadjuvant” means treatment given before surgery, often with the goal of shrinking the tumor before it is removed. In this setting, the goal is usually cytoreduction (shrinkage of the tumor before surgery), potentially making surgery easier or allowing for a less extensive operation. For selected postmenopausal patients with strongly hormone receptor-positive breast cancer, this approach may be particularly useful when tumor shrinkage before surgery is recommended and can provide an alternative to neoadjuvant chemotherapy for appropriate patients.

Whether given before or after surgery, endocrine therapy works by depriving ER+ breast cancer cells of the estrogen signals that can help them grow.

For stages I–III ER+ invasive breast cancer, endocrine therapy can reduce the relative risk of breast cancer recurrence by approximately 50%, although the benefit for an individual person depends on their original risk of recurrence and other characteristics of their cancer.

That distinction is important.

If someone’s baseline recurrence risk were 20%, reducing that risk by approximately half could potentially bring it closer to 10%. If someone’s original risk were much lower, the absolute benefit would naturally be smaller.

Endocrine therapy also reduces the risk of developing a new hormone receptor-positive breast cancer in the opposite breast.

This substantial reduction in recurrence risk is one reason oncologists strongly encourage patients to stay on hormone-blocking therapy when possible.

For many patients, letrozole may be the only additional medication needed. For some people with higher-risk stage II or III disease, however, an aromatase inhibitor may be combined for a period of time with another medication, such as a CDK4/6 inhibitor.

Stage IV: Controlling Cancer While Often Avoiding Chemotherapy

For metastatic, or stage IV, ER+ breast cancer, the goal is different. Treatment is designed to control the cancer, slow its progression, maintain quality of life, and help people live longer.

Endocrine therapy allows many patients with ER+ metastatic breast cancer to control their disease without immediately needing traditional chemotherapy.

Today, an aromatase inhibitor such as letrozole is commonly paired with a CDK4/6 inhibitor as an initial treatment for appropriate patients with metastatic ER+/HER2-negative breast cancer. These combinations have substantially changed the treatment of metastatic hormone receptor-positive breast cancer.

How Does Letrozole Work?

After menopause, the ovaries are no longer the body’s primary source of estrogen. However, the body can still make small amounts of estrogen through other tissues and hormone pathways.

An enzyme called aromatase converts certain hormones called androgens into estrogen. This peripheral estrogen production occurs in tissues throughout the body, including fat tissue, using androgens produced by the adrenal glands.

Letrozole blocks the aromatase enzyme, dramatically reducing estrogen production from these non-ovarian sources.

Think of aromatase as part of an estrogen-producing factory. Letrozole essentially shuts down the machinery.

Why Is Letrozole Usually Used After Menopause?

This mechanism also explains why aromatase inhibitors are generally used in postmenopausal women.

Letrozole is very effective at blocking peripheral estrogen production, but it cannot reliably shut down estrogen production from functioning ovaries.

For a premenopausal patient, an oncologist may therefore recommend ovarian suppression if an aromatase inhibitor is considered the best endocrine therapy.

This can be accomplished with medications such as Lupron (leuprolide), often given as an injection monthly or every three months, or through surgical removal of the ovaries and fallopian tubes, called a bilateral salpingo-oophorectomy (BSO).

Once ovarian estrogen production is adequately suppressed, an aromatase inhibitor can be used.

What Are the Side Effects of Letrozole?

Many people tolerate letrozole very well and have few or even no significant side effects. Others notice symptoms that affect their quality of life.

Because letrozole lowers estrogen levels throughout the body, many of its side effects resemble or intensify symptoms associated with menopause.

Common Side Effects

Joint, muscle, and bone aches or stiffness

This is one of the most commonly reported side effects of aromatase inhibitors. Discomfort may be particularly noticeable in the hands, wrists, knees, ankles, or feet and can sometimes feel worse after periods of inactivity or first thing in the morning.

Hot flashes and night sweats

Lower estrogen levels can cause or worsen hot flashes and other menopausal symptoms.

Vaginal dryness and genitourinary symptoms

Some people develop vaginal dryness, irritation, discomfort with intercourse, urinary symptoms, or recurrent urinary tract infections. These symptoms are important to discuss with your healthcare team because there may be ways to improve them.

Bone loss (osteopenia or osteoporosis)

Estrogen plays an important role in maintaining bone strength, so lowering estrogen with letrozole can gradually decrease bone density and increase the risk of osteoporosis and fractures.

If you are starting or taking an aromatase inhibitor, talk with your healthcare team about your bone health and whether you should have a DEXA (bone density) scan, both at baseline and periodically during treatment when appropriate.

It is also worth discussing whether your vitamin D level should be checked and whether you are getting adequate vitamin D and calcium. Regular weight-bearing and resistance exercise can help maintain bone strength and has many additional health benefits for breast cancer survivors.

For patients who develop significant bone loss or are at higher risk for fracture, your oncology team may also discuss medications that help protect and strengthen the bones.

Hair thinning

Some patients notice gradual thinning or changes in the texture of their hair. This is different from the more dramatic hair loss commonly associated with certain chemotherapy treatments.

Changes in cholesterol

Letrozole can increase cholesterol levels in some people, so periodic cholesterol monitoring may be recommended.

Fatigue

Some patients experience increased tiredness or lower energy while taking an aromatase inhibitor.

Headache or dizziness

These can occur, although they are not usually severe.

Digestive symptoms

Nausea, indigestion, constipation, diarrhea, or changes in appetite can occasionally occur.

Changes in mood or sleep

Some patients report difficulty sleeping, mood changes, or symptoms of depression or anxiety. Many factors can contribute to these symptoms during and after breast cancer treatment, so it is worth discussing significant changes with your healthcare team rather than assuming they are simply something you have to tolerate.

Swelling

Mild swelling of the hands, feet, ankles, or lower legs can occasionally occur.

What If I Can’t Tolerate Letrozole?

This is one of the most important conversations to have with your oncology team.

Most oncologists strongly encourage patients with ER+ invasive breast cancer to remain on endocrine therapy when possible because of its substantial ability to reduce the risk of recurrence. But staying on endocrine therapy does not necessarily mean staying on the exact same medication regardless of how you feel.

If letrozole is causing significant side effects, there may be several options.

Your oncologist may recommend treating the particular side effect, temporarily holding the medication in selected circumstances, or switching to another aromatase inhibitor, such as anastrozole (Arimidex) or exemestane (Aromasin).

Patients sometimes ask:

“If they’re all aromatase inhibitors, why would switching make any difference?”

Surprisingly, it can.

This concept is often referred to as a switching strategy. Some patients who experience troublesome side effects on one aromatase inhibitor tolerate another medication in the same class much better.

A familiar analogy is what sometimes happens with statin medications used for cholesterol. One statin may cause significant muscle aches, while another statin—or a different dose—may be much easier for the same person to tolerate.

A similar phenomenon can occur with aromatase inhibitors.

So having difficulty with letrozole does not necessarily mean you will have the same experience with every aromatase inhibitor.

What About Switching From Letrozole to Tamoxifen?

Another option may be tamoxifen, which is also an endocrine or hormone-blocking therapy but works differently from an aromatase inhibitor.

For postmenopausal women with invasive ER+ breast cancer, aromatase inhibitors generally provide a modest efficacy advantage over tamoxifen in reducing breast cancer recurrence, but tamoxifen has a different side-effect profile and may be considerably easier for some patients to tolerate.

Importantly, endocrine therapy doesn’t always have to be an “all or nothing” decision.

Large clinical trials have studied sequential or switching strategies, in which patients receive one type of endocrine therapy for part of their treatment and then switch to another. These studies support the concept that a patient does not necessarily need to take the same endocrine medication for the entire treatment period.

Therefore, if you’ve already taken an aromatase inhibitor for a period of time and side effects are becoming difficult, don’t simply assume your only choices are to suffer through it or stop endocrine therapy altogether.

Talk with your oncologist about your options.

How Long Will I Need to Take Letrozole?

For stages I–III breast cancer, endocrine therapy is commonly recommended for at least five years, although some people may benefit from a longer duration based on their recurrence risk, lymph node involvement, previous treatments, bone health, side effects, and personal preferences.

The entire treatment course does not necessarily have to consist of the same medication. Depending on an individual’s circumstances and tolerance, a treatment plan may include more than one type of endocrine therapy over those years.

For stage IV breast cancer, endocrine-based therapy is generally continued as long as it is controlling the cancer and the treatment remains tolerable, although the specific medications may change over time.

The Bottom Line

Letrozole (Femara) is an important hormone-blocking medication used in the treatment of ER+ breast cancer.

For ER+ DCIS (stage 0), endocrine therapy can reduce the risk of another DCIS or invasive breast cancer event, although it has not been shown to improve survival, since survival after DCIS is already excellent.

For stages I–III invasive ER+ breast cancer, endocrine therapy can dramatically lower the risk that breast cancer will return. In selected patients, it can also be given before surgery to help shrink the cancer and may provide an alternative to chemotherapy when cytoreduction is needed.

For stage IV ER+ breast cancer, endocrine-based treatment can help control cancer—often for meaningful periods of time—while allowing many patients to delay or avoid traditional chemotherapy.

Many patients do very well on letrozole. But if you’re struggling with side effects, tell your oncology team.

The goal isn’t simply to prescribe a medication. The goal is to find an endocrine therapy strategy that provides meaningful protection against breast cancer and that you can realistically live with.

Sometimes that means continuing letrozole. Sometimes it means addressing a particular side effect or switching to another aromatase inhibitor. And sometimes it means discussing tamoxifen or another endocrine strategy.

There is often more than one way to get to the goal.

This article is for educational and supportive purposes only and is not intended to provide medical advice, diagnosis, or treatment. Treatment decisions should be made with your licensed oncology team based on your individual diagnosis and circumstances.

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