Research studies have compared tamoxifen with aromatase inhibitors (AIs) such as letrozole (brand name: Femara) as adjuvant therapy (after surgery) in early stage breast cancer when taken for five years. Results have shown that AIs are better than tamoxifen treatment in prolonging the time until a breast cancer comes back or having breast cancer spread in the body.

There is also a benefit to switching to an AI after 2 or 3 years on tamoxifen, or continuing an AI after 5 years of tamoxifen treatment (rather than stopping treatment altogether). However, there is no benefit to switching compared to using letrozole alone for 5 years; however, switching may be a reasonable option for patients who experience intolerable side effects with either drug.

Some women may benefit from extended therapy past 5 years based on risk of disease recurrence, side effects and previous treatments. The American Society of Clinical Oncology (ASCO) recommends that for women on extended AI therapy, 10 years should be the maximum duration of therapy, based on their 2019 clinical practice guideline update.

Deciding to extended AI therapy should be a shared decision based on risk of disease recurrence, drug side effects, disease status (node-positive/negative disease), and patient preference. Longer duration of AI use has been associated with increased bone fractures and heart side effects, as well as treatment discontinuation.

Treatment with an AI should be discontinued if breast cancer returns.

What is hormonal therapy?

Hormonal therapy (also called endocrine therapy) helps to prevent the growth of breast cancer cells that depend on hormones. Medicines used in this type of adjuvant treatment are typically the selective estrogen receptor modulators (SERMs), like tamoxifen, or aromatase inhibitors (AIs), such as Femara.

These agents block the ability of estrogen to fuel breast cancer growth, helping to prevent a recurrence. Hormone therapy is now standard treatment and has been shown to reduce the risk of recurrence and death from breast cancer in hormone receptor-positive women. These are oral medications taken as a daily pill for 5 to 10 years.

How is Femara used in early breast cancer treatment?

Femara, an aromatase inhibitor from Novartis, was approved by the FDA in 1997. Femara tablets work by reducing the amount of estrogen in postmenopausal women. Aromasin (generic name: exemestane) and Arimidex (generic name: anastrozole) are other aromatase inhibitors.

Femara is used to treat postmenopausal women to:

• reduce the risk of early-stage, hormone-receptor-positive breast cancer coming back after surgery and other treatments
• reduce the risk of early-stage, hormone-receptor-positive breast cancer coming back after 5 years of tamoxifen
• treat advanced-stage, hormone-receptor-positive breast cancer.

What did clinical studies with Femara find?

Studies with letrozole (Femara) and other AIs have shown that AI treatment used alone provides a significant improvement in time living without a recurrence of breast cancer and time without the breast cancer spreading.

BIG 1-98 trial

Two large studies have shown the benefits of Femara. In the BIG 1-98 trial, started in 1998, over 8,000 postmenopausal women with hormone-receptor-positive, early-stage breast cancer were enrolled to compare the use of Femara to tamoxifen for 5 years after surgery. This study looked at adjuvant treatment of early breast cancer.

The results showed that Femara was better than tamoxifen for:

• increasing the time before the cancer comes back in those who experience recurrence
• reducing the risk of the cancer spreading to other parts of the body.

Disease-free survival is the time after starting treatment when there is no sign of cancer returning. In the BIG 1-98 trial, 73.8% of women who received letrozole alone had a disease-free survival at 8 years, compared to 70.4% of women who received tamoxifen alone.

In addition, in some women, when either 2 years of letrozole was followed by 3 years of tamoxifen treatment, or 2 years of tamoxifen was followed by 3 years of letrozole, there was no difference in results when compared to using letrozole alone.

MA-17 study

In the MA-17 study, over 5,100 postmenopausal women with HR+, early-stage breast cancer were evaluated to see if taking Femara for 5 years after having already taken 5 years of tamoxifen treatment (for a total of 10 years of hormonal therapy) could lower the risk of cancer recurrence. This is called extended adjuvant treatment.

In the MA-17 study, over 5,100 postmenopausal women were evaluated to see if taking Femara for 5 years after taking tamoxifen had a benefit. Women had receptor-positive or unknown primary breast cancer and were disease free after 5 years of treatment with tamoxifen. Women received an additional 24 months of treatment with Femara or placebo (inactive treatment). Results showed that Femara, when compared to the placebo group, lengthened disease-free survival by 42% (the time before the cancer returned) and reduced the time before the cancer spread in the body.

Femara reduced the risk of the cancer coming back and reduced the risk of the cancer spreading to the opposite breast (when compared to not taking Femara) after using 5 years of tamoxifen.

The MA-17 study was planned to go for 5 years, but was stopped early at roughly 24 months due to a strong positive benefit with Femara compared to placebo. Over 60% of women in the study taking the placebo switched over to Femara.

MA-17R study

The follow-up to MA-17 was the MA-17R study in about 2,000 postmenopausal women with HR+ early breast cancer. Results show that extending aromatose inhibitor adjuvant therapy to 10 years can increase disease-free survival (95% in the letrozole group compared to 91% in the placebo group). Lower yearly rates of breast cancer occurring in the opposite breast were also seen in the letrozole group.

However, extending letrozole therapy to 10 years came with side effects. Women who took letrozole had more bone pain, bone fractures, and osteoporosis diagnoses than women who took placebo.

Locally Advanced or Metastatic Breast Cancer

In advanced (locally spread or metastatic) breast cancer in 916 postmenopausal women, Femara as a first-line treatment was shown to be more effective than tamoxifen in Time to Progression (TTP) in a 32-month study.

Time to Progression (TTP) is the length of time from the start of treatment until the cancer gets worse or spreads in the body. In this study, the majority of women receiving Femara went about 9.4 months without their cancer worsening or spreading. This is compared to 6 months for the women receiving tamoxifen.

What are side effects with Femara?

Serious side effects:

• bone effects (fractures, decreased bone density and osteoporosis)
• increases in cholesterol levels.

Common side effects:

• joint pain
• nausea
• weight decrease
• vaginal irritation
• pain in the extremities.

Other reported side effects include blood clots, other cancers, stroke, heart attack and endometrial cancer.

See a full list of letrozole (Femara) side effects here.

Bottom Line

• Treatment with aromatase inhibitors like letrozole (Femara) can extend the length of time for a breast cancer recurrence or breast cancer spreading in the body. In one study, over 70% of women had a disease-free survival period for up to 8 years.
• Treatment with AIs are usually extended for 5 to 10 years after surgery for breast cancer or other treatment. Women with a greater risk of disease recurrence may elect to continue therapy past 5 years, but side effects can be a concern.
• The American Society of Clinical Oncology (ASCO) recommends that for women on extended AI therapy, 10 years should be the maximum duration of therapy, based on their 2019 clinical practice guideline update.