Femara Better than Tamoxifen in Reducing Recurrence in Early-Stage Breast Cancer

Reviewed study: "Femara Better than Tamoxifen in Reducing Recurrence in Early-Stage Breast Cancer" from the BIG 1-98 Collaborative Group, presented by B. Thurlimannby, Primary Therapy of Early Breast Cancer Conference, St. Gallen, Switzerland, January 2005, Abstract #S4

Background and importance of the study: If you are post-menopausal with hormone-receptor-positive, early-stage breast cancer, hormonal therapy may play an important role in your care after surgery. Hormonal therapy keeps estrogen away from receptors on breast cancer cells that get "turned on" by estrogen, growing and making new cells.

You have two options for hormonal treatment as adjuvant (additional) treatment after surgery:

• You can keep estrogen from attaching to the hormone receptors by taking tamoxifen. This drug has been the standard hormonal therapy for more than 25 years.
• You can reduce the estrogen available to the hormone receptors by taking one of the three available aromatase inhibitors. These medications—Femara (chemical name: letrozole), Arimidex (chemical name: anastrozole), and Aromasin (chemical name: exemestane)—work by blocking a substance called aromatase that converts the hormone androgen into estrogen. After menopause, most of the estrogen in a woman's body comes from fat and muscle cells converting androgen into estrogen.

It can be difficult to decide which hormonal therapy to use first, whether to switch from one to another—and whether (and when) you should start taking another medication after you finish your first course of treatment. Clinical studies continue to test and compare many of these treatment options.

Although tamoxifen used to be the "one and only" choice, the U.S. Food and Drug Administration (FDA) has approved the use of aromatase inhibitors under specific circumstances:

• Arimidex shows an advantage over tamoxifen as the first hormonal therapy.
• Two to four years of Femara after five years of tamoxifen was better than tamoxifen alone.

In the study reviewed here, researchers compared Femara and tamoxifen after surgery for early-stage breast cancer. They wanted to see which would do a better job of stopping the cancer from coming back. They also looked at the side effects of both treatments. This is the first time these two treatments have been compared directly after initial surgery.

Study design and results: This study, started in 1998, was conducted by the Breast International Group (BIG) and is known as the BIG 1-98 trial.

More than 8,000 women from 27 countries (not including the United States) participated in the study. The women were all post-menopausal with early-stage, hormone-receptor-positive breast cancer. They all had surgery to remove the breast cancer. About 40% of the women had breast cancers that were smaller than two centimeters (about an inch); 25% of the women had received chemotherapy.

The women were randomly and equally divided into four groups:

• One group took tamoxifen for five years after surgery.
• One group took Femara for five years after surgery.
• One group took tamoxifen for two years after surgery and then switched to Femara for three years.
• One group took Femara for two years after surgery and then switched to tamoxifen for three years.

After following the women for about two years after treatment, the researchers compared the women in the four groups for:

• disease-free survival (how many women were alive without cancer at that time);
• risk of the cancer coming back in the same breast;
• overall survival (how many women were alive, with or without the cancer coming back in the same breast or some place else in the body); and
• side effects of the treatments.

The researchers found significant differences in disease-free survival and recurrence between the women who took Femara compared to the women who took tamoxifen. ("Significant" means the differences were probably not due just to chance.) Compared to the women who took tamoxifen, the women who took Femara:

• were 2.6% more likely to have disease-free survival;
• had a 19% lower risk of the cancer coming back in the same breast; and
• had a 27% lower risk of the cancer coming back in another place in the body.

The researchers noted that Femara benefited women who had had chemotherapy as well as women who had not.

The study also showed a difference in side effects between Femara and tamoxifen. Tamoxifen caused more:

1. blood clots;
2. vaginal bleeding; and
3. endometrial abnormalities (changes in the lining of the uterus).

Femara was associated with more:

• bone fractures;
• high cholesterol (though usually just a little higher); and
• heart attacks and strokes (though these were rare in both treatments).

The amount of nausea and vomiting was similar with both treatments.

The researchers did not give the percentages of women who reported any of these side effects.

Conclusions: After two years of follow-up, early conclusions from the BIG 1-98 study showed that post-menopausal women with hormone-receptor-positive breast cancer who took Femara had a significantly lower risk of recurrence and increased rate of disease-free survival compared to women who took tamoxifen. Women who took Femara had an increased risk of bone fractures, but a lower risk of blood clots. The researchers recommended that more studies be done on cardiovascular side effects, such as high cholesterol, heart attacks, and strokes, which may be related to aromatase inhibitors.

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