Related Pages Search for Clinical Trials 1 NCI's PDQ® Cancer Clinical Trials Registry. Breast Cancer Home Page 2 NCI's gateway for information about breast cancer.

Key Words

Breast cancer, BIG 1-98, letrozole (Femara®), tamoxifen (Nolvadex®), aromatase inhibitors, hormone therapy, endocrine therapy. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ³.)

Summary

In this large international trial of postmenopausal women treated surgically for early-stage hormone-responsive breast cancer, letrozole did better to prevent a recurrence of disease (especially distant metastases) than the commonly prescribed tamoxifen. Sequential therapy, in which letrozole was followed by tamoxifen or tamoxifen was followed by letrozole, did not improve outcomes over letrozole alone.

Sources

The New England Journal of Medicine, December 29, 2005 (see the journal abstract ⁴).
(N Engl J Med 2005 Dec 29;353(26):2747-57)

The New England Journal of Medicine, August 20, 2009 (see the journal abstract ⁵).
(N Engl J Med 2009 Aug 20;361(8);766-76)

Background

Women who have early-stage estrogen receptor (ER)-positive breast cancer usually receive endocrine, or hormone, therapy with an antiestrogen after surgery to reduce the risk that the disease will recur. Approximately seven in ten breast cancer patients have ER-positive tumors and so are candidates for this kind of adjuvant treatment.

Since the 1980s, five years of treatment with the antiestrogen tamoxifen has been considered the standard of care. However, women taking tamoxifen (Nolvadex®) face an increased risk of endometrial cancer and blood clot disorders.

An alternative antiestrogen treatment is letrozole (Femara®), which belongs to a class of drugs called aromatase inhibitors (AIs). Letrozole is one of three AIs approved by the U.S. Food and Drug Administration, the other two being anastrazole (Arimidex®) and exemestane (Aromasin®).

Although studies have shown letrozole to be effective compared to a placebo, the trial described here was designed to compare the efficacy of letrozole and tamoxifen. It is one of a number of large phase III clinical trials undertaken to clarify what role AIs might play in the treatment and prevention of ER-positive breast cancer. (See related stories at Aromatase Inhibitors ⁶.)

The Study

The Breast International Group (BIG) 1-98 study (see the protocol summary ⁷) was a phase III clinical trial designed to compare letrozole and tamoxifen, given alone or sequentially for five years. Between 1998 and 2003, researchers at 27 institutions around the world enrolled 8,010 postmenopausal women who had completed surgery for early, ER-positive invasive breast cancer and who had no evidence of metastasis.

The women were randomly assigned to one of four treatment groups, as follows:

• letrozole for five years (letrozole monotherapy),
• tamoxifen for five years (tamoxifen monotherapy),
• letrozole for two years, followed by tamoxifen for the remaining three years (Let → Tam sequential therapy), or
• tamoxifen for two years, followed by letrozole for the remaining three years (Tam → Let sequential therapy).

The women were followed for disease events (including recurrence, a new cancer in the opposite breast, another cancer, or death) and for possible toxic effects of treatment.

In the 2005 report, researchers compared the 4,007 women in the two groups assigned to take tamoxifen initially to the 4,003 women in the two groups assigned to take letrozole initially. Combining the monotherapy and sequential groups in this way was possible because this analysis was limited to events that occurred in the first twenty-five months on treatment - that is, to events that would reflect only the effects of the initial therapy received by women in the sequential groups. In the 2009 report, researchers compared the sequential treatments with letrozole monotherapy among 6,182 women.

The study was conducted by the BIG 1-98 Collaborative Group. Novartis AG supported the trial and also supplied the drugs.

Results

Monotherapy comparison

The 2005 report found that, after a median follow-up period of just over two years, women in the letrozole groups were 19 percent less likely to have had a disease event. The advantage was even more pronounced when it came to protection against cancer far from the original tumor (distant metastases): women in the letrozole groups were 27 percent less likely to experience a distant recurrence. However, there was no difference in overall survival between the letrozole and tamoxifen groups.

Some of the women in the study received chemotherapy in addition to surgery. Among these women, those in the letrozole groups were 30 percent less likely to have a disease event than those in the tamoxifen groups. Among women whose cancer had spread to their lymph nodes, those in the letrozole groups were 29 percent less likely to have an event than those in the tamoxifen groups.

Researchers also analyzed the data to estimate how many women would likely be alive and free of disease five years after beginning treatment. They concluded that 84 percent of those in the letrozole groups and 81.4 percent of those in the tamoxifen groups would be disease free at five years.

In a subsequent analysis of the trial reported in the 2009 paper, outcomes among the women in the monotherapy groups only were compared after a median follow-up period of six years and four months. This analysis included 2,463 women assigned to letrozole only and 2,459 women assigned to tamoxifen only. The outcome with letrozole was still better than that with tamoxifen, but the difference had narrowed. Women taking letrozole were 12 percent less likely to have a disease event than women taking tamoxifen and 15 percent less likely to have a distant recurrence. The corresponding estimated five-year disease-free survival rates were 85.6 percent for women taking letrozole and 82.6 percent for those on tamoxifen.

Although women in the letrozole group had a lower risk of death than women in the tamoxifen group, the difference was not statistically significant. The 5-year overall survival rates were 91.8 percent in the letrozole group and 90.9 percent in the tamoxifen group.

Sequential therapy comparison

The 2009 analysis found that, after a median follow-up period of just under six years, neither sequential therapy group (Tam → Let or Let → Tam) had improved disease-free or overall survival compared with the letrozole monotherapy group. (The tamoxifen monotherapy group could not be included in the comparison because, after the publication of the 2005 results, women in the tamoxifen group were allowed to cross over to letrozole if they wished.)

Safety

The 2009 analysis showed that women in the letrozole monotherapy group had a lower incidence of blood clots than women in the other groups, all of whom received tamoxifen, Rates of cardiac events and stroke were similar among all the groups. Women who took tamoxifen were somewhat less likely to have high cholesterol and more likely to have vaginal bleeding, hot flashes, and night sweats. More women in the letrozole groups than the tamoxifen monotherapy group experienced joint pain and bone fractures.

(Note: In a paper published in the December 20, 2007, Journal of Clinical Oncology, researchers with the trial reported a safety analysis of the cardiovascular adverse events in BIG 1-98. The analysis found a low overall incidence of such events. For details, see the journal abstract ⁸.)

Comments

The letrozole advantage reported in this trial confirms other results showing the aromatase inhibitors to be generally more effective than tamoxifen, said the study authors, who emphasized the risk reduction in distant metastases. Jo Anne Zujewski, M.D., of NCI's Cancer Therapy Evaluation Program said it was clear from this trial that "aromatase inhibitor therapy is beneficial for the treatment of postmenopausal women with estrogen receptor-positive breast cancer."

Limitations

Although Zujewski noted that letrozole was likely to produce slightly better results than tamoxifen alone, she emphasized that many women on tamoxifen still do very well, pointing out that that "in this trial, more than 80 percent were free of recurrence" five years after beginning treatment. These results further show, she noted, that five years of endocrine therapy that included a sequence of tamoxifen followed by letrozole or letrozole followed by tamoxifen was not superior to five years of letrozole alone. One challenge, she said, "is to sort out which patients may be treated with tamoxifen, to avoid the risk letrozole poses to bone health." Current trials are now addressing whether extended endcocrine therapy (longer than five years, including at least five years of treatment with an AI) is more beneficial than the standard five years.

Glossary Terms

An anticancer drug that is used to decrease estrogen production and suppress the growth of tumors that need estrogen to grow. It is a type of nonsteroidal aromatase inhibitor.

A drug that prevents the formation of estradiol, a female hormone, by interfering with an aromatase enzyme. Aromatase inhibitors are used as a type of hormone therapy for postmenopausal women who have hormone-dependent breast cancer.

The length of time after treatment for a specific disease during which a patient survives with no sign of the disease. Disease-free survival may be used in a clinical study or trial to help measure how well a new treatment works. Also called DFS and disease-free survival time.

Refers to cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes. Also known as distant cancer.

Effectiveness. In medicine, the ability of an intervention (for example, a drug or surgery) to produce the desired beneficial effect.

Treatment that adds, blocks, or removes hormones. For certain conditions (such as diabetes or menopause), hormones are given to adjust low hormone levels. To slow or stop the growth of certain cancers (such as prostate and breast cancer), synthetic hormones or other drugs may be given to block the body’s natural hormones. Sometimes surgery is needed to remove the gland that makes a certain hormone. Also called hormonal therapy, hormone therapy, and hormone treatment.

A protein found inside the cells of the female reproductive tissue, some other types of tissue, and some cancer cells. The hormone estrogen will bind to the receptors inside the cells and may cause the cells to grow. Also called ER.

A drug used to treat advanced breast cancer and to prevent recurrent breast cancer in postmenopausal women who have already been treated with tamoxifen. It is also being studied in the treatment of other types of cancer. Exemestane causes a decrease in the amount of estrogen made by the body. It is a type of aromatase inhibitor. Also called Aromasin.

In oncology, describes cancer that responds to hormone treatment.

Treatment that adds, blocks, or removes hormones. For certain conditions (such as diabetes or menopause), hormones are given to adjust low hormone levels. To slow or stop the growth of certain cancers (such as prostate and breast cancer), synthetic hormones or other drugs may be given to block the body’s natural hormones. Sometimes surgery is needed to remove the gland that makes a certain hormone. Also called endocrine therapy, hormonal therapy, and hormone treatment.

The number of new cases of a disease diagnosed each year.

Cancer that has spread from where it started in the breast into surrounding, healthy tissue. Most invasive breast cancers start in the ducts (tubes that carry milk from the lobules to the nipple). Invasive breast cancer can spread to other parts of the body through the blood and lymph systems. Also called infiltrating breast cancer.

A drug used to treat advanced breast cancer in postmenopausal women. Letrozole causes a decrease in the amount of estrogen made by the body. It is a type of aromatase inhibitor. Also called Femara.

A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Lymph nodes filter lymph (lymphatic fluid), and they store lymphocytes (white blood cells). They are located along lymphatic vessels. Also called lymph gland.

A statistics term. The middle value in a set of measurements.

The percentage of people in a study or treatment group who are alive for a certain period of time after they were diagnosed with or treated for a disease, such as cancer. The overall survival rate is often stated as a five-year survival rate, which is the percentage of people in a study or treatment group who are alive five years after diagnosis or treatment. Also called survival rate.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

Having to do with the time after menopause. Menopause (“change of life”) is the time in a woman's life when menstrual periods stop permanently.

In medicine, treatment that experts agree is appropriate, accepted, and widely used. Health care providers are obligated to provide patients with the standard of care. Also called best practice and standard therapy.

A drug used to treat certain types of breast cancer in women and men. It is also used to prevent breast cancer in women who have had ductal carcinoma in situ (abnormal cells in the ducts of the breast) and in women who are at a high risk of developing breast cancer. Tamoxifen is also being studied in the treatment of other types of cancer. It blocks the effects of the hormone estrogen in the breast. Tamoxifen is a type of antiestrogen. Also called tamoxifen citrate.