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Key Words

Breast cancer, anastrozole (Arimidex®), tamoxifen (Nolvadex®), relapse, aromatase inhibitors, ATAC trial. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary ⁴.)

Summary

Anastrozole (Arimidex) was significantly better than tamoxifen (Nolvadex) - or the combination of tamoxifen and anastrozole - at preventing a recurrence of breast cancer in postmenopausal women whose early-stage tumors were hormone-sensitive, according to the final results of ATAC, a large international clinical trial. Patients on anastrozole also experienced fewer side effects. However, overall survival was similar in the anastrozole and tamoxifen groups.

Source

The Lancet, January 1, 2005 (see the journal abstract ⁵).

Background

Postmenopausal women who have been treated for early breast cancer and whose tumors are “hormone sensitive” (that is, the tumors grow in response to the hormones estrogen and progesterone) have been advised to take the anti-estrogen drug tamoxifen for five years. Such adjuvant treatment has been shown to help prevent a relapse and has been considered the standard of care for this group of patients.

However, women taking tamoxifen are at an increased risk for endometrial cancer and blood clot disorders. Other studies have suggested that a different class of drugs called aromatase inhibitors (AIs) might prove a better alternative.

Like tamoxifen, AIs interfere with cancer cells’ use of hormones but in a different way. Tamoxifen interferes directly with the cancer cells’ ability to use estrogen for fuel, while AIs block the action of a substance called aromatase, which helps the body produce estrogen. Anastrozole is an aromatase inhibitor.

Studies of various AIs have been promising, but the drugs’ long-term effects are unknown. In November 2004, the American Society of Clinical Oncology recommended that postmenopausal women with hormone-sensitive breast cancer consider one of two adjuvant treatment options:

• begin treatment with tamoxifen for two-to-five years, then switch to an AI for another two-to-five years, or
• forego tamoxifen entirely and begin adjuvant treatment with an AI for five years.

The final, five-year results from the Arimidex, Tamoxifen Alone or in Combination (ATAC) study, described here, are the first long-term results about an AI used as an adjuvant treatment for early breast cancer.

The Study

The ATAC study is a double-blinded phase III clinical trial. The study enrolled 9,366 postmenopausal women with localized breast cancer (that is, the cancer hadn’t spread or metastasized). The women were randomly assigned to receive either anastrozole alone, tamoxifen alone, or a combination of the two. The research team was led by Anthony Howell, M.D., of Christie Hospital NHS Trust in Manchester, United Kingdom.

In December 2001, after 33 months of study, ATAC researchers announced early results showing that women taking anastrozole were less likely - by 17 percent - to suffer a relapse, compared to women taking tamoxifen. However, the results were considered too preliminary to justify a recommendation that this patient group take anastrozole instead of tamoxifen after their initial breast cancer treatment.

Now, however, ATAC researchers have announced the results from five years of data, which suggest that anastrozole should perhaps be the preferred adjuvant treatment.

Results

After a median follow-up period of five years and eight months, women taking anastrozole in the ATAC study were significantly better off than those taking tamoxifen. Compared to tamoxifen, anastrozole increased disease-free survival by 10 percent; increased time to relapse by about 20 percent; reduced the occurrence of cancer spreading to other organs (distant metastases) by 14 percent, and reduced the occurrence of cancer in the other breast by more than 40 percent.

In addition, women taking anastrozole were more likely to make it through their scheduled treatment than were women taking tamoxifen - anastrozole was associated with fewer serious side effects (endometrial cancer, blood clots, vaginal bleeding, hot flashes), though bone fractures and joint pain were more common in the anastrozole group. The incidence of hip fracture was low and was similar in both groups.

However, overall survival was similar in the anastrozole and tamoxifen groups.

Note: A substudy of the ATAC trial concerning bone loss appeared in the March 1, 2008, Journal of Clinical Oncology; see the related story ⁶. After the extended follow-up period, overall survival continued to be similar in the anastrozole and tamoxifen groups.

Limitations

These results are valid only for anastrozole. It remains to be seen whether initiating therapy with other AIs (such as letrozole and exemestane) work similarly well at preventing breast cancer relapse. In addition, the optimal timing and duration of the aromatase inhibitors is not known.

Comments

“This study provides strong evidence that anastrozole is both safe and effective in the treatment of postmenopausal women with early stage breast cancer. Other studies using different aromatase inhibitors in early stage breast cancer further support these findings,” says JoAnne Zujewski, M.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program.

“Whether an individual patient should start therapy with an aromatase inhibitor or begin therapy with tamoxifen and then change to an aromatase inhibitor is a subject of medical judgment and clinical research,” she adds. “Patients should talk with their doctors about which drug would be best for them given their particular medical condition.”

Note: In the August 2006 issue of the Lancet Oncology (see the journal abstract), researchers with the ATAC trial report data after an extended follow-up period showing that anastrozole was tolerated better than tamoxifen and resulted in fewer serious complications. Furthermore, anastrozole had a more favorable overall risk-benefit profile and a lower recurrence rate than tamoxifen. Results after 100 months of follow-up were reported in the January 2008 Lancet Oncology (see the journal abstract ⁷).

Glossary Terms

Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.

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.

A clinical trial in which the medical staff, the patient, and the people who analyze the results do not know the specific type of treatment the patient receives until after the clinical trial is over.

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.

One of many chemicals made by glands in the body. Hormones circulate in the bloodstream and control the actions of certain cells or organs. Some hormones can also be made in the laboratory.

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

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.

Restricted to the site of origin, without evidence of spread.

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

To spread from one part of the body to another. When cancer cells metastasize and form secondary tumors, the cells in the metastatic tumor are like those in the original (primary) tumor.

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.

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.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

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.