Anastrozole Reduces Recurrence in Early Breast Cancer: 10-Year Results of the ATAC Trial

Summary

Anastrozole (Arimidex®) is better than tamoxifen (Nolvadex®) at preventing a recurrence of breast cancer in postmenopausal women with early-stage hormone receptor-positive tumors, according to 10-year follow-up results from ATAC, a large international clinical trial. However, it does not improve overall survival compared with tamoxifen.

Source

The Lancet Oncology, November 17, 2010 (see the journal abstract ¹).

Background

Postmenopausal women who have been treated for early breast cancer and whose tumors are hormone receptor positive (that is, their tumors grow in response to the hormone estrogen) have been advised to take 5 years of adjuvant treatment with hormone therapy. For years the standard option was the antiestrogen drug tamoxifen. Tamoxifen treatment had been shown to help prevent a relapse and was considered the standard of care for this group of patients.

However, tamoxifen increases the risk of endometrial cancer and blood clotting disorders. It has been suggested that drugs called aromatase inhibitors (AIs), which are a different type of antiestrogen, might be a better alternative.

Like tamoxifen, AIs interfere with cancer cells’ use of hormones. But whereas tamoxifen interferes directly with the cancer cells’ ability to use estrogen to fuel growth, AIs block the action of an enzyme called aromatase, which helps the body to produce estrogen. Another difference is that tamoxifen can be used by both premenopausal and postmenopausal women, whereas AIs block estrogen production only in postmenopausal women.

The Study

The Arimidex, Tamoxifen Alone or in Combination (ATAC) study was a double-blinded phase III clinical trial that was designed to compare the ability of the AI anastrozole, tamoxifen, and the two drugs in combination to prevent breast cancer recurrence in postmenopausal women with hormone receptor-positive tumors.

The study enrolled 9,366 postmenopausal women with localized breast cancer (that is, cancer that hadn’t spread, or metastasized). The women were randomly assigned to receive 5 years of adjuvant treatment with anastrozole alone, tamoxifen alone, or a combination of the two. (The combination treatment group was subsequently discontinued because outcomes for patients in this group were essentially the same as those in the group receiving tamoxifen alone.) Most of the participants (84 percent) had hormone receptor-positive disease.

Results after a median follow-up of 68 months (5.7 years), published in 2005 (see the journal abstract ²), showed that, compared with tamoxifen, anastrozole prolonged disease-free survival by 13 percent, increased time to relapse by 21 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. The differences were even greater when the analysis was restricted to women with hormone receptor-positive cancer.

In addition, anastrozole was associated with fewer serious side effects (endometrial cancer, blood clots, vaginal bleeding, and hot flashes) than tamoxifen, although bone fractures and joint pain were more common among patients in the anastrozole group. However, overall survival was similar in the two groups.

In 2006, researchers with the ATAC trial reported data showing that anastrozole was better tolerated than tamoxifen and resulted in fewer serious complications (see the journal abstract ³). Furthermore, anastrozole had a more favorable overall risk–benefit profile than tamoxifen, and women taking anastrozole had a lower recurrence rate than those taking tamoxifen.

Mainly on the basis of the results published in 2005, treatment with an AI became the standard adjuvant therapy for hormone receptor-positive breast cancer, although tamoxifen is still considered a reasonable alternative. Other trials, involving a total of more than 30,000 women, confirmed that treatment with an AI alone or after tamoxifen was beneficial for patients with hormone-sensitive breast cancer.

The current study reports findings after participants in ATAC had been followed for median of 10 years.

Results

This analysis continued to show a benefit of anastrozole compared with tamoxifen. Among women with hormone receptor-positive tumors, those randomly assigned to receive treatment with anastrozole had a 4.3 percent lower absolute rate of breast cancer recurrence after 10 years, and a 2.6 percent lower absolute rate of distant metastasis, than those randomly assigned to receive treatment with tamoxifen. 

The differences between anastrozole and tamoxifen in time to relapse, cancer in the other breast, and disease-free survival were greatest in the first two years of treatment but were maintained throughout the follow-up period, including the period after treatment was completed. However, the authors found that this so-called “carryover effect” – in which benefits extend beyond the treatment period – began to wane after about 8 years.

During treatment, women in the anastrozole group had fewer serious adverse events related to treatment than women in the tamoxifen group. After treatment was completed, however, rates of serious adverse events evened out between the two groups. Patients taking anastrozole reported more fractures during treatment than those taking tamoxifen, but after the completion of treatment fracture rates again became similar in both groups.

Patients taking tamoxifen had higher rates of endometrial cancer and melanoma than those taking anastrozole. There was a slight trend toward more colorectal and lung cancers in patients taking anastrozole compared with those taking tamoxifen. Overall, however, cancers other than breast cancer occurred at similar rates in both groups.

The number of patient deaths, with or without breast cancer recurrence, was similar in the two groups after 10 years of follow-up. Thus, treatment with anastrozole did not improve overall survival compared with tamoxifen.

Comments

In an accompanying editorial, Michael Gnant, M.D., of the Medical University of Vienna in Austria, wrote that he is encouraged by the finding that “the benefit of 5 years’ treatment with anastrozole persists and even seems to increase over time. This so-called carryover effect gives reason for hope because it essentially means that we can intervene early in the course of the disease and affect the rate of recurrence and overall survival.”

It is reassuring, Dr. Gnant added, that “the clinically most important side-effect of aromatase inhibition – an increase in fractures because of reduced serum [estrogen] concentrations – subsides soon after intake of the active drug is stopped.”

Jo Anne Zujewski, M.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program, said: “The 10-year results from ATAC provide strong evidence that anastrozole is both safe and effective in the treatment of postmenopausal women with early-stage breast cancer.”

Dr. Zujewski added, however, that “whether an individual patient should start therapy with an AI or begin therapy with tamoxifen and then change to an AI remains a subject of medical judgment and clinical research. Patients should talk with their doctors about which drug would be best for them given their particular medical condition.”

In August 2010, an ASCO expert committee released an updated Clinical Practice Guideline ⁴ that recommends that postmenopausal women with hormone receptor-positive breast cancer consider using an AI during adjuvant treatment, either initially or after a course of adjuvant tamoxifen. The committee noted, however, that patients and their physicians should carefully consider side effect profiles when deciding on whether and when to use AI therapy.