Exemestane Following Tamoxifen Reduces Breast Cancer Recurrences and Prolongs Survival
Long-term follow-up data from a large international phase III trial shows that postmenopausal women with early-stage hormone receptor-positive breast cancer who received 2 to 3 years of tamoxifen and then switched to the drug exemestane (Aromasin®) for a total of 5 years of adjuvant hormone therapy experienced a delay in disease recurrence and a survival advantage, compared with women who took tamoxifen for 5 years.
New England Journal of Medicine March 11, 2004 (see the journal abstract). Updated results were published February 17, 2007, in the Lancet (see the journal abstract) and November 21, 2011, in the Journal of Clinical Oncology (see the journal abstract).
Following surgery for early-stage breast cancer, women with hormone receptor-positive tumors are usually given hormone therapy to reduce the risk that their disease will recur. For many years, the drug tamoxifen, given every day for 5 years, was the most common adjuvant hormone therapy. However, tamoxifen does not prevent all recurrences, and breast cancer cells can become resistant to this drug. In addition, tamoxifen increases a woman's risk for endometrial cancer, blood clots, and stroke. Therefore, researchers have investigated whether other hormone therapy drugs might lead to better outcomes.
One newer hormone therapy drug is exemestane, which, like tamoxifen, blocks the growth of breast tumors that respond to estrogen but does so in a different way. Whereas tamoxifen interferes with the ability of breast cancer cells to use estrogen for growth, exemestane interferes with the body's ability to make estrogen.
Exemestane inactivates the enzyme aromatase, which the body uses to make estrogen. Before menopause, most estrogen is produced in the ovaries, which contain more aromatase than exemestane can block. After menopause, however, the ovaries are no longer a major source of estrogen, and exemestane is able to block estrogen production by other tissues. Therefore, exemestane and other so-called aromatase inhibitors (AIs) are effective only in postmenopausal women.
Early findings from several large international trials suggested that cancer is less likely to recur in women who take an AI after 5 years of tamoxifen or who switch to an AI after a shorter period on tamoxifen. These studies involved AIs other than exemestane—specifically, anastrozole (Arimidex®) and letrozole (Femara®). Unlike tamoxifen, AIs do not increase the risk of endometrial cancer, blood clots, or stroke, but they can promote bone loss and are associated with an increased risk of bone fractures.
The Intergroup Exemestane Study enrolled 4,724 postmenopausal women from 37 countries beginning in 1998. All had been treated for early breast cancer, had been treated with tamoxifen for 2 to 3 years in hopes of preventing a recurrence, and were free of cancer. On entering the trial, the participants were randomly assigned to one of two groups. One group switched to exemestane and took it for an additional 2 or 3 years, for a total of 5 years of hormone therapy. The other group continued to take tamoxifen to complete the 5 years of treatment.
The trial's principal investigator was Raoul Charles Coombes, M.D., Ph.D., of Imperial College in London, England.
Initial results from the trial were published in the March 11, 2004, issue of the New England Journal of Medicine, after the participants had been followed for about 2.5 years. Although this was long enough to show with statistical certainty that recurrence was delayed in women who had switched to exemestane, it was not long enough to know whether the exemestane group actually lived longer.
Updated results published in 2007 and 2011 provided longer follow-up data.
After a median follow-up period of 7.6 years, when most of the patients had been followed for at least 6 years, women who had switched to exemestane had a 14 percent lower risk of death from any cause than those who had continued to take tamoxifen. This translated to a 2.4 percent absolute improvement in survival. Women in the exemestane group also had a 19 percent lower risk of a breast cancer recurrence. In addition, the exemestane group had a 16 percent lower risk of a distant recurrence (metastatic disease). The benefits of exemestane were maintained over time, even after treatment had stopped.
Analyses of adverse events during treatment showed that women who continued to take tamoxifen were more likely to develop blood clots, uterine cancer or polyps, vaginal bleeding, and muscle cramps, whereas women who switched to exemestane had slightly more bone fractures. Rates of heart attack, chest pain, and stroke were similar in the two groups. However, the differences in the incidence of side effects waned after treatment. For example, the two groups had similar risks of bone fractures and of serious gynecologic events during the follow-up period.
A substudy of the trial conducted to compare the two groups' quality of life showed that quality of life did not differ between them. These data were published in the Feb. 20, 2006, issue of the Journal of Clinical Oncology (see the journal abstract).
The researchers knew from earlier studies that patients obtain most of the preventive benefit of tamoxifen during the first 2 or 3 years of therapy, said Judith Bliss, M.D., of the Institute for Cancer Research in London, England.
Their goal in conducting the current study was to find out whether switching patients to exemestane after 2 to 3 years of tamoxifen would improve on the benefit that patients would be expected to receive from 5 years of tamoxifen therapy. The study’s findings have confirmed that this is the case, Bliss said.
"These findings will encourage doctors to consider switching patients to exemestane or another AI after two to five years of tamoxifen therapy," says Jo Anne Zujewski, M.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program. However, she adds, AIs may not be appropriate for women who already have, or are at high risk for, bone fractures.