Exemestane Following Tamoxifen Reduces Breast Cancer Recurrences and Prolongs Survival
Longer follow-up data from a large international phase III trial of postmenopausal women with breast cancer who switched to the drug exemestane (Aromasin®) after several years on tamoxifen confirm a delay in disease progression and also show a survival advantage, compared to women who stayed on tamoxifen.
American Society of Clinical Oncology annual meeting, Atlanta, Georgia, June 3, 2006 (see the meeting abstract).
Following surgery for breast cancer, women whose tumors grow in response to the hormone estrogen usually take the anti-estrogen drug tamoxifen for five years to reduce their risk that the disease will recur. 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.
Tamoxifen and exemestane both block the growth of breast tumors that respond to estrogen, but the two drugs work in different ways. Tamoxifen interferes with the ability of breast cancer cells to use estrogen for growth, whereas 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 have suggested that cancer is less likely to recur in women who take an AI after five years of tamoxifen or 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.
Beginning in 1998, 4,724 postmenopausal women from 37 countries were enrolled in the study. All had been treated for early breast cancer, had been on tamoxifen for two or three years in hopes of preventing a recurrence, and were currently free of cancer. Upon entry to the trial, the participants were randomly assigned to one of two groups. One group (2,352 participants) switched to exemestane and took it for an additional two or three years, for a total of five years of treatment. The other group (2,372) stayed on tamoxifen to complete five years of treatment.
The trial's principal investigator was Raoul Charles Coombes, M.D., Ph.D., of Imperial College in London, England.
Preliminary results from the trial were published in the March 11, 2004, issue of the New England Journal of Medicine (see the journal abstract), after the participants had been followed for about two and a half years. While this was long enough to show with statistical certainty that women switching to exemestane saw a greater delay in disease recurrence, it wasn’t long enough to know whether the exemestane group actually lived longer.
The updated results presented at the 2006 ASCO meeting provided longer follow-up data.
After a median follow-up period of 4.8 years, women who switched to exemestane had a 15 percent lower risk of dying than those who continued to take tamoxifen. They also had a 24 percent lower risk of a breast cancer recurrence or of dying from an illness other than breast cancer.
In addition, the exemestane group had a 44 percent lower risk of developing cancer in the opposite breast and their risk of breast cancer spreading to other organs was reduced by 17 percent. All of these findings were statistically significant.
Women who continued to take tamoxifen were more likely than those who switched to exemestane to develop blood clots, uterine cancer or polyps, vaginal bleeding, and muscle cramps. Women in the exemestane group had slightly more bone fractures. Rates of heart attack, chest pain, and stroke were similar in the two groups of patients.
Women who took exemestane suffered more bone fractures than those who took tamoxifen alone. Some studies of other AIs have also shown an increase in fractures and all have shown that AIs promote bone loss.
The researchers knew from earlier studies that patients obtain most of the preventive benefit of tamoxifen during the first two or three years of therapy, said Judith Bliss, M.D., of the Institute for Cancer Research in London, England, who presented the study findings at the ASCO meeting.
Their goal in conducting the current study was to find out whether switching patients to exemestane after two to three years of tamoxifen would improve on the benefit that patients would be expected to receive from five years of tamoxifen therapy, which is the current standard of care. The study’s findings have confirmed that this is the case, Bliss said.
This study’s results do not mean that all women taking tamoxifen to prevent a recurrence of breast cancer should switch to exemestane after two to three years on the older drug, said Robert E. Coleman, M.D., of the University of Sheffield in Sheffield, England, commenting on the study at an ASCO press briefing.
“No single strategy [is best] for all patients,” he said. “Switching [from tamoxifen to exemestane] will be appropriate for some patients. There will be a few patients for whom remaining on tamoxifen will be appropriate.”
"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.
(Note: A substudy of this trial was conducted to compare the two groups' quality of life. Researchers led by Lesley J. Fallowfield, B.Sc., D.Phil., of the University of Sussex, United Kingdom, found that there was no significant difference between the two, indicating that "the clinical benefits of exemestane over tamoxifen are achieved without significant detrimental effect on quality of life." Data from this substudy were published in the Feb. 20, 2006, issue of the Journal of Clinical Oncology; see the journal abstract.)
This text may be reproduced or reused freely. Please credit the National Cancer Institute as the source. Any graphics may be owned by the artist or publisher who created them, and permission may be needed for their reuse.