Anastrozole After Tamoxifen Better for Early Breast Cancer than Tamoxifen Alone
In published reports from two similar clinical trials, researchers show that switching certain breast cancer patients at two years from the standard post-surgery treatment tamoxifen to another drug called anastrozole provides more protection against recurrence. The weight of evidence now favors such an approach for estrogen-receptor positive postmenopausal women with early breast cancer.
Following surgery for breast cancer, women whose tumors grow in response to the hormone estrogen (estrogen-receptor, or ER, positive) usually receive anti-estrogen therapy to reduce their risk that the disease will recur. Seven in ten breast cancer patients have ER-positive tumors.
Since the 1980s, the adjuvant hormone treatment of choice has been tamoxifen (Nolvodex®), a drug that blocks estrogen from getting to the cancer cells. Tamoxifen has had a major impact on breast cancer, reducing recurrence by about 40 percent in tens of thousands of women participating in hundreds of clinical trials, and has also been used to prevent cancer from occurring in the first place in women who have a higher risk of breast cancer. Tamoxifen’s effectiveness comes at a cost, however: a very small number of women on tamoxifen develop endometrial cancer, severe blood clots, and stroke.
A more recently developed class of drugs called aromatase inhibitors (AIs) appears to be equally or even more effective in combating breast tumors that use estrogen to grow. AIs work against the enzyme (aromatase) responsible for turning the small amount of male hormone produced by the adrenal gland into estrogen. AIs don’t work in women who have estrogen produced by the ovaries, however, which is why AIs are only effective once the ovaries have shut down – that is, in postmenopausal women.
The newest and most promising AIs are anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®). AIs also have some side effects: a reduction in bone density, which can lead to bone fractures; joint pain; and pain in the muscles and bones.
A number of large phase III clinical trials have been undertaken to try to clarify what role the AIs might play in the treatment and prevention of ER-positive breast cancer. (See related stories at Aromatase Inhibitors.)
Study 1 (Germany and Austria)
Two separate but coordinated phase III randomized clinical trials were conducted in medical centers across Austria (ABCSG trial 8) and Germany (ARNO 95), to see if anastrozole might be a better hormone treatment than tamoxifen for women who have already had surgery and two years of tamoxifen. Patients were randomly assigned, but they knew which arm of the study they were on: 1,606 took tamoxifen for five years while another 1,616 switched to anastrozole after two years of tamoxifen (the sequential arm) and continued for the rest of the five-year treatment time.
Cancer in all of the women had spread to the lymph nodes, but had spread no further (distant metastasis). Women whose tumors were sensitive to estrogen were enrolled in the trials between January 1996 and August 2003. To date, 55 percent have completed treatment and were included in these results if their surgery was at least two years earlier. They have been followed thus far for a median of 28 months.
The large team including many study groups throughout Austria and Germany was led by Raimund Jakesz, M.D., of the Vienna Medical University and Vienna General Hospital in Vienna, Austria.
Study 1 Results
Of 1,606 women assigned to five years of tamoxifen, 110 (6.8 percent) had a recurrence of their breast cancer compared to 67 of the 1,608 women (4.2 percent) who switched to anastrozole after two years on tamoxifen. Switching to anastrozole therefore reduced the risk by 40 percent.
There were 59 deaths in the tamoxifen-only group, 31 resulting from breast cancer. In the sequential group, 45 women died, 24 from breast cancer.
Significantly more women in the tamoxifen-alone group had blood clots (12 compared to 3), and in nine patients they led to a blocked artery, compared to only two in the sequential group. More than twice as many women receiving anastrozole had bone fractures (34 compared to 16) and also nausea (25 compared to 10), both statistically significant, and there was a non-significant trend towards more bone pain, reported by 213 compared to 177 taking tamoxifen alone.
Study 2 (Italy)
In a similar study - the Italian Tamoxifen Arimidex (ITA) trial - a total of 448 postmenopausal women who had been taking tamoxifen for two years or more were randomly assigned either to continue on tamoxifen until five years had elapsed, or to switch to anastrozole for the remainder of that time.
All of the women had had surgery for breast cancer that had spread to the lymph nodes, but no further. All had tumors that were sensitive to estrogen. Women enrolled in the trial between March 1998 and December 2002. To date, the women have been followed for a median of three years.
The team of researchers conducting the ITA trial was led by Francesco Boccardo, M.D., of the University and National Cancer Institute in Genoa, Italy. The results were originally presented at the San Antonio Breast Cancer Symposium on December 3, 2003.
Study 2 Results
Of 225 women assigned to continue taking tamoxifen, 32 (14.2 percent) had a recurrence of their breast cancer after a median follow-up period of three years, compared to just 12 of the 223 women taking anastrozole (5.4 percent). Overall, women on anastrozole were 65 percent less likely to suffer a relapse or a new tumor than women on tamoxifen.
There were 10 deaths in the tamoxifen group, seven resulting from breast cancer. In the anastrozole group, four women died, all from breast cancer.
Both treatments caused an array of side effects, ranging from the mild (stomach problems) to the serious (endometrial cancer). Overall, women taking anastrozole experienced more of these adverse events (203 versus 150 in the tamoxifen group). However, more of the adverse events affecting the tamoxifen group were life-threatening or required hospitalization compared to the anastrozole group.
(Note: these results were based on the original report's median follow-up period of three years. Updated data from a longer follow-up period of 64 months were subsequently published in the June 2006 Annals of Oncology; see the journal abstract.)
The results from these three clinical trials tip the balance in favor of using anastrozole at some point in the adjuvant therapy for postmenopausal node-positive women. In the United States this is already commonplace.
“I consider aromatase inhibitors for all of my hormone receptor-positive postmenopausal women,” said Jo Anne Zujewski, M.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program. “Together with other recent results, the data are now strong enough to carve out a role for the aromatase inhibitors, whether following two years of tamoxifen or beginning post-surgical adjuvant therapy.”
In an accompanying editorial, Kathleen I. Pritchard of the Toronto Sunnybrook Regional Cancer Center in Ontario, Canada, wrote: "Now, for women nearing completion of five years of tamoxifen, the decision to consider additional years of endocrine therapy with an aromatase inhibitor seems fairly straightforward." Patients should talk to their doctors about which aromatase inhibitor (anastrozole; letrozole; exemestane) might make sense for them, given the different short- and long-term side effects and the patient's own medical history.
Nonetheless, caution is warranted, said Zujewski. “This doesn’t mean every woman should immediately be switched to anastrozole. Tamoxifen has been a powerful therapy with great results for many years, and may still be appropriate for some women, especially those whose age and bone density put them at elevated risk for fractures.”
These findings apply only to postmenopausal women with ER-positive breast cancer; the trial participants were mostly women in their seventies. “We’re not any closer with these to treatments for younger women,” said Zujewski.
In addition, said Zujewski, “we need longer-term data on how these AI agents interact with one another and with tamoxifen. Resistance to hormone therapy is not clearly understood.”
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