Anastrozole May Be Better than Tamoxifen at Shrinking Large Breast Tumors Before Surgery
In this small European trial of postmenopausal women with estrogen-receptor positive, early stage breast cancer, anastrozole (Arimidex®) did no better overall than tamoxifen (Nolvadex®) or a combination of both drugs at shrinking tumors prior to surgery. However, a subgroup of women did do better with anastrozole: those whose tumors were initially too large to allow for breast-conserving surgery. More data is needed, however, before anastrozole can be considered a new standard in the neoadjuvant (before surgery) treatment of this group of patients.
Journal of Clinical Oncolgy, Aug. 1, 2005 (see the journal abstract).
Seven out of 10 women with breast cancer have tumors that grow in response to estrogen (estrogen-receptor, or ER, positive). The anti-estrogen drug tamoxifen has been the standard adjuvant hormone treatment (following local surgery or radiation) since the 1980s for advanced breast cancer in both premenopausal and postmenopausal ER-positive women.
Postmenopausal women have an additional option: a class of hormone drugs known as aromatase inhibitors (AIs). 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.
In earlier clinical trials, one AI called anastrozole has proven to be more effective than tamoxifen as adjuvant (after surgery) therapy for ER-positive, postmenopausal women with either advanced or early breast cancer (see related information at Aromatase Inhibitors).
One such study was the Arimidex, Tamoxifen Alone or Combination (ATAC) trial (see the related story). Researchers designed the trial described here to make the same drug comparisons among a smaller group of patients comparable to those in ATAC, but this time in the neoadjuvant (before surgery) setting. That is, they wanted to know whether anastrozole was better than tamoxifen at helping to shrink breast tumors and allow breast-conserving surgery rather than mastectomy.
The Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen (IMPACT) study is a phase III clinical trial that enrolled 330 ER-positive postmenopausal women at 19 oncology centers across the United Kingdom and Germany, between 1997 and 2002. The women were randomly assigned to receive either anastrozole alone (113 patients), tamoxifen alone (108), or a combination of the two (109) as a daily pill for 12 weeks prior to surgery. The research team was led by Ian E. Smith, M.D., from the Royal Marsden Hospital, London and Sutton, United Kingdom.
Researchers measured all visible tumors during a physical exam and also using ultrasound. Measurements were taken before treatment began, and again at two, six, and 12 weeks, to see how tumor size was affected by the hormone treatment they were receiving.
No statistically meaningful differences in reducing tumor size were found between the groups when looking at all women in the study. Thirty-eight percent taking anastrozole had significant reductions or a complete response, compared to 36 percent taking tamoxifen, and to 40 percent taking both drugs together.
Anastrozole did prove superior, however, among women whose tumors were large enough initially to classify them as needing mastectomy. In this subgroup of 124 women, 46 percent of women taking anastrozole saw their tumors shrink enough to allow them the option of electing breast-conserving surgery, compared to 22 percent of women on tamoxifen, and 26 percent on the combination. Though the absolute numbers were small, the findings were statistically significant.
All three treatments were generally well tolerated with only minor side effects (dizziness, headache, nausea, fatigue) occurring in less than ten percent of patients. Hot flashes were the most common side effect, occurring in 18 percent of women taking anastrozole, 26 percent taking tamoxifen, and 28 percent taking the combination, but these differences were not statistically significant.
There was a significant difference with regard to vaginal discharge, which was suffered by none of the women in the anastrozole group compared to 5.6 percent of the tamoxifen group and 8.3 percent taking the combination.
The IMPACT trial did not prove anastrozole superior to tamoxifen as neoadjuvant therapy in the overall group of ER-positive, early breast cancer patients, but it was significantly better among those women headed for mastectomy. IMPACT “provides some further supportive data that the third-generation aromatase inhibitors are significantly more effective than tamoxifen in downstaging large breast cancers,” said lead author Smith.
Still, more data from larger trials are needed before anastrozole can be confirmed as a new standard in neoadjuvant therapy for this group of women. In the meantime, this is “an important first step toward identifying which women might benefit most from which hormone treatment,” said Jo Anne Zujewski, M.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program.
She explained that smaller neoadjuvant trials such as IMPACT are “an exciting and novel way to look at early treatment response” and perhaps identify molecular markers that can predict which women are most likely to benefit from the treatment. (Molecular markers are biological substances in the body which, when present, predict subsequent disease or outcomes.) Further results and biological findings from the IMPACT trial will be published separately at a later time.
The failure of the neoadjuvant IMPACT trial to produce outcomes similar to the larger adjuvant ATAC trial may be a result of the study design. In an accompanying editorial, Matthew J. Ellis, M.D., from the Siteman Comprehensive Cancer Center at Washington University in St. Louis, Mo., pointed out potential flaws that might explain why IMPACT (with 330 patients) failed to mirror ATAC (with more than 9,000).
Zujewski agreed, saying “if IMPACT had included more women and specifically more women with larger tumors, the results may have been different.”
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