Letrozole More Effective Than Tamoxifen Against Breast Cancer Recurrence

Larry Schuster

May 23, 2005

May 23, 2005 (Orlando) — A five-year study of breast cancer recurrence in 8,028 postmenopausal women with breast cancer showed that use of letrozole resulted in a nearly 20% lower risk of recurrence compared with tamoxifen, researchers reported here at the American Society of Clinical Oncology 2005 Annual Meeting.

In the largest study to date to compare letrozole (Femara) with tamoxifen, researchers found the relative risk of recurrence was 19% lower among those receiving letrozole than tamoxifen, with 351 recurrences in the letrozole group compared with 428 in the tamoxifen group. Additionally, the relative risk of distant metastases was 27% lower with letrozole vs tamoxifen.

Beat J. Thürlimann, MD, senior lecturer in medical oncology at the University of Basel in Switzerland and chairman of the study Breast International Group 1-98 trial, presented the results at the meeting.

"Of the women using tamoxifen, one of five women would have reduced their risk of breast cancer recurrence by switching to letrozole," Dr. Thürlimann said in an interview. The ability of letrozole to reduce distant recurrence in breast cancer was a particular advantage of letrozole.

Although the study design included four groups, the results were presented for only two of the groups. The other two groups comprised women initially given letrozole for two years and then switched to tamoxifen for three years or conversely, those initially given tamoxifen for two years and switched to letrozole for three years. The results from those two groups are expected in 2008.

Those additional results will actually be the most interesting, commented Julie R. Gralow, MD, associate breast cancer program head at the Fred Hutchinson Cancer Research Center, Seattle, Washington.

In an interview, Dr. Gralow said there is a reason to believe that there will be subsets of women who will do better if the two drugs are used sequentially. How the subsets might be characterized will remain to be answered.

Meanwhile, Dr. Gralow said, letrozole has some adverse effects, and the long-term effects that are associated with the drug still are being studied.

Researchers reported fatal cerebrovascular and cardiac events more frequently with letrozole, although these are rare. In addition, women receiving letrozole compared with tamoxifen were more likely to report joint pain, bone fractures, and slightly elevated cholesterol levels. Further, as has been published previously, women taking tamoxifen are more likely to have blood clots, vaginal bleeding, and endometrial cancer.

The study follows a positive head-to-head study of anastrozole (Arimidex) and tamoxifen in the Arimidex or Tamoxifen Alone or in Combination trial. Anastrozole is approved for adjuvant treatment of postmenopausal women with hormone receptor–positive early breast cancer. A third aromatase inhibitor, exemestane (Aromasin), has also entered clinical trials where it is being compared with tamoxifen.

A trial published in 2003 in The New England Journal of Medicine tested whether five years of letrozole following five years of tamoxifen was superior to tamoxifen alone in early-stage breast cancer. The combination was indeed better.

The current study represents the first time that letrozole was used in a straight head-to-head comparison with tamoxifen in early-stage breast cancer.

What remains unanswered is how the aromatase inhibitors compare with each other, said Pamela N. Munster, MD, assistant professor, Department of Interdisciplinary Oncology and Comprehensive Breast Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa.

Some physicians choose to use letrozole compared with other aromatase inhibitors because they think it is more potent than the others, but there are no current data verifying this. Whether letrozole is better or the same is not known, said Dr. Munster, who commented to Medscape on the report.

Further, what is also uncertain and needs long-term monitoring and assessment is any association of letrozole with cerebrovascular and cardiac events. This latest study found that these events were rare but did occur more frequently with letrozole.

Dr. Thürlimann speculated that the occurrence of cardiac and cerebrovascular events simply might reflect a cholesterol-lowering effect of tamoxifen or that more of the women taking letrozole were cancer-free after five years and perhaps living longer, and thus had an increased risk of other medical conditions.

However, both Drs. Munster and Gralow said it is not clear as to the reasons for the cerebrovascular and cardiac events, but further assessments need to be made in future studies. Also, the optimum duration for taking letrozole remains inconclusive, whereas for tamoxifen it has been established at five years, Dr. Munster said.

Meanwhile, until further studies clarify issues around sequencing and other questions, the researchers suggest that tamoxifen still might be the drug of choice for women who have joint pain and osteoporosis, which is a risk factor with letrozole that is not well-controlled with bisphosphonates.

Letrozole may be considered the drug of choice for women with a higher risk of breast cancer recurrence. In addition, women who have concerns about endometrial cancer may also be advised to consider letrozole. For those at risk for thromboembolic events, however, tamoxifen may be a more prudent choice.

ASCO 2005 Annual Meeting: Abstracts 4, 511. Presented May 15, 2005.

Reviewed by Gary D. Vogin, MD

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