ATLAS: 10 Years of Adjuvant Tamoxifen Offers More Benefit

Nick Mulcahy

December 10, 2012

SAN ANTONIO, Texas — Ten years of adjuvant treatment with tamoxifen was significantly better than the standard 5 years in terms of reducing the risk for breast cancer recurrence and disease-specific death, according to findings from the international ATLAS (Adjuvant Tamoxifen, Longer Against Shorter) study.

Just how clinical practice will be affected was less clear than the statistical results, noted a number of experts here at the 35th Annual San Antonio Breast Cancer Symposium (SABCS).

"The benefits far outweigh the risks — that's the main finding from the ATLAS study," said study author Richard Gray, MSc, professor of medical statistics at Oxford University in the United Kingdom, about taking the antiestrogen drug for 10 years. He spoke during a meeting press conference.

Dr. Gray explained that daily tamoxifen for 5 years is widely used around the world to treat estrogen-receptor (ER)-positive breast cancer and has repeatedly been proven to reduce breast cancer mortality. However, it has not been clear whether continuing beyond 5 years produces further benefit.

ATLAS addressed this by randomizing 6846 women with ER-positive disease who had been using tamoxifen for 5 years to continue for another 5 years (continuers group) or to stop immediately (control group).

Many participants have been followed for 10 years (the median is 7.6 years), which creates a study period of 15 years so far. The women, who are from 36 countries, are both pre- and postmenopausal.

Continuing tamoxifen reduced the risk for breast cancer recurrence, compared with stopping tamoxifen (617 vs 711; P = .002), reduced breast cancer mortality (331 vs 397 deaths; P = .01), and reduced overall mortality (639 vs 722 deaths; P = .01).

The risk for recurrence by year 15 was 21.4% in the continuers group and 25.1% in the control group.

In addition, breast cancer mortality by year 15 was significantly reduced by nearly 3%; it was 12.2% in the continuers group and 15.0% in the control group.

The study was published online today in the Lancet to coincide with its presentation.

The public health implications could be quite large.

"The public health implications could be quite large, even for this small effect," said William Barlow, PhD, from the Fred Hutchison Cancer Research Center in Seattle, Washington, about this 2.8% absolute reduction in mortality. He served as discussant of the study.

The results will eventually change clinical practice, according to another expert.

But first, the results of ALTAS must be confirmed with a meta-analysis of the other extended tamoxifen studies, such as the NSABP B-14 trial, writes Trevor J. Powles, PhD, from the Cancer Centre London in the United Kingdom, in an accompanying comment.

A confirmation "should herald a change of practice, with the standard of care revised to 10 years rather than 5 years of tamoxifen in patients for whom tamoxifen is indicated," he writes.

The practice change is justified because the benefits of 10 years of treatment "substantially" outweigh the harms, according to Dr. Powles.

After 10 years of treatment with tamoxifen, there was an increased risk for endometrial cancer (relative risk [RR], 1.74) and for pulmonary embolism (RR, 1.87). Specifically, endometrial cancers occurred in 3.1% (with mortality of 0.4%) of the continuers group and in 1.6% (with mortality of 0.2%) of the control group. There were only 18 pulmonary embolism events and there was an equal amount of mortality (0.2%) in each treatment group. Additionally, there was no increase in the incidence of stroke and a decrease in the incidence of ischemic heart disease in the continuers group.

Which Patients?

The ATLAS findings raise questions about how to treat postmenopausal women, Dr. Powles notes.

Five years of aromatase inhibitors, such as letrozole, is the preferred treatment for these women, particularly those with a poor prognosis. "No data are available to suggest that letrozole for 5 years is better for long-term benefit than 10 years of tamoxifen," he writes, referring to the ATLAS findings.

"Should these patients be given 10 years of treatment with an aromatase inhibitor? Should they have 5 years of an aromatase inhibitor followed by 5 years of tamoxifen? Would more than 10 years of tamoxifen be even better than 10 years?" No data exist to support any of these speculative options, Dr. Powles concludes.

However, Dr. Barlow, who is a biostatistician, said that the 10-year data from the MA 17 trial "tend to favor letrozole" over the 10-year tamoxifen data from ATLAS for postmenopausal women. He acknowledged that a head-to-head comparison of the data is not possible because of the difference in outcome measures between the 2 studies. The MA 17 trial randomly allocated women who had completed 5 years of tamoxifen to 5 years of letrozole or no further treatment. In that trial, the rate of relapse was significantly lower with letrozole (and there was a significant reduction in mortality in the node-positive subgroup).

Clearer Direction for Younger Women

The ATLAS study provides clearer direction for the treatment of premenopausal women, partly because aromatase inhibitors do not work in these women.

"Extension of treatment to 10 years would seem to provide added benefit," Dr. Powles writes about tamoxifen for young women.

Another expert agrees.

The results of ATLAS are most relevant for younger women.

"The results of ATLAS are most relevant for younger women," said Peter Ravdin, MD, who moderated the press conference. Dr. Ravdin is codirector of the SABCS and director of the Comprehensive Breast Health Clinic at the University of Texas Health Science Center at San Antonio.

Dr. Ravdin plans on telling his premenopausal patients with ER-positive disease that 10 years of tamoxifen has benefit over the standard of 5 years. "I am going to be comfortable doing that," he said. The risk for endometrial cancer with tamoxifen is "very low" in these younger women, he added. "I think this trial will have a major immediate impact on premenopausal women."

However, tamoxifen beyond 5 years is not for every premenopausal woman.

He explained that he would lean toward recommending it to women who are at high risk for late relapse (those with positive nodes and/or bigger tumors). Women with small grade 1 cancers are not good candidates because their risk for recurrence is so low. Taking tamoxifen comes with quality-of-life issues, such as hot flashes and other effects, he reminded reporters. Many women already struggle to complete 5 years of tamoxifen because of the adverse effects, so taking the drug for 10 years will present challenges.

The study was funded by Cancer Research UK, the UK Medical Research Council, AstraZeneca, the United States Army, and EU Biomed. Dr. Gray and coauthors Dr. Ravdin, Dr. Barlow, and Dr. Powles have disclosed no relevant financial relationships.

Lancet. Published online December 5, 2012. Abstract, Comment

35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S1-2. Presented December 5, 2012