Nick Mulcahy

June 02, 2013

Ten years of adjuvant treatment with tamoxifen was better than the standard 5 years in terms of reducing the risk for breast cancer recurrence and disease-specific death, according to results from a second large study of this issue.

The trial, known as aTTom (adjuvant Tamoxifen Treatment offers more?), was conducted in the United Kingdom and confirms the results from another major international trial, ATLAS (Adjuvant Tamoxifen, Longer Against Shorter). The results from ATLAS, which involved 6800 women, were reported in late 2012 by Medscape Medical News.

In the new study, nearly 7000 women received 5 years of tamoxifen and then were randomly assigned to either stop treatment or continue treatment to 10 years; the longer-treatment group had fewer breast cancer recurrences compared with the 5-year treatment group (28% vs 32%; P = .003).

Dr. Richard Gray

Longer treatment also reduced breast cancer mortality compared with 5 years of treatment (392 vs 443 deaths after recurrence; 21% vs 24%; P = .06). On a down note, in the new study, endometrial cancer was increased with longer tamoxifen use, report the authors, led by Richard G. Gray, a professor of medical statistics at the University of Oxford in the United Kingdom.

Gray will present the full aTTom study results here today at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

The results are "practice changing" for premenopausal women with hormone-receptor-positive breast cancer, said an oncologist not involved with the study.

"These results are...especially relevant for women who are at high risk of recurrence," added Sylvia Adams, MD, ASCO spokesperson and breast cancer expert, in a press statement. She is from New York University School of Medicine in New York City.

The new study shows a "modest but real benefit," Claudine Isaacs, MD, of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, told Medscape Medical News. She was not involved with the study.

Daily tamoxifen for 5 years is already the current worldwide standard for the treatment of hormone-receptor-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, explained Gray.

"Five years of adjuvant tamoxifen is already an excellent treatment, but we thought that longer treatment might be even better because women with ER-positive [estrogen-receptor positive] breast cancer can have recurrences long after treatment is completed. Until now, though, there have been doubts whether continuing tamoxifen beyond 5 years is worthwhile," he said in a press statement.

Now, the combination of results from the 2 major trials provides strong evidence that benefits come from extending tamoxifen treatment, he suggested.

Whether or not women will embrace 5 more years of tamoxifen — and its attendant side effects — is not certain.

However, Dr. Isaacs pointed out the obvious: "These women have already taken 5 years of tamoxifen." As a result, they will have experienced side effects such as hot flashes and, less commonly, vaginal discharge, vaginal dryness, and joint pain, she said, suggesting that they may be inclined to continue because of their familiarity with the treatment annoyances.

Timing of Benefit and Adverse Events

From 1991 to 2005, aTTom investigators randomly assigned 6953 women from 176 UK centers who had been using tamoxifen for 5 years to either continue treatment with tamoxifen for another 5 years or to stop immediately.

The women were either ER-positive (n = 2755) or untested (n = 4198; estimated to be 80% ER-positive if status unknown).

About 5000 women were followed for more than 10 years after randomization.

The women were contacted annually to assess treatment compliance, recurrence, hospital admissions, and death rates. About 75% of women in the 10-year group continued to take tamoxifen as directed, according to meeting press materials.

The additional years on tamoxifen had little effect on recurrence and mortality during the period of 5 to 9 years after diagnosis. By contrast, during the second decade after diagnosis, the women who had been allocated to continue tamoxifen treatment had a 25% lower breast cancer mortality rate than the women who had been allocated to stop after only 5 years.

Non-breast-cancer mortality was little affected in the longer treatment and 5-year treatment groups (457 vs 467 deaths; rate ratio, 0.94).

The longer time on tamoxifen increased the risk for endometrial cancer, a known side effect of treatment. There were 102 vs 45 endometrial cancers in the 10-year and the 5-year treatment groups, respectively. This translated to a relative risk for the cancer of 2.20 (P < .0001) with the longer treatment.

Also, among the longer treatment group, there were 37 deaths from endometrial cancer (1.1%) compared with 20 such deaths (0.6%) in the 5-year group (absolute hazard, 0.5%; P = .02).

Dr. Isaacs described the excess endometrial cancer as a "relatively small risk" and said the cancer was "treatable."

The risk-benefit ratio, in terms of lives saved from breast cancer and lives lost to endometrial cancer, is "clearly in favor of the additional treatment with tamoxifen," said Dr. Isaacs. She also pointed out that the investigators did not find an increased risk for stroke or heart disease.

The researchers have estimated that for every endometrial cancer death that occurs as a side effect of long-term tamoxifen, there would be 30 deaths from breast cancer prevented.

Therefore, the benefits of continuing tamoxifen to 10 years greatly outweigh the risks, according to Gray.

The study was funded by Cancer Research UK and the UK Medical Research Council. Richard Gray has disclosed no relevant financial relationships. Dr. Isaacs reported that she is on the speaker's bureau of AstraZeneca Pharmaceuticals LP. Dr. Adams reports financial ties to GlaxoSmithKline.

2013 Annual Meeting of the American Society of Clinical Oncology. Abstract 5. Presented June 2, 2013.

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