SAN ANTONIO – Five years of adjuvant tamoxifen in women with estrogen receptor–positive early breast cancer is well established as being excellent therapy with a long-term carryover effect. Now 10 years has been shown to be even better.
A new analysis from the large international ATLAS trial demonstrated that participants randomized to 10 years of adjuvant tamoxifen had a 25% reduction in recurrences and a 29% lower mortality due to breast cancer in years 10-14 after diagnosis, compared with women who stopped the drug after the standard 5 years, Richard Gray, M.Sc., reported at the San Antonio Breast Cancer Symposium.
Richard Gray
These findings from ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) are all the more impressive in light of the 2011 Early Breast Cancer Trialists’ Collaborative Group overview analysis, which features 15 years of follow-up of more than 10,000 women in randomized trials pitting 5 years of tamoxifen versus no tamoxifen (Lancet 2011;378:771-84). The meta-analysis showed that 5 years of tamoxifen reduced deaths due to breast cancer by 34% during the first 5 years after treatment ended and by 27% in the subsequent 5 years.
Thus, 10 years of tamoxifen had to compete against a big carryover effect of 5 years of the drug, noted Mr. Gray, professor of medical statistics at the University of Oxford (U.K.).
By multiplying the risk reduction ratios from ATLAS and the Oxford overview, he estimated that 10 years of tamoxifen reduces breast cancer mortality by one-third in the first decade following diagnosis and by fully half in the second decade, compared with no tamoxifen.
Benefits Far Outweigh Risks
The ATLAS analysis involved 6,846 randomized women with estrogen receptor–positive disease. The cumulative risk of recurrence during years 5-14 after diagnosis was 21.4% in women assigned to 10 years of tamoxifen and 25.1% in controls. Breast cancer mortality during years 5-14 was 12.2% in patients on 10 years of tamoxifen and 15.0% in those who stopped after 5 years, for an absolute mortality reduction of 2.8%.
The benefits of 10 years of tamoxifen compared with 5 far outweighed the risks, Prof. Gray continued. The cumulative risk of endometrial cancer in years 5-14 was 3.1% for women randomized to continue therapy for 10 years, compared with 1.6% for controls. Mortality due to endometrial cancer was rare, however: 0.4% in the extended therapy group and 0.2% in controls.
"I think these ATLAS results are relevant to quite a wide range of women. And the findings encourage one to think that aromatase inhibitors, too, might be more effective with longer therapy," he said.
Indeed, ongoing clinical trials are comparing outcomes with 10 versus the standard 5 years of adjuvant aromatase inhibitor therapy.
But aromatase inhibitors are not an option in premenopausal patients because they’re ineffective in that setting. In addition, some postmenopausal breast cancer patients can’t tolerate aromatase inhibitors due to arthralgias, bone pain, or other side effects. And while aromatase inhibitors are now the standard of care for adjuvant therapy in postmenopausal patients in the United States and Europe, tamoxifen remains widely used in developing countries because it’s so much less expensive, he added.
Data Are Compelling
Dr. Peter Ravdin called the ATLAS data compelling.
"I think the results of this trial will have a major immediate impact on premenopausal women. For women who are now approaching 5 years of therapy, up until this point we’d have told them we’re going to be stopping the drug. Now we’re going to be telling them that there’s clinical evidence that 10 years is superior to 5 years. And I’m going to be comfortable doing that," said Dr. Ravdin, director of the breast health clinic at the Cancer Therapy and Research Center of the University of Texas, San Antonio.
"One of the things that I think is profoundly important about this study is that the biology of the disease shows that there are some women fated to have late relapse that our early treatments aren’t effective in blocking, but that we can do better by treating women with hormonal therapy beyond 5 years," he added.
Women with a relatively high risk of late relapse – that is, those with larger tumors and/or positive lymph nodes – will definitely be strong candidates for continuation of therapy. Those with small grade 1 tumors and a very low risk of both early and late relapse might rationally decide they don’t want to take tamoxifen for longer than 5 years, according to the oncologist.
The risk of tamoxifen-related endometrial cancer in premenopausal patients is negligible. But some women experience such problematic tamoxifen-induced hot flashes or vaginal symptoms that they may balk at continuing treatment beyond 5 years.