10 Years of Adjuvant Tamoxifen Better Than 5

Abstract & Commentary

By Gary R. Shapiro, MD, Medical Director, Cancer Center of Western Wisconsin, New Richmond, WI. Dr. Shapiro reports no financial relationships relevant to this field of study.

Synopsis: Ten years of adjuvant tamoxifen is significantly better than the standard 5 years of treatment. Continuing adjuvant tamoxifen for 10 years substantially reduces rates of both recurrence and breast cancer-specific mortality in women with estrogen receptor-positive breast cancer.

Source: Davies C, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomized trial. Lancet 2012 http://dx.doi.org/10.1016/S0140-6736(12)61963-1 [Epub ahead of print].

The worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial randomized 12,894 women with early breast cancer who had completed 5 years of adjuvant tamoxifen to continue tamoxifen to 10 years or stop at 5 years. The effects of extended tamoxifen therapy on breast cancer outcomes for the 6846 women with estrogen receptor (ER)-positive disease were reported simultaneously at the 2012 San Antonio Breast Cancer Symposium and in this Lancet Early Online Publication.

Continuing tamoxifen in this group of pre- and postmenopausal women reduced overall mortality (639 deaths vs 722 deaths, P = 0.01), breast cancer mortality (331 deaths vs 397 deaths, P = 0.01), and breast cancer recurrence (617 recurrences vs 711, P = 0.002). With a median of 7.6 years of follow-up, the study is able to report outcomes to 15 years. The cumulative risk of recurrence during years 5-14 was 21.4% for the extended treatment group, compared to 25.1% for the control group that received only 5 years of adjuvant tamoxifen. Breast cancer mortality by year 15 was significantly reduced by approximately 3% (12.2% vs 15.0% in the control group).

The ATLAS Collaborative Group reported side effects among all 12,894 women: ER-positive, ER-negative, and unknown hormone receptor status. The cumulative risks of endometrial cancer (relative risk [RR] 1.74) and of pulmonary embolism (RR 1.87) were increased during years 5-14. The mortality rate from pulmonary embolism was only 0.2%, and was equal in each of the treatment groups. Endometrial cancers occurred in 3.1% (with mortality of 0.4%) of the extended treatment group compared to 1.6% (with mortality of 0.2%) of the control group that received only 5 years of adjuvant tamoxifen. The study found no increase in the incidence of stroke and a decrease in the incidence of ischemic heart disease in the extended treatment group.

Commentary

The ATLAS data are in keeping with the results of other studies that support longer courses of adjuvant anti-estrogen therapy in women with ER-positive breast cancer. Not only do the data show that women who continue tamoxifen for 10 years actually do better, but their lower risk of recurrence and improved survival come with little added risk.

Of interest is the finding that 10 years of tamoxifen in patients with ER-positive breast cancer produces significant reductions in rates of recurrence and in breast cancer mortality, not only during the 10 years of actual treatment, but also during the second decade after treatment ends. Indeed, the ATLAS analysis suggests that breast cancer mortality during the second decade after diagnosis is halved when tamoxifen is taken for a full 10 years compared to no adjuvant tamoxifen at all. Although the reductions in adverse breast cancer outcomes appeared to be less extreme before (years 5-9) than after 10 years (RR 0.90 vs 0.75 for recurrence and RR 0.97 vs 0.71 for mortality), it is important to realize that the benefit from even 5 years of tamoxifen extends to year 10.

Only endometrial cancer deaths were increased in those women receiving 10 years of tamoxifen compared to 5, but the ATLAS authors point out that the actual difference may be even smaller than the 0.2% reported, when one makes allowances for compliance issues. Whatever the case may be, the risk of endometrial cancer is extremely low and is dwarfed by the survival benefit afforded by the longer tamoxifen regimen. Indeed, the increased incidence of endometrial cancer in this and other studies1 is primarily in postmenopausal women who have not had a hysterectomy. Premenopausal women, the group probably most affected by this study, have little increased risk.

Postmenopausal women with ER-positive breast cancers have been offered post-tamoxifen aromatase inhibitor therapy, ever since the MA.17 trial showed they did better with an additional 5 years of adjuvant therapy using letrozole.2 The ATLAS findings will probably not change that practice for the time being. Like MA.17, ATLAS convincingly demonstrates the benefit of 10 years, as opposed to 5 years, of adjuvant anti-estrogen therapy in women with ER-positive breast cancer. It does not, however, provide any information regarding the relative merits of 10 years of tamoxifen vs 5 years of tamoxifen followed by 5 years of an aromatase inhibitor. Although the trend does seem to be in favor of longer over shorter therapy, no data are yet available to suggest that 10 years of tamoxifen is better than 5 years of an aromatase inhibitor or that postmenopausal women should continue with 5 additional years of either an aromatase inhibitor or tamoxifen after they have completed the standard 5-year course of aromatase inhibitor adjuvant therapy.

Until further studies clarify these issues, the ATLAS findings are probably most useful for women with ER-positive breast cancers who remain premenopausal after they have completed 5 years of adjuvant tamoxifen. Here the data are clear — an additional 5 years of tamoxifen significantly improves survival with very little added risk.

References

1. Early Breast Cancer Trialists Collaborative Group (EBCTCG), et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level meta-analysis of randomized trials. Lancet 2011;378:771-784.

2. Goss PE, et al, National Cancer Institute of Canada Clinical Trials Group MA.17. Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Cancer Institute of Canada Clinical Trials Group MA.17. J Clin Oncol 2007;25:2006-2011.