In the EST-5181 trial, node-positive women who had already received 5 years of tamoxifen following chemotherapy were randomly assigned to continue therapy or observation. In the ER-positive subgroup, a longer time to relapse was associated with continued tamoxifen use, but no improvement in OS was observed.
Long-term follow-up of the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial, which randomly assigned 12,894 women with early breast cancer between 1996 and 2005, revealed that 10 years of tamoxifen reduced the risk of breast cancer recurrence (617 recurrences vs. 711 recurrences, 10 years vs. 5 years, respectively; P = .002), reduced breast- cancer mortality (331 deaths vs. 397 deaths, P = .01), and reduced overall mortality (639 deaths vs. 722 deaths, P = .01).[Level of Evidence: 1iiA]. Of note, from the time of the original breast cancer diagnosis, the benefits of 10 years of therapy were less extreme before than after year 10. At 15 years from the time of diagnosis, breast cancer mortality was 15% versus 12.2%, at 10 years and 5 years, respectively. Compared with 5 years, 10 years of tamoxifen therapy increased the risks of the following:
- Pulmonary embolus relative risk (RR), 1.87 (95% CI, 1.13–3.07, P = .01).
- Stroke RR, 1.06 (0.83–1.36).
- Ischemic heart disease RR, 0.76 (0.6–0.95, P = .02).
- Endometrial cancer RR, 1.74 (1.30–2.34, P = .0002).
Notably, the cumulative risk of endometrial cancer during years 5 to 14 from breast cancer diagnosis was 3.1% for women who received 10 years of tamoxifen versus 1.6% for women who received 5 years of tamoxifen. The mortality for years 5 to 14 was 12.2 versus 15 for an absolute mortality reduction of 2.8%.
These trials raise important questions about the optimal duration of endocrine therapy. Of note, the long-term ATLAS data are really applicable for women who remain premenopausal after 5 years of tamoxifen therapy. Randomized clinical trial data support the use of aromatase inhibitors in postmenopausal women. (Refer to the Aromatase Inhibitors section of this summary for more information.) For women who remain premenopausal after 5 years of tamoxifen, discussion with the patient about the risks and benefits of extending tamoxifen therapy should occur. Because of the conflict in data, the optimal duration is controversial.