Stage I, II, IIIA, and Operable IIIC Breast Cancer
Whether the optimal duration of adjuvant tamoxifen therapy in premenopausal women is 5 years or 10 years is controversial. Results from the NSABP-B-14 study, which compared a 5-year regimen to a 10-year regimen of adjuvant tamoxifen for women with early-stage breast cancer, indicated no advantage for continuation of tamoxifen beyond 5 years in women with node-negative, ER-positive breast cancer.[Level of evidence: 1iA] Another trial demonstrated the equivalence of 5 years and 10 years of therapy.[Level of evidence: 1iiDii] In both trials, there was a trend toward a worse outcome associated with a longer duration of treatment.
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 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 to 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.
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.