The ATLAS trial: Duration of adjuvant tamoxifen in ER-positive breast cancer [Classics Series]

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1. Among women with early ER-positive breast cancer, continuing adjuvant tamoxifen for 10 years versus stopping at 5 years after diagnosis significantly reduced breast cancer recurrence, breast cancer mortality, and overall mortality 

2. Patients treated with adjuvant tamoxifen for 10 years had significantly higher risk of endometrial cancer and pulmonary embolism

Original Date of Publication: March 9, 2013

Study Rundown: In women with estrogen receptor (ER)-positive breast cancer, previous trials had demonstrated that treatment with adjuvant tamoxifen for 5 years significantly reduced the risk of recurrence both during the treatment time and for 10 years after. During this 15-year period, mortality from breast cancer was also significantly reduced. Tamoxifen treatment, however, is linked with significantly increased risk of certain side effects, including endometrial cancer and thromboembolic disease. The Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial compared the effects of 10 years of adjuvant tamoxifen treatment with 5 years of adjuvant tamoxifen treatment on outcomes in patients with ER-positive breast cancer. Over the duration of follow up, 10-year treatment significantly reduced breast cancer recurrence (RR 0.84; 95%CI 0.76-0.94), breast cancer mortality (RR 0.83; 95%CI 0.72-0.96), and overall mortality (RR 0.87; 95%CI 0.78-0.97) compared to the standard 5-year course of tamoxifen. However, this increased benefit came at the expense of significantly increased rates of endometrial cancer and pulmonary embolism. The study remains ongoing and future data will help elucidate the longer-term effects of prolonged tamoxifen treatment in patients with early ER-positive breast cancer.

Click to read the study in The Lancet

In-Depth [randomized, controlled study]: This multinational study included 12,894 women with early breast cancer, 6,454 of whom were randomized to continue tamoxifen for 10 years (i.e., the intervention group) after diagnosis and 6,440 of whom were randomized to stop tamoxifen use at 5 years (i.e., the control group). While all 12,894 were included in the analysis for side effects, only women with ER-positive disease were included in the main analysis for breast cancer recurrence and mortality – a total of 6,846 women. Patients were eligible for inclusion if they had early breast cancer (i.e., completely resectable disease), they had subsequently received tamoxifen and were still on it (or had stopped in the past year and could resume treatment quickly), they were clinically free of disease (i.e., local recurrence resected, no distant recurrence), follow-up was practicable, and there was uncertainty between the patient and her physician regarding whether to continue tamoxifen treatment. There were no restrictions based on patient age, the type of initial surgery or histology, hormone receptor status, nodal status, or other treatments. Patients were not eligible if they had any contraindications to continuing tamoxifen (e.g., pregnancy, breastfeeding, retinopathy, endometrial hyperplasia).

In women with ER-positive disease, continuing tamoxifen treatment for 10 years significantly reduced the risk of breast cancer recurrence (RR 0.84; 95%CI 0.76-0.94), breast cancer mortality (RR 0.83; 95%CI 0.72-0.96), and overall mortality (RR 0.87; 95%CI 0.78-0.97) when compared to 5 years of treatment. Notably, during years 5-14 after diagnosis, the absolute recurrence reduction was 3.7% with extended tamoxifen treatment (21.4% vs. 25.1%). The relative risk of pulmonary embolus (RR 1.87; 95% CI 1.13-3.07) and endometrial cancer (RR 1.74; 95%CI 1.30-2.34) were significantly higher in women who continued tamoxifen compared to the control group, while the risk of ischemic heart disease was significantly reduced (RR 0.76; 95%CI 0.60-0.95).

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