Tamoxifen therapy benefit in luminal A and B breast cancer with 20-year follow-up

BACKGROUND: Patients with estrogen receptor-positive breast cancer have a substantial late risk of distant recurrence, but the long-term subtype-specific tamoxifen benefit remains poorly understood. METHODS: A secondary analysis of the Stockholm Tamoxifen randomized trials (1976-1997, n = 3930) with 20-year follow-up was conducted. Formalin-fixed, paraffin-embedded blocks were available for 2250 patients. A total of 952 patients with estrogen receptor-positive and HER2-negative tumors, classified as luminal A (n = 688) and luminal B (n = 264) using Agilent microarrays, were analyzed. Patients were randomly assigned to at least 2 years of tamoxifen therapy or no endocrine therapy. Distant recurrence-free interval was assessed by Kaplan-Meier analysis and multivariable Cox proportional hazards regression. RESULTS: Patients with luminal A tumors had low early risk and modest early benefit from tamoxifen therapy (5-year distant recurrence-free interval treated vs control: 93% vs 89%; absolute difference = 4%) that increased over the 20-year follow-up (20-year distant recurrence-free interval: 76% vs 66%; absolute difference = 10%), highlighting long-term benefit. In contrast, patients with luminal B tumors had larger early risk and treatment benefit (5-year distant recurrence-free interval: 72% vs 57%; absolute difference = 15%), which remained stable over time (20-year distant recurrence-free interval: 55% vs 37%; absolute difference = 18%). Multivariable analyses showed that luminal patients benefited from tamoxifen therapy (luminal A: adjusted hazard ratio [HR] = 0.57, 95% confidence interval [CI] = 0.42 to 0.78; luminal B: adjusted HR = 0.68, 95% CI = 0.46 to 0.99). Patients with favorable tumor characteristics benefited regardless of luminal subtype. CONCLUSIONS: Tamoxifen reduces the long-term risk of distant recurrence in luminal A and B tumors, although timing of benefit varies by subtype. Even after treatment, patients with luminal tumors have a substantial late risk, highlighting the need for long-term follow-up. CLINICAL TRIAL REGISTRATION: The trial center for the Stockholm Tamoxifen trials was the Regional Cancer Center Stockholm-Gotland, in Stockholm, Sweden. The start of the Stockholm Tamoxifen trials in 1976 was before the custom of trial registration started in Sweden, therefore no trial number is available.