Tamoxifen's hidden strength: Benefits grow over two decades for certain breast cancers

BACKGROUND: Patients with ER-positive breast cancer have a substantial late risk of distant recurrence, but the long-term subtype-specific tamoxifen benefit remains poorly understood. METHODS: Secondary analysis of the Stockholm Tamoxifen (STO) randomized trials (1976-1997, n = 3930) with 20-year follow-up. FFPE blocks were available for 2250 patients. 952 patients with ER-positive/HER2-negative tumors classified as luminal A (n = 688) and luminal B (n = 264) using Agilent microarrays were analyzed. Patients were randomized to at least 2 years of tamoxifen therapy or no endocrine therapy. Distant recurrence-free interval (DRFI) 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 DRFI treated vs control: 93% vs 89%, absolute difference 4%) that increased over the 20-year follow-up (20-year DRFI: 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 DRFI: 72% vs 57%, absolute difference 15%), which remained stable over time (20-year DRFI: 55% vs 37%, 18% absolute difference).Multivariable analyses showed that luminal patients benefited from tamoxifen therapy (luminal A adjusted hazard ratio [aHR]=0.57, 95% CI 0.42-0.78 and luminal B aHR = 0.68, 95% CI 0.46-0.99). Patients with favorable tumor characteristics benefited regardless of luminal subtype. CONCLUSIONS: Tamoxifen reduces the long-term risk of distant recurrence in both 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.