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Original Investigation
August 8, 2019

Assessment of Long-term Distant Recurrence-Free Survival Associated With Tamoxifen Therapy in Postmenopausal Patients With Luminal A or Luminal B Breast Cancer

Author Affiliations
  • 1Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
  • 2Department of Surgery, University of California, San Francisco, San Francisco
  • 3Buck Institute for Research on Aging, Novato, California
  • 4Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
  • 5Department of Laboratory Medicine, University of California, San Francisco, San Francisco
  • 6Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill
  • 7Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  • 8Department of Oncology, Linköping University, Linköping, Sweden
  • 9Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
JAMA Oncol. 2019;5(9):1304-1309. doi:10.1001/jamaoncol.2019.1856
Key Points

Question  What is the long-term survival associated with tamoxifen therapy for postmenopausal patients with luminal A or luminal B subtype tumors?

Findings  This secondary analysis of the Stockholm Tamoxifen (STO-3) trial of 462 postmenopausal patients with lymph node-negative breast cancer found that patients with luminal A or luminal B tumor subtypes had a long-term risk of distant metastatic breast cancer and benefited from tamoxifen therapy for 15 years and 5 years after diagnosis, respectively.

Meaning  Patients with luminal A tumor subtype appeared to have a long-term benefit from tamoxifen therapy, and patients with luminal B subtype appeared to have an early benefit from therapy, when the risk of distant metastatic disease was high.


Importance  Patients with estrogen receptor (ER)–positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood.

Objective  To compare the long-term survival from tamoxifen therapy for patients with luminal A or luminal B tumor subtype.

Design, Setting, and Participants  Secondary analysis of patients from the Stockholm Tamoxifen (STO-3) trial conducted from 1976 to 1990, which randomized postmenopausal patients with lymph node–negative breast cancer to receive adjuvant tamoxifen or no endocrine therapy. Tumor tissue sections were assessed in 2014 using immunohistochemistry and Agilent microarrays. Only patients with luminal A or B subtype tumors were evaluated. Complete long-term follow-up data up to the end of the STO-3 trial on December 31, 2012, were obtained from the Swedish National registers. Data analysis for the secondary analysis was conducted in 2017 and 2018.

Interventions  Patients were randomized to receive at least 2 years of tamoxifen therapy or no endocrine therapy; patients without recurrence who reconsented were further randomized to 3 additional years of tamoxifen therapy or no endocrine therapy.

Main Outcomes and Measures  Distant recurrence-free interval (DRFI) by luminal A and luminal B subtype and trial arm was assessed by Kaplan-Meier analyses and time-dependent flexible parametric models to estimate time-varying hazard ratios (HRs) that were adjusted for patient and tumor characteristics.

Results  In the STO-3 treated trial arm, 183 patients had luminal A tumors and 64 patients had luminal B tumors. In the untreated arm, 153 patients had luminal A tumors and 62 had luminal B tumors. Age at diagnosis ranged from 45 to 73 years. A statistically significant difference in DRFI by trial arm was observed (log rank, P < .001 [luminal A subtype, n = 336], P = .04 [luminal B subtype, n = 126]): the 25-year DRFI for luminal A vs luminal B subtypes was 87% (95% CI, 82%-93%) vs 67% (95% CI, 56%-82%) for treated patients, and 70% (95% CI, 62%-79%) vs 54% (95% CI, 42%-70%) for untreated patients, respectively. Patients with luminal A tumors significantly benefited from tamoxifen therapy for 15 years after diagnosis (HR, 0.57; 95% CI, 0.35-0.94), and those with luminal B tumors benefited from tamoxifen therapy for 5 years (HR, 0.38; 95% CI, 0.24-0.59).

Conclusions and Relevance  Patients with luminal A subtype tumors had a long-term risk of distant metastatic disease, which was reduced by tamoxifen treatment, whereas patients with luminal B tumors had an early risk of distant metastatic disease, and tamoxifen benefit attenuated over time.