J Clin Oncol. 2022 Jul 21:JCO2102844. Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial. Johansson A, Dar H, van 't Veer LJ, Tobin NP, Perez-Tenorio G, Nordenskjold A, Johansson U, Hartman J, Skoog L, Yau C, Benz CC, Esserman LJ, Stal O, Nordenskjold B, Fornander T, Lindstrom LS. Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; Linkoping University, Linkoping, Sweden; Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden; University of California San Francisco, San Francisco, CA; Buck Institute for Research on Aging, Novato, CA. PURPOSE: To assess the long-term (20-year) endocrine therapy benefit in premenopausal patients with breast cancer. METHODS: Secondary analysis of the Stockholm trial (STO-5, 1990-1997) randomly assigning 924 premenopausal patients to 2 years of goserelin (3.6 mg subcutaneously once every 28 days), tamoxifen (40 mg orally once daily), combined goserelin and tamoxifen, or no adjuvant endocrine therapy (control) is performed. Random assignment was stratified by lymph node status; lymph node-positive patients (n = 459) were allocated to standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). Primary tumor immunohistochemistry (n = 731) and gene expression profiling (n = 586) were conducted in 2020. The 70-gene signature identified genomic low-risk and high-risk patients. Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and multivariable time-varying flexible parametric modeling assessed the long-term distant recurrence-free interval (DRFI). Swedish high-quality registries allowed a complete follow-up of 20 years. RESULTS: In estrogen receptor-positive patients (n = 584, median age 47 years), goserelin, tamoxifen, and the combination significantly improved long-term distant recurrence-free interval compared with control (multivariable hazard ratio [HR], 0.49; 95% CI, 0.32 to 0.75, HR, 0.57; 95% CI, 0.38 to 0.87, and HR, 0.63; 95% CI, 0.42 to 0.94, respectively). Significant goserelin-tamoxifen interaction was observed (P = .016). Genomic low-risk patients (n = 305) significantly benefitted from tamoxifen (HR, 0.24; 95% CI, 0.10 to 0.60), and genomic high-risk patients (n = 158) from goserelin (HR, 0.24; 95% CI, 0.10 to 0.54). Increased risk from the addition of tamoxifen to goserelin was seen in genomic high-risk patients (HR, 3.36; 95% CI, 1.39 to 8.07). Moreover, long-lasting 20-year tamoxifen benefit was seen in genomic low-risk patients, whereas genomic high-risk patients had early goserelin benefit. CONCLUSION: This study shows 20-year benefit from 2 years of adjuvant endocrine therapy in estrogen receptor-positive premenopausal patients and suggests differential treatment benefit on the basis of tumor genomic characteristics. Combined goserelin and tamoxifen therapy showed no benefit over single treatment. Long-term follow-up to assess treatment benefit is critical. KEY OBJECTIVE: The long-term endocrine therapy benefit in premenopausal patients with breast cancer, diagnosed early in life, is important to understand, given the long-term risk of distant recurrence in estrogen receptor (ER)-positive disease. The unique STO-5 trial with a complete follow-up of 20 years randomly assigned premenopausal patients to adjuvant goserelin, tamoxifen, combined goserelin-tamoxifen therapy, or no endocrine therapy (control). To our knowledge, for the first time the long-term benefit of goserelin and tamoxifen in premenopausal patients is assessed. KNOWLEDGE GENERATED: This study demonstrates long-term benefit from 2 years of adjuvant endocrine therapy in ER-positive premenopausal patients. Furthermore, it suggests long-lasting benefit from tamoxifen in genomic low-risk patients with long-term risk of distant recurrence, whereas genomic high-risk patients have early risk and benefit from goserelin. RELEVANCE: Premenopausal patients with ER-positive breast cancer have long-term benefit of endocrine therapy; however, the heterogenous metastatic potential gives rise to differential treatment benefit and a need for personalized endocrine therapy. PMID: 35862873 DOI: 10.1200/JCO.21.02844
