Stockholm part of the Zoladex in Premenopausal Patients study (STO-5) of premenopausal patients with oestrogen receptor (ER)-positive breast cancer demonstrates a significant 20-year benefit of 2 years of goserelin, tamoxifen, and the combination, compared with no adjuvant endocrine treatment. Furthermore, the study suggests that genomic low-risk patients have significant long-lasting benefit from tamoxifen, whereas genomic high-risk patients have early benefit from goserelin. The combination of goserelin and tamoxifen showed no long-term benefit over single treatment. Dr. Annelie Johansson of the Department of Oncology and Pathology, Karolinska Institutet in Stockholm, Sweden and colleagues commented in the article published on 21 July 2022 in the Journal of Clinical Oncology that for patients unable to endure 5 years of endocrine treatment, the significant benefit from 2 years of treatment as seen in this study could be helpful. The study has limited sample size, but allows unique assessment of the long-term effects of adjuvant endocrine treatment in premenopausal patients with breast cancer.
The authors wrote in the study background since premenopausal patients with breast cancer are diagnosed early in life, the long-term risk and treatment benefit are of particular interest in this patient group. Standard adjuvant treatment of premenopausal ER-positive breast cancer is tamoxifen for 5 years or more. Additional ovarian function suppression, such as goserelin, and/or chemotherapy is recommended in high-risk disease, often defined by standard clinical markers including lymph node involvement, high tumour grade, high proliferation, high genomic risk signature scores, and an age below 40 years. It is not clear which patients should be offered the ovarian function suppression.
Patients with ER-positive breast cancer have a long-term risk of developing distant metastatic recurrences, with a large proportion of these events occurring beyond 10 years after primary diagnosis. Therefore, longer follow-up is needed to understand the true endocrine treatment benefit in ER-positive breast cancer. In addition, the long-term benefit of adjuvant ovarian function suppression remains unknown, as there is a general lack of clinical studies with 10 or more years outcome data.
The STO-5 study has reached a complete follow-up of 20 years. In the latest article, the authors present the long-term endocrine treatment benefit in premenopausal patients with breast cancer randomly assigned to two years of goserelin, tamoxifen, the combination of the two, or no adjuvant endocrine treatment. They also assessed treatment arm specific endocrine treatment benefit according to genomic risk stratification, using the molecular 70-gene signature risk prediction tool. This signature has known prognostic utility among young patients with breast cancer, but whether it has endocrine treatment predictive value remains unexplored.
The study team performed secondary analysis of STO-5 that randomly assigned 924 premenopausal patients to one of four arms. Random assignment was stratified by lymph node status and 459 lymph node–positive patients were allocated to adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. Primary tumour immunohistochemistry in 731 and gene expression profiling in 586 samples were performed 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.
In 584 patients with ER-positive tumours, goserelin, tamoxifen, and the combination significantly improved long-term DRFI compared with control (multivariable hazard ratio [HR] 0.49, 95% confidence interval [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 = 0.016). In total, 305 genomic low-risk patients significantly benefitted from tamoxifen (HR 0.24, 95% CI 0.10 to 0.60), and 158 genomic high-risk patients 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). Long-lasting 20-year tamoxifen benefit was seen in genomic low-risk patients, whereas genomic high-risk patients had early goserelin benefit.
The authors commented that advantages of the STO-5 study include long-term high-quality follow-up and inclusion of a control group of patients randomly assigned to no endocrine treatment. For the first time the long-term benefit of goserelin and tamoxifen in premenopausal patients with breast cancer is assessed. The study shows 20-year benefit from 2 years of adjuvant endocrine treatment in ER-positive premenopausal patients and suggests differential treatment benefit based on the tumour genomic characteristics. Combined goserelin and tamoxifen therapy showed no benefit over single treatment. Long-term follow-up to assess treatment benefit is critical as premenopausal patients with ER-positive breast cancer have long-term benefit of endocrine treatment. However, the heterogenous metastatic potential gives rise to differential treatment benefit and a need for personalised endocrine treatment.
The study findings were previously presented at 2021 ESMO Breast Cancer Virtual Congress.
The study was supported by multiple grants from the Swedish Research Council, the Swedish Research Council for Health, Working life and Welfare, ALF medicine, the Gösta Milton Donation Fund, the Swedish Cancer Society, Stockholm Cancer Society, the California Breast Cancer Research Program, the US National Institutes of Health, and the Horizon 2020 in collaboration with Agendia.
Reference
Johansson A, Dar H, van’t Veer LJ, et al.Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial. JCO; Published online 21 July 2022. DOI: 10.1200/JCO.21.02844