Twenty-year benefit from adjuvant goserelin and tamoxifen in premenopausal patients with breast cancer

September 2022 Therapy Andrea Enguita

To gain information on the long-term benefit of endocrine therapy in premenopausal patients with breast cancer, the STO-5 trial randomly assigned  oestrogen receptor–positive premenopausal patients to adjuvant goserelin, tamoxifen, combined goserelin-tamoxifen therapy, or no endocrine therapy. After 20 years of follow-up, the results show long-term benefit from two years of adjuvant endocrine therapy and suggest differential treatment benefit on the basis of tumour genomic characteristics.

Premenopausal patients with breast cancer have an increased risk of fatal disease. Standard adjuvant treatment of premenopausal oestrogen receptor (ER)-positive breast cancer is tamoxifen for five years or more. Additional ovarian function suppression (OFS) with goserelin and/or chemotherapy is recommended in high-risk disease. However, the potential benefit of the combination tamoxifen and goserelin is still unclear in this setting, since diverse studies showed different results. Additionally, patients with ER-positive breast cancer have a steady long-term risk of developing distant metastatic recurrences, with a large proportion of these events occurring beyond ten years after primary diagnosis. Given this, longer follow-up is needed to understand the true endocrine treatment benefit in ER-positive breast cancer. The STO-5 trial therefore analysed the long-term benefit of 2-year treatment with goserelin, tamoxifen, the combination of the two, or no adjuvant endocrine therapy, in premenopausal patients with breast cancer. The STO-5 trial has now reached a complete follow-up of 20 years, and the results were recently published.

Study design

From 1990 to 1997, the Stockholm trial (STO-5) enrolled 924 premenopausal patients diagnosed with invasive operable breast cancer. Patients were randomly assigned to one of the four arms: two years of goserelin (3.6 mg subcutaneously once every 28 days), tamoxifen (40 mg orally once daily), combination of goserelin and tamoxifen, or no adjuvant endocrine therapy (control). Immunohistochemical (IHC) analysis of ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and proliferation marker Ki-67 was performed in 2020. Analysis was conducted for 731 patients with available primary tumour formalin-fixed paraffin-embedded blocks with sufficient invasive tumour cells for analysis. Gene expression profiling was also performed in 2019-2020 and classified primary tumours into low or high genomic risk. In total, 586 tumours passed the 70-gene signature quality check, whereof 463 were ER-positive. Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and multivariable time-varying flexible parametric modelling assessed the long-term distant recurrence-free interval (DRFI). Swedish high-quality registries allowed a complete follow-up of 20 years.

Results

Survival proportions at 20 years by DRFI were 71.6%, 66.0%, 67.1%, and 59.7% for patients randomly assigned to goserelin, tamoxifen, the combination, or control, respectively. Multivariable Cox proportional hazard regression analysis showed significantly improved long-term DRFI from goserelin, tamoxifen, and the combination (HR[95%]:0.49[0.32-0.75], HR[95%CI]:0.57[0.38-0.87], and HR[95%CI]:0.63[0.42-0.94], respectively), compared with control. Significant goserelin-tamoxifen interaction was observed (p= 0.016). Genomic low-risk patients (N= 305) significantly benefitted from tamoxifen (HR[95%CI]: 0.24[0.10-0.60]), and genomic high-risk patients (N= 158) from goserelin (HR[95%CI]: 0.24[0.10-0.54]). Compared with either therapy alone, further multivariable analyses showed no significant long-term benefit from the combination in genomic low-risk or high-risk patients. However, in genomic high-risk patients, a significantly increased long-term risk of distant recurrence from the addition of tamoxifen to goserelin was seen (HR[95%CI]: 3.36[1.39-8.07]). The interaction between goserelin and tamoxifen was significant in genomic high-risk patients (p= 0.006), but not in genomic low-risk patients (p= 0.080). Genomic low-risk patients had a steady long-term risk of distant recurrence. The estimated hazard rates were slightly increased from year five to ten, and remained steady throughout the 20-year follow-up. Moreover, a long-lasting benefit from tamoxifen was observed from year 4 to 20 compared with control, with significantly estimated HRs at years 5, 10, 15, and 20 showing a reduced risk (HR[25%CI]: 0.23[0.06-0.92] at year 20). Genomic high-risk patients had early risk and early benefit from goserelin. A large increase in the hazard rates was observed within the first five years that rapidly decreased thereafter. Significantly improved DRFI from goserelin was seen in the first eight years compared with control with a statistically significant estimated HR of 0.26 (95%CI: 0.11-0.61) at year 5.

Conclusions

The STO-5 trial study shows a 20-year benefit from 2-year of adjuvant endocrine therapy in ER-positive premenopausal patients with breast cancer. Additionally, genomic low-risk patients significantly benefitted from tamoxifen, while genomic high-risk patients benefitted from goserelin. For patients unable to endure five years of endocrine therapy, the significant benefit from two years of treatment, as seen in this study, could be helpful for both patients and clinicians. Moreover, no long-term benefit from combined goserelin-tamoxifen therapy over single treatment was observed in the STO-5 trial.

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. J Clin Oncol. 2022 Jul 21;JCO2102844.

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