Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial

Abstract

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.

Short Bouts of Physical Activity—Good for Health?

“…A recent study by the first and last authors 10 of the present study suggested that a little more than 4 min/d of VILPA is also associated with a reduction in risk of cardiovascular disease, cancer, and all-cause mortality in both exercisers and nonexercisers. 10 Lifestyle and habits of physical activity have been shown to be mostly stable over time; however, there is a need for large and extended longitudinal studies to give a more complete understanding and the possibility for exploring the importance of other factors associated with physical activity. Rarely measured precisely (eg, with pedometers or microcomputer sensors), physical activity is most frequently quantified by responses to questionnaires.…”

“…For most diseases including cancer, different types of physical activity may possibly also give a differential risk decrease depending on the specific subtype of the disease. For instance, premenopausal and postmenopausal breast cancers with different biology and hormonal milieu may be influenced differently by physical exercise…”

In It for the Long Haul: Long-Term Benefit With Adjuvant Endocrine Therapy for Premenopausal Women With Early-Stage Steroid Receptor–Positive Breast Cancer

“…No adverse interaction between tamoxifen and goserelin was identified although this larger patient population was not selected for genomic risk. Nonetheless, findings of differential efficacy as demonstrated by Johansson et al, 2 if replicated in other data sets, would be extremely useful to try to tailor adjuvant endocrine therapy for premenopausal women in a more precise way than through reliance on traditional clinical markers such as stage and conventional biomarkers alone. A challenge for any validation is likely to be the availability of tissues for analysis from some of the older trials of OFS and selection of the best multigene test.…”

“…In the article that accompanies this editorial, Johansson et al 2 report better distant recurrence free interval at 20 years in a randomized trial for premenopausal women with early‐stage estrogen receptor–positive breast cancer after only 2 years of tamoxifen, goserelin, or the combination when compared with placebo. The results confirm the long-term value of endocrine therapy for these young women and suggest that further work using multigene assays may help to tailor selection of endocrine therapy in this setting.…”

Tamoxifen Modulates the Immune Landscape of the Tumour Microenvironment: The Paired Siglec-5/14 Checkpoint in Anti-Tumour Immunity in an In Vitro Model of Breast Cancer

“…This is of particular importance, since the sialylation pattern is known to be modulated by chemical and biological stimuli. Although the advances in immunotherapy and targeted therapy of breast cancer are in the focus of clinicians, selective oestrogen receptor modulators (SERMs) are the strategy of choice for the management of breast tumours in clinical practice [ 24 , 25 ]. Tamoxifen (TMX) is a non-steroid anti-oestrogen drug widely used in the therapy for and prevention of breast cancer in pre- and post-menopausal women [ 26 ].…”