Background

Premenopausal breast cancer patients have an increased long-term risk for fatal disease, and endocrine therapy benefit including ovarian suppression is unexplored. Here for the first time, we assessed the 20-year benefit of goserelin and tamoxifen stratified by the molecular 70-gene signature risk prediction in premenopausal women in a randomized trial.

Methods

In 1990-1997, n=924 premenopausal patients (age range 26-57, median 46) were randomized into 4 well-balanced trial arms; 2 years of goserelin, tamoxifen, the combination of goserelin and tamoxifen, or no endocrine therapy. Lymph-node positive women (n=459) received standard chemotherapy. Swedish high-quality National registries allowed long-term (20 years) complete follow-up after randomization. Immunohistochemistry of the clinically used breast cancer markers was performed in 2020 (n=729) together with Agilent microarray profiling (n=589). The 70-gene signature classified patients into low or high risk of recurrence. Kaplan-Meier analysis and multivariable Cox proportional hazard regression were used to assess the endocrine therapy benefit.

Results

Adjusted multivariable analyses show that in estrogen receptor (ER)-positive patients (n=610) goserelin, tamoxifen, and the combination of goserelin and tamoxifen reduced the 20-year risk of distant recurrence compared to no endocrine therapy, see table. Stratification by the 70-gene signature showed a significant benefit in low risk patients (n=306) from tamoxifen therapy (Hazard Ratio [HR]=0.38, 95% Confidence Interval [CI]: 0.18-0.82), whereas high risk patients (n=159) had a significant benefit from goserelin therapy (HR=0.22, 95% CI: 0.10-0.49). Similar findings were seen when using breast cancer-specific survival as the end-point. Table: LBA1

Long-term (20 year) risk of distant recurrence adjusted for tumour size, grade, lymph-node status, PR, HER2, Ki-67, chemotherapy, and radiotherapy

Conclusions

This study with unique long-term follow-up in premenopausal patients suggests that high risk patients significantly benefit from goserelin, whereas low risk patients benefit from tamoxifen.

Legal entity responsible for the study

The authors.

Funding

The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare (FORTE), and The Swedish Cancer Society (Cancerfonden).

Disclosure

L. van 'T Veer: Shareholder/Stockholder/Stock options, Full/Part-time employment, Dr van't Veer is one of the inventors of the MammaPrint 70-gene risk signature (patent no WO2002103320): Agendia.

Background

Premenopausal breast cancer patients have an increased long-term risk for fatal disease, and endocrine therapy benefit including ovarian suppression is unexplored. Here for the first time, we assessed the 20-year benefit of goserelin and tamoxifen stratified by the molecular 70-gene signature risk prediction in premenopausal women in a randomized trial.

Methods

In 1990-1997, n=924 premenopausal patients (age range 26-57, median 46) were randomized into 4 well-balanced trial arms; 2 years of goserelin, tamoxifen, the combination of goserelin and tamoxifen, or no endocrine therapy. Lymph-node positive women (n=459) received standard chemotherapy. Swedish high-quality National registries allowed long-term (20 years) complete follow-up after randomization. Immunohistochemistry of the clinically used breast cancer markers was performed in 2020 (n=729) together with Agilent microarray profiling (n=589). The 70-gene signature classified patients into low or high risk of recurrence. Kaplan-Meier analysis and multivariable Cox proportional hazard regression were used to assess the endocrine therapy benefit.

Results

Adjusted multivariable analyses show that in estrogen receptor (ER)-positive patients (n=610) goserelin, tamoxifen, and the combination of goserelin and tamoxifen reduced the 20-year risk of distant recurrence compared to no endocrine therapy, see table. Stratification by the 70-gene signature showed a significant benefit in low risk patients (n=306) from tamoxifen therapy (Hazard Ratio [HR]=0.38, 95% Confidence Interval [CI]: 0.18-0.82), whereas high risk patients (n=159) had a significant benefit from goserelin therapy (HR=0.22, 95% CI: 0.10-0.49). Similar findings were seen when using breast cancer-specific survival as the end-point. Table: LBA1

Long-term (20 year) risk of distant recurrence adjusted for tumour size, grade, lymph-node status, PR, HER2, Ki-67, chemotherapy, and radiotherapy

Conclusions

This study with unique long-term follow-up in premenopausal patients suggests that high risk patients significantly benefit from goserelin, whereas low risk patients benefit from tamoxifen.

Legal entity responsible for the study

The authors.

Funding

The Swedish Research Council (Vetenskapsrådet), The Swedish Research Council for Health, Working life and Welfare (FORTE), and The Swedish Cancer Society (Cancerfonden).

Disclosure

L. van 'T Veer: Shareholder/Stockholder/Stock options, Full/Part-time employment, Dr van't Veer is one of the inventors of the MammaPrint 70-gene risk signature (patent no WO2002103320): Agendia.

Background

The clinically used breast cancer markers are known to predict short-term survival, but whether these markers predict long-term (25-year) survival is unclear. We therefore aimed to determine whether the clinically used markers are long-term prognosticators and predictors of tamoxifen therapy benefit in patients with lymph node-negative and ER-positive/ HER2-negative breast cancer.

Methods

Secondary analysis of the Stockholm Tamoxifen (STO-3) trial conducted from 1976 to 1990, randomizing postmenopausal lymph node-negative breast cancer patients to receive adjuvant tamoxifen therapy versus no adjuvant therapy. Distant recurrence-free interval (DRFI) by the clinically used markers was assessed by Kaplan-Meier and multivariable Cox proportional hazards analysis. Recursive partitioning analysis was performed to evaluate which markers best predict long-term survival.

Results

A statistically significant difference in 25-year DRFI was seen by tumor size (Log-rank, P<0.001) and tumor grade (Log-rank, P=0.019), but not by PR and Ki-67 status. Patients with smaller tumor size (T1a/b Hazard ratio [HR], 0.31; 95% CI, 0.17-0.55; T1c HR, 0.58; 95% CI, 0.38-0.88), and tumor grade 1 had a significantly reduced long-term risk (Grade 1 HR, 0.48; 95% CI, 0.24-0.95), compared to patients with larger (T2) tumor size and grade 3 tumors, respectively. A significant tamoxifen therapy benefit was suggested for patients with larger tumor size (T1c HR, 0.53; 95% CI, 0.32-0.89; T2 HR, 0.34; 95% CI, 0.16-0.73), lower tumor grade (Grade 1 HR, 0.24; 95% CI, 0.07-0.82; Grade 2 HR, 0.50; 95% CI, 0.31-0.80), and PR-positivity (HR=0.38, 95% CI, 0.24-0.62). Recursive partitioning analysis selected tumor size as the most important characteristic to predict survival, followed by trial arm for patients with larger tumors.

Conclusions

Our findings suggest that tumor size followed by grade are significant 25-year prognosticators of DRFI outcome. Further, a significant 25-year benefit from tamoxifen therapy was seen in patients with larger tumor size, lower tumor grade and PR-positive tumors.

Clinical trial identification

The trial center for the STO-3 trial was the Regional Cancer Center Stockholm-Gotland, in Stockholm Sweden. However, the start of the Stockholm Tamoxifen trial (STO-3) in 1976 was well before trial registration started in Sweden, therefore information on trial number is not available.

Legal entity responsible for the study

The authors.

Funding

Swedish Research Council and Swedish Cancer Society.

Disclosure

All authors have declared no conflicts of interest.