Clinical Benefit With Endocrine Therapy Differs By Risk of Distant Disease Recurrence in Premenopausal ER+ Breast Cancer

Stratification by the molecular 70-gene risk prediction signature revealed that patients with estrogen receptor (ER)–positive breast cancer who are low risk for disease recurrence derive greater benefit from tamoxifen, while those who are high risk have greater benefit from goserelin vs no endocrine therapy, according to long-term findings from a Swedish study presented during the ESMO Breast Virtual Congress 2021.

Results indicated that any patient who received endocrine therapy had a significant reduction in distant recurrence-free survival compared with the control group of no endocrine treatment. Patients who received goserelin had a hazard ratio (HR) or 0.48 (95% CI, 0.32-0.72), while those who received tamoxifen had a HR of 0.59 (95% CI, 0.39-0.88); those who received goserelin plus tamoxifen had a HR of 0.67 (95% CI, 0.46-0.97).

When stratifying patients by their risk score using the molecular 70-gene risk prediction signature, investigators found that high-risk patients derived greater benefit from goserelin vs low-risk patients, with HRs of 0.22 (95% CI, 0.10-0.49) and 0.80 (95% CI, 0.42-1.52), respectively. Moreover, low-risk patients derived greater benefit from tamoxifen vs high-risk patients, with HRs of 0.38 (95% CI, 0.18-0.82) and 0.69 (95% CI, 0.33-1.46), respectively. No significant benefit from the combined treatment was reported in either the low- or high-risk subgroups.

“This study with unique long-term follow-up in premenopausal patients with breast cancer suggests that goserelin, tamoxifen, and the combination of the 2, reduced the 20-year risk of distant recurrences and fatal breast cancer, compared with no endocrine therapy,” lead study author Annelie Johansson, MSc, PhD, of the Department of Oncology and Pathology at Karolinska Institute, said during a presentation on the data. “Moreover, stratification by the 70-gene signature suggests that low-risk patients have a greater benefit of tamoxifen, whereas high-risk patients have a greater benefit of goserelin. The benefit with goserelin was also observed when we compared with the combined therapy or tamoxifen only.”

Premenopausal patients with breast cancer are diagnosed early in life and are known to have an increased long-term risk of fatal disease. The long-term benefit of endocrine therapy, including ovarian suppression, has been largely unexplored, according to Johansson.

For the Stockholm tamoxifen randomized trial (STO-5), investigators sought to examine the long-term, or 20-year, benefit of goserelin and tamoxifen stratified by the molecular 70-gene risk prediction signature in this patient population.

The trial was conducted between 1990 and 1997 and included a total of 924 premenopausal patients with breast cancer. All patients were stratified by lymph node status and divided into 3 groups: patients with lymph node–negative status, those with 1 to 3 positive lymph nodes who

received chemotherapy, and those with 4 or more positive lymph nodes who received chemotherapy and locoregional radiotherapy. All of these patients were then randomized into 1 of 4 arms where they received: goserelin (n = 230), tamoxifen (n = 231), goserelin plus tamoxifen (n = 230), or the control, who did not receive endocrine therapy (n = 233).

Over the past year, investigators collected and evaluated primary tumor blocks from the study participants through the use of immunohistochemistry. Of the 729 patients, 610 patients had ER-positive disease. Tumor DNA expression data were also collected for 465 patients who also have the 70-gene signature risk classification, where they were classified into subgroups with either low or high risk of recurrence. Of the 465 patients with those data available, 131 received goserelin, 105 received tamoxifen, 120 had the combination, and 109 received the control.

During the meeting, Johnsson shared the complete 20-year follow-up from the high-quality Swedish National registries. The median age of study participants was 46 years (range, 26-57).

In the study, investigators also compared the long-term risk of distant recurrence among the endocrine therapy trial arms. When goserelin monotherapy was compared with goserelin/tamoxifen among those with low- and high-risk, the HRs were 1.22 (95% CI, 0.66-2.25) and 0.33 (95% CI, 0.15-0.72), respectively. When single-agent tamoxifen was compared with the doublet, the HR in the low-risk group was 0.59 (95% CI, 0.28-1.24), while it was 1.25 (95% CI, 0.61-2.54) in the high-risk group. When comparing goserelin alone with tamoxifen alone, the HRs were 1.60 (95% CI, 0.77-3.33) and 0.30 (95% CI, 0.13-0.67), respectively.

“Again, we observed benefit from goserelin in high-risk patients, when we compared it with the combined therapy and when we compared it with tamoxifen only,” Johannsson noted.

Investigators concluded that the data demonstrate that the long-term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification, and thus, tumor characteristics.

Reference

1. Johansson A. 20-year benefit of endocrine therapy in premenopausal breast cancer patients by the 70-gene risk signature. Presented at: ESMO Breast Virtual Congress 2021; May 5-8, 2021; Virtual. Abstract LBA1.