The benefits of ovarian function suppression were sustained long term for premenopausal women with hormone receptor–positive breast cancer, according to updates from SOFT and TEXT, two randomized, controlled trials, presented at the 2021 San Antonio Breast Cancer Symposium.¹ A separate large meta-analysis of four randomized trials in the same population by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) also found that aromatase inhibitors were superior to tamoxifen when combined with ovarian function suppression.²

In a combined updated analysis of the SOFT and TEXT trials, at 12 and 13 years’ median follow-up, the rate of distant metastasis–free interval at 12 years was 88.4% in those who received the aromatase inhibitor exemestane plus ovarian function suppression vs 86.6% in those given tamoxifen plus ovarian function suppression. This difference represented a statistically significant 17% reduction favoring the aromatase inhibitor strategy (P = .03). Overall survival did not significantly differ between the two treatment arms: 90% and 89% at 12 years, respectively. Patients in the lower-risk subgroups who did not receive chemotherapy in either SOFT or TEXT had a 12-year survival rate of about 95%, regardless of which endocrine therapy they received.

Meredith M. Regan, ScD

“From the results of the SOFT trial alone, meaningful relative reductions in distant recurrences and deaths persist with longer follow-up of ovarian suppression with either endocrine therapy vs tamoxifen alone. Absolute reductions are more substantial for those at higher risk, on the order of a 10% reduction in death, emphasizing appropriate selection of patients to receive ovarian suppression,” said lead author of the combined analysis study, Meredith M. Regan, ScD, of Harvard Medical School and Dana-Farber Cancer Institute, Boston, and the International Breast Cancer Study Group, Bern, Switzerland.

“For patients with low clinical risk features who did not receive chemotherapy and enrolled in SOFT, the longer follow-up continues to support the use of tamoxifen alone,” she added. Dr. Regan noted that the investigators plan to continue to follow participants for 5 more years.

Details of the Updated Combined Analysis

The total number of participants in both trials was 5,700. All were premenopausal and had early hormone receptor–positive breast cancer.

The SOFT trial randomly assigned patients to 5 years of adjuvant tamoxifen alone or ovarian function suppression plus tamoxifen or ovarian function suppression plus exemestane. Some women enrolled in SOFT had received -chemotherapy and remained premenopausal after its completion; for some premenopausal women enrolled, it had been decided not to give chemotherapy. The design of the TEXT trial was similar but did not have a tamoxifen-alone arm: all women received ovarian function suppression and were randomly assigned to receive either tamoxifen or exemestane; some did and some did not also receive chemotherapy after enrollment. The primary endpoint of both trials was disease-free survival.

Results of SOFT reported at earlier time points (5 and 8 years’ median follow-up) demonstrated that the addition of ovarian function suppression to tamoxifen reduced the risk of distant recurrence and death. Using ovarian function suppression with exemestane further reduced the risk of distant recurrence compared to tamoxifen alone.

In the three-arm SOFT trial, 12-year distant metastasis–free survival rates were 87.8% with exemestane plus ovarian function suppression, 86.2% with tamoxifen plus ovarian function suppression, and 84.8% with tamoxifen alone. A combined analysis of both trials found a significant absolute 1.8% difference in 12-year distant metastasis–free survival favoring exemestane plus ovarian function suppression over tamoxifen plus ovarian function suppression (P = .03). No significant difference in overall survival was observed between the two treatment arms after 13 years’ median follow-up.

Patients in the SOFT trial who did not receive chemotherapy had 12-year distant metastasis–free rates of 95.8% with tamoxifen alone, 95.9% with tamoxifen plus ovarian function suppression, and 97.7% with exemestane plus ovarian function suppression. The 12-year overall survival rates were 95.8%, 95.2%, and 97.1%, respectively. Among patients in the SOFT trial treated with chemotherapy, the 12-year distant metastasis–free interval rates were 75.1% with tamoxifen alone, 77.7% with tamoxifen plus ovarian function suppression, and 79.6% with exemestane plus ovarian function suppression. The 12-year overall survival rates were 78.9%, 83.6%, and 82.9%, respectively.

In the TEXT trial, patients who received chemotherapy had 12-year distant metastasis–free rates of 84.7% with exemestane plus ovarian function suppression and 82.3% with tamoxifen plus ovarian function suppression. Overall survival rates were 87% and 84.4%, respectively.

Regarding the HER2-negative subgroup of the SOFT trial, patients younger than age 35 and those who received neoadjuvant chemotherapy prior to enrollment derived the most benefit from ovarian function suppression. In both subgroups of patients, tamoxifen plus ovarian function suppression achieved approximately a 10% absolute improvement in overall survival vs tamoxifen alone, and exemestane plus ovarian function suppression achieved at least a 15% absolute benefit over tamoxifen alone.

Meta-analysis of More Than 7,000 Women

In a related presentation at the San Antonio Breast Cancer Symposium, a large meta-analysis of four trials involved a total of 7,030 premenopausal women with estrogen receptor–positive breast cancer receivingovarian function suppression and randomly assigned to an aromatase inhibitor or tamoxifen. The investigators found the annual rate of breast cancer recurrence was one-fifth lower with an aromatase inhibitor compared with tamoxifen (P = .0005). The main benefit was observed in the first 5 years, and follow-up beyond 10 years is limited.

Rosie Bradley, BSc, MSc

“Using aromatase inhibitors rather than tamoxifen in premenopausal women receiving ovarian suppression reduces the risk of breast cancer recurrence by around a fifth,” stated lead author Rosie Bradley, BSc, MSc, of Oxford Population Health, University of Oxford. “The reduction in distant recurrence is 17%, but there was no effect on breast cancer mortality or overall survival. Longer follow-up is needed. There was no increase in deaths unrelated to cancer in either group, but there were more fractures among those women receiving aromatase inhibitors.”

The meta-analysis was conducted by EBCTCG and included the ABCSG-12, TEXT, SOFT, and HOBOE trials. All participants had received ovarian function suppression or ovarian ablation. Trial participants were randomly assigned to receive either an aromatase inhibitor or tamoxifen for 3 years in ABCSG-12 or 5 years in the other three trials. Primary outcomes included the time to invasive breast cancer recurrence (ie, distant, locoregional, or new contralateral primary tumor) and breast cancer–specific mortality.

At 10 years, the absolute rate of recurrence among the four trials was 14.7% for those treated with an aromatase inhibitor in combination with ovarian function suppression vs 17.5% among those treated with tamoxifen plus ovarian function suppression. The 5-year rate of recurrence was 6.9% vs 10.1%, respectively. Breast cancer mortality was similar at the 5-year time point, and longer follow-up with more mature data is needed to assess survival. 

DISCLOSURE: Dr. Regan reported financial relationships with Bristol Myers Squibb and Tolmar. Ms. Bradley reported no conflicts of interest.

REFERENCES

1. Regan MM, Walley BA, Fleming GF, et al: Randomized comparisons of adjuvant aromatase inhibitor exemestane plus ovarian function suppression vs tamoxifen in premenopausal women with hormone receptor–positive early breast cancer: Update of the TEXT and SOFT trials. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-05. Presented December 8, 2021.

2. Bradley R, Braybrooke J, Gray R, et al: Aromatase inhibitors versus tamoxifen in premenopausal women with estrogen receptor positive early stage breast cancer treated with ovarian suppression: A patient level meta-analysis of 7,030 women in four randomised trials. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-04. Presented December 8, 2021.