A meta-analysis of randomized trials has revealed a benefit to ovarian ablation or suppression in preventing breast cancer recurrence in premenopausal women with estrogen receptor–positive tumors.¹ The findings, based on almost 15,000 women in studies spanning several decades, were presented at the 2023 ASCO Annual Meeting by Richard G. Gray, MA, MSc, Emeritus Professor at the University of Oxford in the United Kingdom. Dr. Gray presented the study on behalf of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).

“There is a substantial and persistent benefit from ovarian suppression and from ovarian ablation for premenopausal women with estrogen receptor–positive tumors,” Dr. Gray reported. “Similar benefits were seen in women who received prior chemotherapy and remained premenopausal after chemotherapy, as in women who received no chemotherapy.”

Richard G. Gray, MA, MSc

About the Study

As Dr. Gray noted, ovarian ablation (by surgery or irradiation) and ovarian suppression (usually with gonadotropin-releasing hormone [GnRH] agonists) may improve breast cancer outcomes by preventing estrogenic stimulation of any residual cancer, particularly in premenopausal women with estrogen receptor–positive tumors. To further elucidate these benefits, the EBCTCG investigators analyzed patient-level data from 23 randomized trials involving 14,999 women (younger than age 55) who were premenopausal when randomly assigned to ovarian ablation or suppression or to no ovarian ablation or suppression.

About half the women received no chemotherapy or received chemotherapy prior to randomization, and their premenopausal status was confirmed afterward. The other half received chemotherapy after randomization, which can result in chemotherapy-induced menopause and would be expected to dilute the benefit of ovarian ablation or suppression.

Significant Effect on Breast Cancer Recurrence

“When quite a lot of the women become postmenopausal as a result of chemotherapy, we would expect to see less benefit in those trials, and that’s exactly what we saw,” Dr. Gray said. For the two key subsets, the effect of ovarian ablation or suppression on recurrence differed:

• Women receiving no chemotherapy or remaining premenopausal after chemotherapy (n = 7,213): Recurrence rate of 39.3% in the control group vs 29.5% in the ovarian ablation or suppression group, yielding an absolute benefit of 9.8% at 15 years and a rate ratio (RR) of 0.71 (P < .00001).
• Women premenopausal before chemotherapy but with uncertain menopausal status after chemotherapy (n = 7,786): Recurrence rate of 44.4% in the control group vs 43.1% in the ovarian ablation or suppression group, yielding an absolute benefit of 1.3% at 15 years (RR = 0.91; P = .02).

For patients who had no chemotherapy or who remained premenopausal, the benefit grew larger over time, with the absolute difference increasing from approximately 6% at 5 years to 8% at 10 years and to 10% at 15 years. Differences for the other half of patients, on the other hand, were “barely discernible,” noted Dr. Gray. Although the studies spanned decades, their findings were consistent, with no significant heterogeneity between trials, he added.

Effect According to Age

The effect of age is best observed in the population of patients described as having no chemotherapy. Age had no clear effect on benefit, although hazard ratios were more robust in the younger women:

• Age younger than 45 (n = 4,437): Recurrence rate of 41.3% in the control group and 30.4% with ovarian ablation or suppression, reflecting a 15-year gain of 10.9% and a rate ratio of 0.66 (P < .00001).
• Age 45 to 54 (n = 2,776): Recurrence rate of 36.1% in the control group and 28.6% with ovarian ablation or suppression, reflecting a 15-year gain of 7.5% and rate ratio of 0.82 (P = .02).

Describing the analysis according to age, Dr. Gray first presented data for the population who received chemotherapy. He pointed out that most “older” premenopausal patients will become amenorrheic from the chemotherapy; therefore, additional ovarian ablation or suppression offers no benefit for them. About 50% of younger premenopausal patients will also become amenorrheic. The results of the meta-analysis reflected this, showing “a small benefit” (RR ≈ 0.80) in women younger than age 39 and no real benefit in older women. He said this group of trials should be “dismissed” as not truly testing ovarian ablation in premenopausal women.

Significant Reductions in Mortality

In patients who had no chemotherapy or were premenopausal after treatment, ovarian ablation or suppression was also associated with significant reductions in breast cancer–related mortality and all-cause mortality, with no increase in deaths without recurrence. Gains at 20 years were 10.9% for breast cancer–related mortality (RR = 0.71; P < .00001) and 11.6% for all-cause mortality (RR = 0.75; P < .00001).

“This is quite an impressive achievement in reducing breast cancer mortality and highly significant. And, with very long follow-up in many of these trials, we can see that benefits persist for at least 20 years,” Dr. Gray commented.

Are There Predictors of Benefit?

Similar proportional benefit was seen for women with node-negative disease (RR = 0.70; P < .00001) and for those with node-positive disease (RR = 0.72; P = .00005). However, understandably, the 15-year recurrence rate was higher (54.5%), and therefore the absolute gain from ovarian ablation or suppression was greater (11.9%), in the node-positive subgroup.

One factor that did, however, make a significant difference was the use of tamoxifen. In the absence of tamoxifen, the early recurrence risk was very high—greater than 40% at 5 years—whereas those who received tamoxifen had a 5-year recurrence risk of less than 14%. “You see a big benefit from tamoxifen: It reduces the recurrence risk by 50% in the first 5 years and by 30% in the next 5 years,” Dr. Gray noted.

In that setting, with tamoxifen already exerting a protective effect, the benefit of ovarian ablation or suppression would be less, although it did seem to have value, especially by extending protection into natural menopause. Women not receiving tamoxifen had a 15-year gain in recurrence-free survival with ovarian ablation or suppression of 17.5% (RR = 0.61; P < .00001), but for women treated with tamoxifen, the gain was only 4.5% (RR = 0.80; P = .002). He emphasized that these comparisons are potentially unreliable because of differences in follow-up and the receipt of ovarian ablation vs suppression, which varied according to receipt of tamoxifen.

In closing, Dr. Gray commented: “It’s been 40 years since the Early Breast Cancer Trialists’ Collaborative Group was established. And it’s continuing to produce a lot of very interesting results.”

DISCLOSURE: Dr. Gray reported no conflicts of interest.

REFERENCE

1. Gray RG, Bradley R, Braybrooke J, et al: Effects of ovarian ablation or suppression on breast cancer recurrence and survival: Patient-level meta-analysis of 14,993 premenopausal women in 25 randomized trials. 2023 ASCO Annual Meeting. Abstract 503. Presented June 2, 2023.