Adjuvant Hormonal Therapy for Premenopausal Breast Cancer: Considerations for Ovarian Function Suppression

Matthew Goetz, MD

Understanding the role of the estrogen receptor (ER) in the pathogenesis of breast cancer has led to the development of treatment options that lead to reduced estrogen levels. In addition, the expression level of ER can serve as a prognostic indicator for disease recurrence and treatment response. Several ER-blocking strategies are available, including selective ER modulators (eg, tamoxifen) and ER degraders. Estrogen level–lowering strategies, such as oophorectomy or concurrent use of luteinizing hormone–releasing hormone agonists and aromatase inhibitors (AIs), can be utilized as well.

Previous studies have demonstrated the clinical benefit of adjuvant treatment with tamoxifen and AIs for postmenopausal patients with ER-positive breast cancer by reducing the risk of recurrence.¹ A collaborative meta-analysis of 194 unconfounded randomized clinical trials found that 5 years of adjuvant tamoxifen reduced the annual breast cancer death rate by 31%, irrespective of the use of chemotherapy and age, progesterone receptor status, or other tumor characteristics.¹ Recent studies have shown that the addition of ovarian function suppression (OFS) to endocrine therapy provides further benefit to premenopausal women with hormone receptor–positive breast cancer. In the TEXT and SOFT trials, tamoxifen plus OFS was compared with exemestane plus OFS.² The chemotherapy cohorts both exhibited reductions in distant recurrence (SOFT: 1.9% and TEXT: 2.4%) when comparing tamoxifen plus OFS with exemestane plus OFS at 12 years.²

Analysis of the Early Breast Cancer Trialists’ Collaborative Group trial data from 25 randomized trials of approximately 15,000 premenopausal women demonstrated that ovarian ablation/suppression resulted in a robust reduction in the risk of cancer recurrence.³ Overall, fewer breast cancer recurrences were observed with ovarian ablation/suppression than control (rate ratio [RR], 0.82; 95% confidence interval [CI], 0.77-0.88; P<.0001). Recurrence reductions were significantly (P=.0003) larger among women known to be premenopausal prior to ovarian suppression (RR, 0.70; CI, 0.63-0.78; P=.0003) compared with those whose menopausal status was uncertain after chemotherapy (RR, 0.91; CI, 0.83-0.99; P=.03). For known premenopausal women, 15-year risk of recurrence was improved by 12.1% (28.9% vs 41.0%; P<.0001). Fifteen-year breast cancer and all-cause mortality were improved by 8.0% (20.9% vs 28.9%; RR, 0.69; CI, 0.60-0.80; P<.0001) and 7.2% (26.0% vs 33.1%; RR, 0.73; CI, 0.64-0.82; P<.0001), respectively, with no increase in deaths without recurrence. Recurrence reductions were significantly (P=.003) larger among premenopausal women aged <45 years (RR, 0.63; CI, 0.55-0.72; P<.0001) than among those aged 45 to 54 years (RR, 0.84; CI, 0.70-1.00; P=.045).³

A recently published meta-analysis of breast cancer recurrence compared AIs with tamoxifen in 7030 women with ER-positive tumors in which all received OFS (via goserelin or triptorelin) or ovarian ablation who enrolled between June 17, 1999, and August 4, 2015, from 4 randomized trials. This analysis showed that AIs resulted in approximately 3% improvement in 5-year absolute risk of breast cancer recurrence compared with tamoxifen. However, longer follow-up is needed to assess mortality.⁴

With this growing evidence supporting the benefit of OFS, what are the long-term implications of profound estrogen deprivation? A study examining the impact of oophorectomy on survival showed that mortality was not increased in women who underwent bilateral oophorectomy compared with referent women.⁵ However, mortality was significantly higher in women who had received prophylactic bilateral oophorectomy before the age of 45 years than in referent women (hazard ratio, 1.67; 95% CI, 1.16-2.40; P=.006). Additionally, the Nurses’ Health Study showed that bilateral oophorectomy was associated with significantly increased all-cause mortality in women aged <50 years at time of hysterectomy who never used estrogen therapy.⁶ However, in the Early Breast Cancer Trialists’ Collaborative Group trial mentioned above, the use of AIs was shown to be associated with a nonsignificant increase in the risk of death, increased risk of endometrial cancer, and mortality not related to breast cancer.⁵ However, the 5-year incidence of endometrial cancer was low and actually numerically higher in the tamoxifen group (0.3%) than in the AI group (0.2%). For all-cause mortality, there was no difference between the tamoxifen and AI groups, and most deaths not related to breast cancer were due to second primary cancer.

With the emerging benefit of OFS in the treatment of ER-positive breast cancer, there is a need to balance risk versus benefit when developing treatment plans based on patients’ preferences and treatment goals.

References

1. Group EBCTC. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet. 2005;365:1687-1717.
2. Pagani O, Walley BA, Fleming GF, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer: long-term follow-up of the combined TEXT and SOFT trials. J Clin Oncol. 2023;41:1376-1382.
3. 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 14,999 pre-menopausal women in 25 randomized trials. J Clin Oncol. 2023;41(16_suppl):503-503.
4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). 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 7030 women from four randomised trials. Lancet Oncol. 2022;23:382-392.
5. Rocca WA, Grossardt BR, de Andrade M, et al. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol. 2006;7:821-828.
6. Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses’ Health Study. Obstet Gynecol. 2013;121:709-716.