Inadequate ovarian function suppression and endocrine therapy manipulations in premenopausal patients with early breast cancer on adjuvant LHRH agonist and aromatase inhibitor: a cohort study

Background: Up to 20% of premenopausal patients with early breast cancer (eBC) receiving adjuvant endocrine therapy with luteinizing hormone-releasing hormone agonists (LHRHas) plus aromatase inhibitors (AIs) exhibit inadequate ovarian function suppression (iOFS), defined by elevated serum estradiol (E2) levels. In clinical practice, endocrine therapy manipulations (ETMs) are frequently used to manage iOFS, as AIs are ineffective when iOFS occurs. However, the dynamics of serum E2 during LHRHa therapy and their changes after ETMs remain poorly characterized. Methods: This is a single-center cohort study including premenopausal women with eBC receiving adjuvant LHRHa plus AI who exhibited iOFS (E2 ≥24 ng/l on immune assays) between 2015 and 2024. The primary endpoint was time to optimal OFS (<24 ng/l). Serum E2 levels were monitored every 6 months during LHRHa therapy, and at least every 3 months following an iOFS episode. Results: A total of 125 patients were included: 72 in the ETM group and 53 in the non-ETM group (median E2 levels at study entry: 47 and 33 ng/l, respectively). Overall, 14% reported concomitant vaginal bleeding or spotting (all in the ETM group), and 78% had their first iOFS within the second year of LHRHa-based therapy. The most common ETMs were shortening the LHRHa dosing interval (71%) and switching to a different LHRHa agent (25%); 38% required a second ETM during the same episode due to persistent E2 ≥24 ng/l. With a median follow-up of 54.9 months, the median time to optimal OFS was 6.1 months [95% confidence interval (CI) 5.0-7.1 months] in the ETM group and 5.5 months (95% CI 4.5-6.6 months) in the non-ETM group. A second episode of iOFS occurred in 37% of patients. Conclusions: This study shows that iOFS is a transient, potentially recurring, and clinically manageable event that may occur at any point during LHRHa therapy. Among patients receiving LHRHa plus an AI, given the pharmacodynamic implications, our findings support continuous E2 monitoring throughout LHRHa-based treatment to guide the timely implementation of ETMs.