Three-monthly gonadotropin-releasing hormone agonist for ovarian function suppression in premenopausal breast cancer: A systematic review and meta-analysis.

542 Background: Ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHa) is a cornerstone of endocrine therapy (ET) for premenopausal women with hormone receptor–positive (HR+) breast cancer (BC), most commonly administered on a monthly (1M) schedule. Three-monthly (3M) formulations have been proposed to improve convenience and adherence, but comparative efficacy and safety versus 1M regimens remain uncertain. Methods: PubMed, Cochrane, and Embase libraries were systematically searched for randomized clinical trials (RCTs) and non-randomized interventional studies comparing 3M versus 1M GnRHa regimens in premenopausal women with HR+ BC receiving ET. Outcomes included the incidence of ovarian escape (OE), mean estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels, disease-free survival (DFS), progression-free survival (PFS), and adverse events, with a minimum follow-up of 12 weeks. Random-effects models were used to estimate pooled risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). Subgroup analyses were performed by estradiol assay type, and a sensitivity analysis restricted to RCTs was conducted. Results: Fifteen studies comprising 4,324 patients were included; 2,098 (48%) received a 3M regimen. The overall incidence of OE was low (10%) and did not differ between 3M and 1M schedules (RR 0.86; 95% CI 0.60–1.22). Ultrasensitive assays revealed higher absolute OE rates (31%), without inter-regimen differences (RR 0.90; 95% CI 0.38–2.14). Mean E2 levels at 12 weeks were comparable across dosing strategies (MD 1.36 pg/mL; 95% CI −3.66 to 6.38), with no significant differences in mean FSH or LH levels; analyses restricted to RCTs yielded consistent findings (MD −1.77 pg/mL; 95% CI −5.71 to 2.17). DFS (RR 1.02; 95% CI 0.67–1.56) and PFS (RR 0.86; 95% CI 0.72–1.04) were similar between regimens. The most frequently reported adverse events were hot flashes, arthralgia, headache, and nausea, with no clinically relevant differences between dosing schedules. Conclusions: 3M GnRHa achieved OFS comparable to 1M dosing, with similar survival outcomes and safety profiles in premenopausal women with HR+ BC.