Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Premenopausal Patients With Early Breast Cancer: A Systematic Review and Meta-Analysis of Individual Patient-Level Data

Abstract

Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient-level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer.

Figures

Fig 1.

Premature ovarian insufficiency (A) by trial, and (B) by patient subgroup. GBG-37 ZORO, German Breast Group-37 ZOladex Rescue of Ovarian function; GnRHa, gonadotropin-releasing hormone agonists; OPTION, Ovarian Protection Trial in Oestrogen Non-responsive Premenopausal Breast Cancer Patients Receiving Adjuvant or Neo-adjuvant Chemotherapy; OR, odds ratio; POEMS, Prevention Of Early Menopause Study; PROMISE-GIM6, PRevention Of Menopause Induced by chemotherapy: a Study in Early breast cancer patients—Gruppo Italiano Mammella 6; pts, patients.

Fig 2.

Post-treatment pregnancies by trial. GnRHa, gonadotropin-releasing hormone agonists; IRR, incidence rate ratio; OPTION, Ovarian Protection Trial in Oestrogen Non-responsive Premenopausal Breast Cancer Patients Receiving Adjuvant or Neo-adjuvant Chemotherapy; POEMS Prevention Of Early Menopause Study; PROMISE-GIM6, PRevention Of Menopause Induced by chemotherapy: a Study in Early breast cancer patients—Gruppo Italiano Mammella 6; pts, patients.

Fig 3.

Disease-free survival (DFS) in (A) the whole study population, (B) patients with estrogen receptor–positive disease, and (C) patients with estrogen receptor–negative disease. GnRHa, gonadotropin-releasing hormone agonists.

Fig 4.

Overall survival (OS) in (A) the whole study population, (B) patients with estrogen receptor–positive disease, and (C) patients with estrogen receptor–negative disease. GnRHa, gonadotropin-releasing hormone agonists.