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.

Challenges of fertility preservation in non‐oncological diseases

“…In some cases, this may even reduce the risk of atherosclerosis (in SLE) or encephalomyelitis (in multiple sclerosis) . Based on large randomized prospective trials, this controversial approach has produced positive results in preventing adjuvant and neoadjuvant treatment‐induced amenorrhea in women with breast cancer . Several observational or retrospective studies have analyzed the effectiveness of these treatments in autoimmune diseases .…”

“…35,44 Based on large randomized prospective trials, this controversial approach has produced positive results in preventing adjuvant and neoadjuvant treatment-induced amenorrhea in women with breast cancer. 45 Several observational or retrospective studies have analyzed the effectiveness of these treatments in autoimmune diseases. 46,47 Although the number of individuals analyzed was low, the data suggested a beneficial effect of this treatment on ovarian reserve and POI rate.…”

Fertility, sexuality and cancer in young adult women

“…Nevertheless, several randomized trials have been conducted particularly among premenopausal breast cancer patients. The largest studies, recently pooled in a meta-analysis based on individual patient data, have provided consistent results in terms of significant reduction in the risk of treatment-induced POI with the administration of GnRHa during chemotherapy (15% absolute reduction and 40% relative risk reduction) [51]. Only three studies reported pregnancy rates in a cohort of more than 100 patients [52][53][54].…”

“…Concerning the safety of this strategy, there were concerns in the past on the potential antagonism between concurrent administration of hormonal agents during chemotherapy [64]. However, this has been shown for tamoxifen only and not with GnRHa; in addition, clinical data from large randomized trials have recently provided reassuring evidence showing no difference in survival outcomes between patients who received chemotherapy alone or concurrently with GnRHa including among women with hormone receptor-positive breast cancer [51,65].…”

Baby steps: Pregnancy outcomes after human epidermal growth factor receptor 2–targeted therapy

“…Temporary ovarian suppression during chemotherapy with gonadotropin‐releasing hormone (GnRH) agonists such as goserelin or leuprolide has shown some promise as a way to decrease the incidence of chemotherapy‐induced ovarian failure . However, in their study, Lambertini et al did not describe the use of GnRH agonists during experimental chemotherapy in the NeoALLTO and ALLTO studies, although adjuvant use was mentioned.…”