Preserving Ovarian Function in Women with Breast Cancer

In an effort to preserve fertility in women with breast cancer without compromising efforts to reduce the risk of disease recurrence, many strategies have been employed, including the use of gonadotropin-releasing hormone analogs (GnRHa) to make the ovaries quiescent during adjuvant chemotherapy. Two prior studies, POEMS and PROMIS-GIM6, demonstrated that GnRHa administered during adjuvant chemotherapy had a protective effect on ovarian function and reduced the risk of early menopause induced by chemotherapy; however, the sample sizes were modest. Furthermore, prior studies used traditional markers of ovarian function, such as menstrual history, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and inhibin B, which have proven to be unstable over time and not particularly sensitive.

Now, investigators in China report a trial in which 330 premenopausal women with stage I to III breast cancer were randomized to receive adjuvant chemotherapy with or without a GnRHa (either goserelin or leuprorelin administered monthly). GnRHa treatment was started 1 to 2 weeks prior to chemotherapy initiation and continued until 4 weeks after completion of chemotherapy. Although a variety of adjuvant chemotherapy regimens were allowed, all patients received cyclophosphamide, an alkylating agent with potent gonadotoxic properties. Anti-Müllerian hormone (AMH), a more sensitive biomarker of ovarian reserve was utilized to evaluate the protective effect of a GnRHa co-administered during adjuvant chemotherapy. The primary outcome was the rate of chemotherapy-induced premature ovarian insufficiency (POI; defined as an AMH level <0.5 ng/mL) 12 months after completion of chemotherapy.

At 6 months after chemotherapy, POI was present in 17.1% of the GnRHa group and 28.4% of the control group. At 12 months, the rate of POI was 10.3% in the GnRHa group and 44.5% in the control group, a significant difference (P<0.001). AMH resumption at 12 months — meaning that an originally normal AMH value dropped to <0.5 ng/mL with receipt of chemotherapy but later recovered to >0.5 ng/mL — occurred in 15 of 25 patients in the GnRHa group and 6 of 44 in the control group (P<0.001). There was no difference in overall survival between the groups, but among women younger than 35 years, those in the GnRHa group had longer tumor-free survival than controls.