GnRH Analogs Reduce Risk of Premature Ovarian Insufficiency in Premenopausal Breast Cancer

A phase 3 study from China identified that gonadotropin-releasing hormone analogs administered with chemotherapy reduced the risk of premature ovarian insufficiency among premenopausal patients with breast cancer.

The risk of premature ovarian insufficiency was reduced for premenopausal patients with breast cancer following administration of gonadotropin-releasing hormone analogs (GnRHa) with chemotherapy, according to results from a randomized phase 3 clinical trial (NCT02518191) published in JAMA Oncology.

Twelve months after chemotherapy, the rate of premature ovarian insufficiency was 10.3% in the GnRHa group compared with 44.5% in the control group (OR, 0.23; 95% CI, 0.14-0.39; P <.001).

“Fertility is a major concern for those young women with breast cancer,” the investigators wrote. “But, to our knowledge, there has been no prospective randomized clinical study on ovarian function related to breast cancer in Chinese or Asian populations to date.”

From September 2015 to August 2017, the randomized phase 3 trial was conducted at Shanghai Jiao Tong University Affiliated Shanghai Sixth People’s Hospital and Zhejiang Cancer Hospital.

Eligibility criteria required that patients be premenopausal and between the ages 18 to 49 years with stage I to III breast cancer in which adjuvant or neoadjuvant cyclophosphamide–containing chemotherapy was planned. Additionally, patients couldn’t have received previous treatment with estrogens, antiestrogens, selective estrogen receptor modulators, aromatase inhibitors, or hormonal contraceptives within a month of enrollment.

Patients received of 3.6 mg of goserelin or 3.75 mg of leuprorelin subcutaneously every 28 days. Treatment was administered from 1 to 2 weeks before the first chemotherapy cycle to 4 weeks after the last chemotherapy cycle.

Patients received 1 of several chemotherapy regimens, which included docetaxel, epirubicin, and cyclophosphamide (TEC); epirubicin, 4 cycles of cyclophosphamide and 4 additional cycles of docetaxel with or without trastuzumab (EC-T[H]); docetaxel, cyclophosphamide with or without trastuzumab (TC[H]); and 5-fluorouracil, epirubicin, and cyclophosphamide (FEC).

The primary end point of the study was premature ovarian insufficiency rate 12 months after chemotherapy. Secondary end points included overall survival (OS) and tumor-free survival (TFS).

A total of 405 patients were enrolled on the study. The median patient age was 41 years. Baseline demographics and clinical characteristics were well balanced across the GnRHa and control groups. Three hundred and thirty patients were eligible for the survival and safety analyses.

The four-year OS rate was 96% in the GnRHa group and 97% in the control group, with a 4-year TFS of 85% in both groups, respectively. Although no differences were observed in OS and TFS between both groups, patients younger than 35 years in the GnRHa group had significantly better OS (100%) and TFS (93%) rates vs those in the control group (81% and 62%).

The safety profile was encouraging, with no severe adverse effects (AEs) reported according to the investigators. Most intervention-related AEs were grade 1/2 in severity, and the proportion of grade 3 AEs was less than 5%.

The investigators determined that, although some studies have shown that pregnancy after breast cancer does not increase the likelihood of long-term disease recurrence, they do not recommend pregnancy and delivery within 3 years of the breast cancer diagnosis.

“At the time of enrollment, we reached a consensus with all patients on this issue, so this study did not take posttreatment fertility as an end point of the study. Therefore, the conclusion of this study cannot be extended to actual fertility after chemotherapy,” the investigators explained.

Reference

Zong X, Yu Y, Yang H, et al. Effects of gonadotropin-releasing hormone analogs on ovarian function against chemotherapy-induced gonadotoxic effects in premenopausal women with breast cancer in China: A randomized clinical trial. JAMA Oncol. Published online December 30, 2021. doi:10.1001/jamaoncol.2021.6214