Ovarian Function and Fertility Preservation in Breast Cancer: Should Gonadotropin-Releasing Hormone Agonist be administered to All Premenopausal Patients Receiving Chemotherapy?

Abstract

Chemotherapy-induced premature ovarian insufficiency (POI) is one of the potential drawbacks of chemotherapy use of particular concern for newly diagnosed premenopausal breast cancer patients. Temporary ovarian suppression obtained pharmacologically with the administration of a gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy has been specifically developed as a method to counteract chemotherapy-induced gonadotoxicity with the main goal of diminishing the risk of POI. In recent years, important clinical evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients, including women who are not interested in conceiving after treatment or that would not be candidates for fertility preservation strategies because of their age. Nevertheless, in women interested in fertility preservation, this is not an alternative to gamete cryopreservation, which remains as the first option to be offered. In this setting, temporary ovarian suppression with GnRHa during chemotherapy should be also proposed following gamete cryopreservation or to women who have no access, refuse, or have contraindications to surgical fertility preservation techniques. In this article, we present an overview about the role of temporary ovarian suppression with GnRHa during chemotherapy in breast cancer patients by addressing the available clinical evidence with the aim of identifying both the best candidates for the use of this strategy and the still existing gray zones requiring further investigation.

<p>Controversies Regarding Ovarian Suppression and Infertility in Early Stage Breast Cancer</p>

“…However, the mechanisms, by which LHRHa can protect ovarian function during chemotherapy are not fully known. 15,16…”

“…In ASTRRA study, 1282 premenopausal patients with 45 or less were randomized to 5 years of endocrine therapy with tamoxifen alone or tamoxifen with ovarian function suppression for 2 years. 15 Patients who had received prior chemotherapy and were premenopausal up to 2 years after the end of chemotherapy (based on menstrual history or follicle-stimulating hormone levels) were included. After a median follow-up of 5.6 years, the extension of 2 years of ovarian function suppression to 5 years of tamoxifen showed significant improvement in DFS (HR, 0.69; 95% CI, 0.48-0.97; P ¼ 0.033), and OS (HR, 0.31; 95% CI, 0.10-0.94; P ¼ 0.029).…”

“…The benefit was concordant among all patient subgroups. 15 Data from these three randomized trials suggest that premenopausal women with estrogen receptor-positive breast cancer at intermediate or high risk of disease recurrence enjoy the addition of ovarian function suppression to tamoxifen. The ABCSG 12 study and the joint analysis of the SOFT and TEXT are the trials addressing the role of combining ovarian function suppression and aromatase inhibitors as an adjuvant endocrine treatment in premenopausal women with estrogen receptor-positive early breast cancer.…”

Preserving fertility in female patients with hematological malignancies: the key points

“…Prior to ovarian tissue extraction, ovarian stimulation and mature ovum pick up for further embryo or egg freezing could be attempted in young women when feasible and not contraindicated. Administration of GnRH analogs during chemotherapy can provide ovarian protection to postpubertal patients and may increase pregnancy rates in survivors [13][14][15][16][17]. As the autotransplantation of frozen-thawed ovarian tissue should be contraindicated in hematological malignancies patients due to the risk of ovarian tissue contamination with hematological malignant cells or minimal residual disease (MRD) especially in leukemia [18], the safest ways to restore fertility in those patients using their stored ovarian tissue may be the experimental options of in vitro maturation (IVM) of oocytes and artificial ovary technology [12].…”

Update on the management of early-stage breast cancer

“…In addition, it is now recommended that all pre-menopausal women have treatment with a gonadotropin-releasing hormone (GnRH) agonist during chemotherapy (regardless of their wishes for future pregnancy) as this has been shown to protect against premature ovarian failure. 24,25 Targeted therapy for HER2-positive cancer Some breast cancer cells have an over-expression or amplification of a protein called human epidermal growth factor receptor 2 (HER2) on their surface, which makes them divide and grow aggressively (HER2 positive). Blocking HER2 receptors in HER2-positive tumours will inhibit cancer cells from growing.…”