The use of gonadotrophin-releasing hormone (GnRH) agonists in early and advanced breast cancer in pre- and perimenopausal women

Abstract

Gonadotrophin-releasing hormone (GnRH) agonists, in particular goserelin (‘Zoladex’), are increasingly being used for the treatment of breast cancer in women with functioning ovaries. They act by downregulating pituitary GnRH receptors, thereby suppressing the release of luteinising hormone (LH) and follicle stimulating hormone (FSH), which, in turn, reduce the main source of oestradiol production in the ovaries. GnRH agonists have been shown to be as effective therapeutically as surgical ovarian ablation in pre- and perimenopausal women with advanced breast cancer. The combination of a GnRH agonist such as goserelin with the peripheral oestrogen antagonist, tamoxifen, may be used to produce ‘combined oestrogen blockade’. In advanced breast cancer, this regimen prolongs progression-free survival and increases both the response rate and duration relative to the use of a GnRH agonist alone. In patients with early breast cancer, the addition of goserelin to ‘standard treatment’ (i.e. surgery±tamoxifen, chemotherapy or radiotherapy) results in a significant benefit in recurrence-free survival and overall survival. This benefit was most apparent in patients with oestrogen receptor (ER) +ve tumours. Goserelin, when used either alone or in combination with tamoxifen as an adjuvant systemic therapy in women with ER +ve tumours, has been shown in clinical trials to produce recurrence-free survival rates equivalent to cytotoxic chemotherapy such as cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Evidence suggests that at least part of the effect of adjuvant cytotoxic chemotherapy in premenopausal women is produced by ovarian ablation. Endocrine therapy with goserelin or goserelin plus tamoxifen should now be considered a treatment option in the management of premenopausal women with ER +ve early breast cancer.

Introduction

More than 100 years ago, Beatson demonstrated that endocrine ablation by oophorectomy was accompanied by a regression of disease in a patient with advanced breast cancer [1]. He also understood that control of lactation in cows that had recently calved was mediated by the ovaries and not through the central nervous system; an early description of hormone action.

In the premenopausal woman, gonadotrophin-releasing hormone (GnRH) is released from the hypothalamus in a pulsatile fashion (pulses approximately every 90 min) under normal physiological conditions and is carried by the portal veins directly to the anterior pituitary gland where it binds to GnRH receptors, stimulating the release of luteinising hormone (LH) and follicle stimulating hormone (FSH) [2]. The occupied receptors form clusters and are taken up into the pituitary cells. These inactivated receptors are replaced by newly synthesised receptors on the cell surface, ready for the next pulse of GnRH. LH stimulates the ovaries to produce oestrogens, including oestradiol.

This process is responsible for producing up to 90% of circulating oestradiol, depending on the phase of the menstrual cycle; the remainder in premenopausal women, and all in postmenopausal women, is produced by aromatisation of androgens by the adrenal glands and other tissues. Therapeutic approaches to the endocrine treatment of breast cancer have targeted both this regulatory pathway and the point of peripheral action of oestrogens by oestrogen receptor (ER) blockade.

Following Beatson's pioneering work, ovarian ablation by means of surgical castration, or later by irradiation, became a well-established means of endocrine manipulation in premenopausal women with advanced breast cancer. Response rates in metastatic breast cancer range from approximately 30% in unselected patients 3, 4 up to 79% in patients with ER +ve tumours 5, 6.

Surgical ablation is a relatively straightforward procedure with little perioperative morbidity, but it is an invasive method and has the potential of psychological upset, particularly in non-responders. An alternative to surgery is to use irradiation. Radiation ablation produces similar response rates to surgical ablation, but also has occasional long-term complications, takes longer to achieve castrate levels of oestradiol and long-term suppression is unreliable. Both procedures are irreversible and since only around one-third of patients may respond to this type of therapy, a sizeable proportion will have undergone these procedures for no clinical benefit.

The possibility of being able to suppress oestradiol levels medically is an attractive option. Use of GnRH agonists to downregulate GnRH production by the hypothalamus effectively produces a ‘medical ablation’ of the ovaries which is potentially reversible on discontinuation of therapy. Data showing the effectiveness of GnRH agonists in patients with advanced breast cancer were first published using buserelin [7], and goserelin (‘Zoladex’) [8]. Other members of this class include leuprorelin and triptorelin. Goserelin is the most extensively investigated member of the GnRH agonists, accounting for over 90% of the published data on GnRH agonists in the treatment of breast cancer, and no comparisons between the GnRH agonists have been reported.

During long-term administration, the GnRH receptors are effectively over-stimulated, resulting in downregulation of the GnRH receptors in the pituitary gland. Experience over the last decade shows that goserelin provides an effective means of ‘medical oophorectomy’ for as long as the agent is administered. In the clinical setting, goserelin has been widely tested in early and advanced breast cancers. Ovarian suppression with goserelin has a more rapid onset than ovarian irradiation and its effects on ovarian function are reversible in most women [9], which may be important in premenopausal women in the adjuvant setting.

The pharmacodynamics of goserelin in breast cancer were studied in the 1980s. The early work used daily subcutaneous (s.c.) injections [8], which were superseded by the monthly depot formulation of goserelin (3.6 mg) [8] that is now used in clinical practice. Goserelin produced an initial rise in LH and FSH for 7–10 days followed by a decrease in LH and FSH after 14–21 days in premenopausal women with advanced breast cancer. Progesterone and oestradiol levels followed those of the gonadotrophins with a short-lived rise followed by a fall to levels seen in oophorectomised or postmenopausal women 14–21 days after continuous administration. Similar endocrine responses were seen in women who received either daily (s.c.) injections or the monthly depot formulation of goserelin [8].

The ability of the monthly depot of goserelin to suppress serum concentrations of FSH, LH and oestradiol was also demonstrated in a study of 118 evaluable pre- and perimenopausal patients with metastatic breast cancer. This study showed that mean serum oestradiol values fell into the range seen in castrated or postmenopausal women (i.e. <30 pg/ml) after 2–3 weeks of treatment and suppression was maintained throughout therapy (up to 24 months) [10].

While GnRH agonists suppress gonadotrophins and oestrogens to castrate levels in premenopausal women, leading to the cessation of menses, it is important to understand the effects of GnRH agonists on folliculogenesis and follicular maturation since these may indicate the potential for maintaining fertility following discontinuation of treatment.

The expectation was that goserelin would inhibit folliculogenesis by decreasing FSH and LH to very low levels. However, a study of ovarian histology showed that goserelin inhibits follicular maturation, but not folliculogenesis [11]. This is an important finding for young women with breast cancer as it may be expected that after discontinuation of goserelin, and the return of the pretreatment endocrine environment, maturation of the follicles will occur with a resumption of fertility. This would not be possible following surgical oophorectomy, irradiation or chemotherapeutic ablation.

An important question is whether there are any advantages to ‘combined oestrogen blockade’ using goserelin and tamoxifen in premenopausal women, gaining a double effect by first rendering the patient postmenopausal by the use of goserelin and then an additional effect from the use of tamoxifen, as in postmenopausal women.

In addition to the potentially greater antitumour effect, tamoxifen may theoretically shield the tumour from the initial surge in oestradiol seen with goserelin monotherapy. In addition, goserelin has been shown to prevent the intermittent spikes of oestradiol seen with tamoxifen monotherapy [12]. Co-treatment with a GnRH agonist has been shown to prevent the formation of ovarian cysts when added to tamoxifen therapy [13].

The pharmacodynamics of goserelin in combination with tamoxifen have been compared with the effects of goserelin alone in pre- and perimenopausal women with advanced breast cancer. The initial surge in gonadotrophin levels with goserelin alone or in combination with tamoxifen lasted 7–10 days and was followed by a profound suppression of LH and FSH on both regimens. The combination had a more marked effect on serum FSH than goserelin alone [14] and the combination prevented the upward drift of FSH seen with goserelin alone. Both regimens suppressed serum oestradiol and progesterone to levels equivalent to those seen after surgical oophorectomy and there were no peaks in serum oestradiol with the combination.