Timing, Schedule, and Length of Gonadotropin-Releasing Hormone Agonist Therapy in Breast Cancer

Letícia Varella, MD

With the availability of approaches for preserving fertility and ovarian function, physicians should be prepared to discuss the impact of chemotherapy on fertility and ovarian function with patients newly diagnosed with breast cancer in order to personalize treatment plans based on patients’ goals. In the modern era, an increasing number of women are opting to delay pregnancy. However, data from the Young Women’s Breast Cancer Study prospective cohort, which included 620 women aged ≤40 years with breast cancer, indicates that 37% of women wished to have future biological children prior to their breast cancer diagnosis, and 51% of women were concerned about treatment-associated infertility.^1,2

Several factors have been shown to impact fertility in patients with breast cancer, including chemotherapy and endocrine therapy (ET).³ Furthermore, the impact on female fertility is affected by the type of therapeutic regimen and patient age.⁴ For instance, a cohort study of approximately 1600 chemotherapy-treated premenopausal women demonstrated that amenorrhea was more common in older premenopausal patients and in those who received adjuvant tamoxifen.⁵ Amenorrhea was also significantly associated with worse insomnia, systemic adverse effects, and sexual dysfunction.⁵ Observations such as these have sparked interest in evaluating the use of temporary ovarian function suppression (OFS) via a gonadotropin-releasing hormone agonist (GnRHa) as a potential ovarian protective therapy in premenopausal patients with breast cancer who are undergoing chemotherapy. While GnRH agonists have the potential to decrease risk of premature ovarian insufficiency, the exact mechanism of action is not fully understood.⁶ In the POEMS trial, pregnancy occurred in more women who received goserelin (a GnRHa) alongside chemotherapy than in women who received chemotherapy only.⁷ Most of these studies have used amenorrhea as a marker for premature ovarian insufficiency.

The majority of studies have initiated GnRHa therapy 1 to 2 weeks prior to the start of chemotherapy, and at 4-week intervals throughout the duration of chemotherapy until the last cycle.⁸ Current data support 5-year treatment with GnRHa therapy. This length of treatment was found to be effective in the SOFT and TEXT trials.⁹ The HOBOE phase 3 trial is another study that utilized 5 years of GnRHa therapy and analyzed whether letrozole and zoledronic acid plus letrozole are more effective than tamoxifen as adjuvant ET of premenopausal patients with estrogen receptor (ER)-positive breast cancer.¹⁰

Several studies support treatment with GnRHa for 2 years. The ZIPP trial, which included premenopausal women aged <50 years with stage I or II breast cancer irrespective of ER status, evaluated goserelin, tamoxifen, goserelin + tamoxifen, or no ET for 2 years. The study demonstrated that the use of goserelin was associated with improved survival compared with the control arm.¹¹ Similarly, the ASTRRA trial showed that goserelin treatment for 2 years plus 5 years of tamoxifen resulted in 8-year disease-free survival of 85.4% compared with 80.2% for tamoxifen alone (hazard ratio, 0.67; 95% confidence interval, 0.51-0.87).¹² However, the risk of recurrence does not stop at 5 years; it continues beyond 20 years. Young women have a higher risk of recurrence relative to older women. This led to the investigation of extended GnRHa therapy. In the ATLAS and aTTom trials, tamoxifen use for 5 additional years reduced breast cancer mortality; however, there is a need to balance benefits versus long-term side effects.^13,14 Based on these results, the current European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) guidelines recommend a 5-year duration for GnRHa therapy.^15,16 However, extended duration of GnRHa therapy is recommended by St. Gallen International Consensus Guidelines 2021 for a subset of patients with stage II (N0 [node negative] and N1 [1-3+LN]) and stage III disease.¹⁷

Although most studies utilized a monthly dosing interval, 3-month dosing is also an option. Several studies have shown no difference in clinical outcomes or drug-related side effects between dosing every month and dosing every 3 months.^18,19 The current ASCO and ESMO guidelines prefer a monthly dose of GnRHa therapy, especially in very young women and those on aromatase inhibitors. Still, dosing every 3 months is an alternative for convenience for some patients.

References

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