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Ovarian Function Supression Summit

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

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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.


  1. Ruddy KJ, Gelber SI, Tamimi RM, et al. Prospective study of fertility concerns and preservation strategies in young women with breast cancer. J Clin Oncol. 2014;32:1151-1156.
  2. Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients with cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2018;36:1994-2001.
  3. Kyvernitakis I, Ziller V, Hars O, et al. Prevalence of menopausal symptoms and their influence on adherence in women with breast cancer. Climacteric. 2014;17:252-259.
  4. Poorvu PD, Frazier AL, Feraco AM, et al. Cancer treatment-related infertility: a critical review of the evidence. JNCI Cancer Spectr. 2019;3:pkz008.
  5. Kabirian R, Franzoi MA, Havas J, et al. Chemotherapy-related amenorrhea and quality of life among premenopausal women with breast cancer. JAMA Network Open. 2023;6:e2343910.
  6. Lambertini M, Horicks F, Del Mastro L, et al. Ovarian protection with gonadotropin-releasing hormone agonists during chemotherapy in cancer patients: from biological evidence to clinical application. Cancer Treat Rev. 2019;72:65-77.
  7. Moore HC, Unger JM, Phillips KA. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med. 2015;372:923-932.
  8. Lambertini M, Moore HCF, Leonard RCF, et al. Gonadotropin-releasing hormone agonists during chemotherapy for preservation of ovarian function and fertility in premenopausal patients with early breast cancer: a systematic review and meta-analysis of individual patient–level data. J Clin Oncol. 2018;36:1981-1990.
  9. Francis PA, Pagani O, Fleming GF, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379:122-137.
  10. Perrone F, De Laurentiis M, De Placido S, et al. Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial. Eur J Cancer. 2019;118:178-186. doi:10.1016/j.ejca.2019.05.004
  11. Baum M, Hackshaw A, Houghton J, et al. Adjuvant goserelin in pre-menopausal patients with early breast cancer: results from the ZIPP study. Eur J Cancer. 2006;42:895-904.
  12. Baek SY, Noh WC, Ahn SH, et al. Adding ovarian suppression to tamoxifen for premenopausal women with hormone receptor-positive breast cancer after chemotherapy: an 8-year follow-up of the ASTRRA trial. J Clin Oncol. 2023;41:4864-4871.
  13. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381:805-816.
  14. Gray RG, Rea D, Handley K, et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol. 2013;31(18_suppl):5-5.
  15. Paluch-Shimon S, Cardoso F, Partridge AH, et al. ESO–ESMO fifth international consensus guidelines for breast cancer in young women (BCY5). Ann Oncol. 2022;33:1097-1118.
  16. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression. J Clin Oncol. 2016;34:1689-1701.
  17. Burstein HJ, Curigliano G, Thürlimann B, et al. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol. 2021;32:1216-1235.
  18. Noguchi S, Kim HJ, Jesena A, et al. Phase 3, open-label, randomized study comparing 3-monthly with monthly goserelin in pre-menopausal women with estrogen receptor-positive advanced breast cancer. Breast Cancer. 2016;23:771-779.
  19. Matsuda et al. Monthly versus 3-monthly goserelin acetate treatment in pre-menopausal patients with estrogen receptor-positive early breast cancer. Breast Cancer Res Treat. 2011;126(2):443-451.

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