Rationale and Evidence for Ovarian Function Suppression as a Strategy for Ovarian Function Preservation: The POEMS Trial and Beyond

Matteo Lambertini, MD, PhD

Studies have demonstrated that at least half of patients undergoing treatment for breast cancer are concerned about potential infertility and demonstrate interest in becoming pregnant after the conclusion of their treatment. Even those not interested in pregnancy seek to avoid ovarian insufficiency and early menopause, which can negatively impact patients’ quality of life—an important treatment goal.^1,2

Most research regarding fertility in young women with breast cancer has focused on long-term survivors. Little is known about how fertility concerns affect treatment decisions or fertility preservation strategies at the time of initial cancer diagnosis. The PREFER study is an ongoing, observational, prospective study investigating the need for preservation of ovarian function and/or fertility in premenopausal women with early breast cancer.³ The study showed that approximately 1 in 3 women aged ≤40 years were interested in receiving fertility counseling, with almost 1 in 5 ultimately opting for the offered cryopreservation procedure. Thus, failure to adequately address fertility concerns may negatively impact patients’ compliance and adherence to treatment.³

Treatment guidelines, such as those published by the European Society for Medical Oncology, recommend that all cancer patients of reproductive age receive oncofertility counseling as early as possible, irrespective of the type and stage of their disease.⁴ Every patient should be considered as being at potential risk of developing treatment-related gonadotoxicity.⁴ Patient counseling should be personalized based on the type of treatment and age. It is also worth noting that some patients at low risk of ovarian dysfunction opt to receive fertility preservation.

The gonadotropin-releasing hormone (GnRH) agonists are believed to preserve ovarian function by shutting down ovarian function during chemotherapy, thereby minimizing sensitivity to the gonadotoxic effects of chemotherapy. However, GnRH agonist therapy is not a substitute for cryopreservation for patients who desire pregnancy after treatment.⁵ Preclinical evidence supporting the clinical benefit of ovarian function suppression is debatable, with some preclinical studies demonstrating ovarian protective effects of GnRH agonists during chemotherapy, and others failing to demonstrate any effects.⁵ Notably, the majority of these studies have utilized rodent models (primarily mice); very few studies have utilized human ovarian tissue.

In the clinical setting, the use of GnRH agonist therapy to prevent ovarian insufficiency is supported by the results of the POEMS trial.⁶ The study randomized 257 premenopausal women with operable estrogen receptor–negative breast cancer to receive standard chemotherapy with or without ovarian function suppression using the GnRH agonist, goserelin. The primary study end point was the rate of ovarian failure at 2 years. In the goserelin group, an ovarian failure rate of 8% was observed compared with 22% in the chemotherapy-alone group (odds ratio [OR], 0.30; 95% confidence interval [CI], 0.09-0.97; P=.04). Patients in the goserelin arm also had higher pregnancy rates than the chemotherapy-alone arm (21% vs 11%; P=.03), and improved disease-free survival (P=.04) and overall survival (P=.05).⁶

Supportive of the POEMS results are findings from a meta-analysis of 12 randomized controlled trials demonstrating that use of GnRH agonists was associated with a reduced risk of premature ovarian failure (OR, 0.36; 95% CI, 0.23-0.57; P<.001), but with high heterogeneity possibly due to varying characteristics of the included studies (eg, different definitions of premature ovarian failure).⁷ In the 5 studies that reported pregnancies, more patients treated with GnRH agonists achieved pregnancy compared with those who were not (33 vs 19 women; OR, 1.83; 95% CI, 1.02-3.28; P=.041).⁷ Regarding disease outcomes, no differences in survival outcomes were observed.

The impact of GnRH agonist therapy on ovarian reserve requires further exploration. Recently, a study conducted in China demonstrated that treatment with a GnRH agonist was associated with higher recovery rates of anti-Mullerian hormone, a marker of ovarian reserve.⁸ In non-breast malignancies, evidence is more limited. For instance, studies in lymphoma have demonstrated no protective effects of GnRH agonist therapy; however, these trials were small, and additional larger studies are needed.⁵

References

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. Howard-Anderson J, Ganz PA, Bower JE, Stanton AL. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review. J Natl Cancer Inst. 2012;104:386-405.
3. Blondeaux E, Massarotti C, Fontana V, et al. The PREgnancy and FERtility (PREFER) Study investigating the need for ovarian function and/or fertility preservation strategies in premenopausal women with early breast cancer. Front Oncol. 2021;11:690320.
4. 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.
5. 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.
6. Moore HCF, Unger JM, Phillips KA, et al. Goserelin for ovarian protection during breast-cancer adjuvant chemotherapy. N Engl J Med. 2015;372:923-932.
7. Lambertini M, Ceppi M, Poggio F, et al. Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies. Ann Oncol. 2015;26:2408-2419.
8. Wang S, Pei L, Hu T, et al. Protective effect of goserelin on ovarian reserve during (neo)adjuvant chemotherapy in young breast cancer patients: a prospective cohort study in China. Hum Reprod. 2021;36:976-986.