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

Kathryn J. Ruddy, MD, MPH

Despite the fact that 51% of patients with breast cancer have reported fertility concerns, evidence indicates that fertility preservation methods are underutilized.¹ Early results demonstrate that the rates of utilization for fertility preservation, embryo cryopreservation, oocyte cryopreservation, and ovarian function suppression (OFS) with a gonadotropin-releasing hormone (GnRH) agonist among women with breast cancer in the United States are 10%, 7%, 1%, and 3%, respectively.¹ Updated results did not show much improvement with rates of 12%, 8%, 3%, and 3%, respectively.² In contrast, a single-center study from Italy showed higher rates of OFS (92%) and cryopreservation (12%), indicating that the clinical provider, healthcare system, and regional healthcare policies may influence the utilization of these methods.³

Many questions remain regarding pregnancy after breast cancer. In a meta-analysis of studies that included patients with a pregnancy after breast cancer, of 46,780 patients, 2026 (4.2%) patients had a subsequent pregnancy.⁴ Compared with the general population, breast cancer survivors had a 60% reduced likelihood of having a succeeding pregnancy (relative risk, 0.40; 95% confidence interval [CI], 0.32-0.49).⁴ These low rates of pregnancy could be attributed to the nature of breast cancer therapies, which are associated with amenorrhea, a surrogate marker for ovarian dysfunction.⁵

Studies have shown that pregnancy after breast cancer has no negative impact on treatment outcomes, including disease-free survival (DFS) and overall survival. A systematic literature review was conducted to identify studies that include patients with a pregnancy after breast cancer. Compared with patients with breast cancer who did not have a pregnancy, those with a pregnancy had better DFS (hazard ratio [HR], 0.66; 95% CI, 0.49-0.89) and overall survival (HR, 0.56; 95% CI, 0.45-0.68).⁴

Initial results from the POSITIVE trial showed that interruption of endocrine and OFS therapy (selective estrogen receptor modulator [SERM] alone, SERM and OFS, or aromatase inhibitor and OFS) can be a practical approach for helping patients achieve pregnancy without impacting their treatment outcomes or increasing risk of recurrence.⁶ Patients discontinued therapy within 1 month before study enrollment, with a 3-month washout period prior to attempting pregnancy. Of 497 women, 368 (74%) had ≥1 pregnancies (70% within 2 years) for a total of 507 pregnancies, and 317 had ≥1 live births (64% of all women, 86% of those who became pregnant).

Furthermore, several trials have examined the efficacy of GnRH agonists in facilitating pregnancy and preserving fertility. GBG-37 ZORO was a small study (n=60) that investigated the potential benefit of goserelin for fertility preservation. The primary objective of the study was to evaluate the reappearance of normal ovarian function (as assessed by resumption of menses) in those who received a GnRH agonist (goserelin) alongside chemotherapy compared with those who received chemotherapy without goserelin. There was no difference in the resumption of menses between groups.⁷ Another small study evaluated the use of triptorelin for preserving fertility during chemotherapy. The trial also showed no difference in amenorrhea rates between the study arms.⁸

More recent trials (OPTION and PROMISE-GIM6) suggested that a GnRH agonist may reduce the risk of premature ovarian insufficiency.^9,10 The OPTION trial included 227 patients; 106 patients received chemotherapy plus goserelin and 121 patients received chemotherapy alone.⁹ There was a higher prevalence of amenorrhea during chemotherapy in the goserelin group than in the chemotherapy-alone group (97.9% vs 63.5%; P<.0001). The goserelin group was found to have a reduced prevalence of amenorrhea between 12 and 24 months compared with the control group (22% vs 38%; P=.015), suggesting a protective effect of goserelin. Furthermore, the prevalence of premature ovarian insufficiency in the goserelin group was 18.5% versus 34.8% in the chemotherapy-alone group (P=.048). These effects are particularly seen in women aged ≤40 years.

In summary, pregnancy appears to be safe for patients with breast cancer, with no apparent increases in disease recurrence. Moreover, GnRH agonists given before and during chemotherapy may reduce gonadotoxicity and help patients achieve pregnancy after completion of their treatment.

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. Lewinsohn R, Zheng Y, Rosenberg SM, et al. Fertility preferences and practices among young women with breast cancer: germline genetic carriers versus noncarriers. Clin Breast Cancer. 2023;23:317-323.
3. Lambertini M, Fontana V, Massarotti C, et al. Prospective study to optimize care and improve knowledge on ovarian function and/or fertility preservation in young breast cancer patients: results of the pilot phase of the PREgnancy and FERtility (PREFER) study. Breast. 2018;41:51-56.
4. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: a systematic review and meta-analysis. J Clin Oncol. 2021;39:3293-3305.
5. Poorvu PD, Frazier AL, Feraco AM, et al. Cancer treatment-related infertility: a critical review of the evidence. JNCI Cancer Spectr. 2019;3:pkz008.
6. Partridge AH, Niman SM, Ruggeri M, et al. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656.
7. Gerber B, von Minckwitz G, Stehle H, et al. Effect of luteinizing hormone-releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: the GBG 37 ZORO study. J Clin Oncol. 2011;29:2334-2341.
8. Munster PN, Moore AP, Ismail-Khan R, et al. Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol. 2012;30:533-538.
9. Leonard RCF, Adamson DJA, Bertelli G, et al. GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial. Ann Oncol. 2017;28:1811-1816.
10. Lambertini M, Boni L, Michelotti A, et al. Long-term outcomes with pharmacological ovarian suppression during chemotherapy in premenopausal early breast cancer patients. J Natl Cancer Inst. 2022;114:400-408.