Role of Ovarian Suppression for Young Women's Breast Cancer

The treatment of young women's breast cancer continues to undergo refinement, including dual goals of improving scientific knowledge and developing tools to positively affect long-term survivorship. The expanded use of gonadotropin-releasing hormone agonists (GnRHa) as an ovarian protectant and in combination with endocrine therapy represents a substantial achievement for both.

Cytotoxic chemotherapy has clinically significant risk for gonadotoxic effects, influenced by the regimen and age of the women. Rates of premature ovarian insufficiency and negative effects on fertility and sexual functioning are serious concerns to many patients.^[1–5] In young women's breast cancer, concomitant GnRHa with chemotherapy can preserve ovarian function and increase subsequent pregnancies.^[6–11] These data resulted in multiple breast cancer guidelines adopting recommendations for incorporating GnRHa as ovarian protection during cytotoxic chemotherapy.^[7,12–15] Nonetheless, concerns remained over the efficacy of the approach and long-term safety, particularly in hormone receptor–positive disease.^[11,16]

In the article accompanying this editorial, Lambertini et al.^[17] present the mature data from the PROMISE-GIM6, a multicenter, randomized, open-label, phase III, superiority study of GnRHa as ovarian protection for premenopausal women undergoing chemotherapy, now with a median follow-up of more than 12 years. The primary endpoint, prevention of chemotherapy-induced premature ovarian insufficiency at 1 year, was met with a statistically significant reduction from 25.9% to 8.9% (odds ratio = 0.28, 95% confidence interval [CI] = 0.14 to 0.59) for the women cotreated with GnRHa. In this post hoc extension analysis, the authors report on 10 women identified as having a BRCA1 (n = 5) or BRCA2 (n = 5) germline pathologic variant, with 0 of 4 patients receiving GnRHa and 2 of 6 patients in the control arm experiencing premature ovarian insufficiency. The authors also provide long-term follow-up with no differences seen in 12-year disease-free survival (DFS) (65.7% in GnRHa arm vs 69.2% in control arm; hazard ratio = 1.16, 95% CI = 0.76 to 1.77) or in 12-year overall survival (OS) (81.2% in GnRHa arm vs 81.3% in control arm; hazard ratio = 1.17, 95% CI = 0.67 to 2.03). DFS and OS for the hormone receptor–positive subgroup were also similar. There were 13 subsequent pregnancies in this study, which did not preselect participants by intent for future childbearing, with 9 in the GnRHa group and 4 in control group. The number of pregnancies was similar (6 vs 7) for hormone receptor–positive and hormone receptor–negative groups, with 1 pregnancy among the BRCA patients. When the data were analyzed excluding 89 women who reported no attempt for pregnancy after treatment, the hazard ratio was 2.41 in favor of GnRHa improving subsequent pregnancy achievement.

The Lambertini et al.^[17] study results cement the need to strongly consider incorporating ovarian protection at onset of chemotherapy for hormone receptor–positive or –negative breast cancers, when preventing premature ovarian insufficiency and enhancing future fertility are desired goals. Resumption of menses in young women's breast cancer may occur up to 24 months later, and therefore studies with earlier endpoints potentially underestimated the benefit of GnRHa, addressing prior efficacy concerns.^[17] In addition, with these long-term safety data, especially for hormone receptor–positive breast cancer as well as prior robust follow-up data for hormone receptor–negative patients from the POEMS-S0230 trial,^[18] providers can feel more secure in offering ovarian protection.

These scientific gains for young women's breast cancer occur in parallel with the ongoing delay of onset of childbearing across the globe, which is expected to increase the diagnosis.^[19–22] Likewise, data support that childbearing after treatment appears to be neutral on breast cancer outcomes.^[23] Data from the POSITIVE trial, which has completed accrual, will refine this understanding, including any differences in outcomes for early sequencing off therapy for childbearing and then resuming treatment.^[24] Thus, more young women who may not have completed their desired childbearing are expected to be diagnosed, with data supporting preservation of fertility, prevention of premature ovarian insufficiency, and subsequent childbearing without negating outcomes. This perfect storm requires medical oncologists to approach young women's breast cancer with nuanced discussion and patient-tailored decisions. Fertility preservation, contraception, utilization of ovarian protection, and future reproduction are mandatory items to be addressed at the initial management of the cancer.

For hormone receptor–positive disease, the SOFT and TEXT clinical trials provided practice-changing data on the improved DFS and OS for the addition of ovarian suppression to tamoxifen or the combination of ovarian suppression with aromatase inhibitors, with the freedom from recurrence increasing with maturation of the data.^[25,26] In the TEXT trial, ovarian suppression was directly overlapped with the chemotherapy and demonstrated no detriment to treatment benefit,^[25] dispelling concerns that had arisen from prior preclinical and clinical data with tamoxifen^[27–29] and consistent with the Lambertini et al.^[17] data. It is currently unknown whether continuous ovarian suppression is better than "testing the waters" to see if a woman's ovaries regain function and then starting ovarian suppression as part of treatment only if function returns. In Lambertini et al.,^[17] GnRHa was stopped after chemotherapy and resumed in 60% of the patients as endocrine treatment after resumption of ovarian function, with similar outcomes observed in this hypothesis-generating study. At present, data for reversible ovarian suppression with GnRHa in combination endocrine regimens only exist for 5 years of therapy. New data supporting the use of CDK4/6 inhibitors for high-risk hormone receptor–positive breast cancer^[30] and PARP-inhibition for high-risk BRCA germline carriers^[31] add to the complexity of what future extended therapy should entail and need to weigh against potential late toxic effects of early permanent menopause.

There remain additional questions for future research to tackle for young women's breast cancer. Firstly, treatment trials specifically for women aged 45 years and younger would permit larger enrollment of young and very young (younger than 35 years) women. Additionally, recent expert opinion has highlighted that parity status at diagnosis should be identified and accounted for in young women's breast cancer research as an underrecognized effect on outcomes.^[32] Young women diagnosed within 5–10 years of their most recent childbirth face increased risk for metastatic disease, whereas nulliparous women and women with their last childbirth more than 10 years prior appear to have more favorable outcomes.^[33,34] Thus, postpartum breast cancers are a unique high-risk subset meriting further treatment improvements, and other young women's breast cancer could perhaps be spared some of the toxicities of current therapies in a patient-tailored approach.^[33–37]