Prevention of Premature Menopause and Preservation of Fertility in Young Cancer Survivors: Hopeful Though Modest Long-term Results

Young adults diagnosed with cancer may confront not only a potentially life-threatening malignancy at an untimely age but often must contend with the risk of infertility following cancer therapy and during their survivorship. Infertility is an important consequence of cancer, and cancer therapy for some patients—and concerns about fertility and premature menopause for young women—may contribute to long-term psychosocial distress and feelings of unresolved grief.1,2 In recent years, efforts have beenmade to improve communication about the potential for fertility impairment and to develop and implement interventions to reduce the risk of subsequent infertility in young patients with cancer. Preservation of fertility for men with cancer typically involves sperm banking (which has its own limitations), whereas fertility preservation options for women are generally more complex and have included embryo or oocyte cryopreservation. However, these strategies are resourceand time-intensive, requiring reproductive endocrinology specialty care, ovarian stimulation with resulting exposure to additional hormones, and surgery for optimal harvesting of oocytes. Despite efficacy and limited safety data for ovarian stimulation protocols designed to minimize hormonal levels, barriers and safety concerns remain, particularly for young women with hormonesensitive breast cancer.3-5 Temporary ovarian suppression using a luteinizing hormone–releasinghormoneanalogue (LHRHa),whichcanbe administered by the oncologist in the week before initiating chemotherapy, hasbeen tested as apotential alternative strategy for fertility preservation with fewer logistical issues and cost considerations. The experience of prepubescent females and findings from animal models have suggested that suppression of ovarian function through treatment may protect theprimordial follicles of theovary fromdestruction thatmay occur with cytotoxic chemotherapy.6 However, the biological plausibility and potential mechanism of protection have beendebated,anddata fromwell-conductedrandomizedclinical trials (RCTs)havebeenawaited tounderstand the risks and benefits of this approach.6,7 Among young women with breast cancer, anxieties related to fertility and preservation of ovarian function are further complicated by the potential risks of hormonal effects associated with continued ovarian function, fecundity, and preservation strategies, as well as the theoretical relationship of subsequent pregnancy with breast cancer recurrence and mortality.8 Most breast cancer, including disease diagnosed in women younger than 45 years, is hormone receptor–positive, and hormonal treatments (aimed at reducing or blocking estrogen, in particular), are a mainstay of therapy. Thus, additional clinical data have been greatly needed to inform these aspects of care for young women with breast cancer. In this issue of JAMA, Lambertini and colleagues9 present long-term follow-up data from the PROMISE-GIM6 Trial, a phase 3 RCT to evaluate the use of an LHRHa (triptorelin) to preserve menstrual functioning in young women with breast cancer. The investigators enrolled 281 women (median age, 39 [range, 25-45] years) with earlystage breast cancer and randomized them to either a control group that received adjuvant or neoadjuvant chemotherapy alone or to an intervention group that received treatment with triptorelin beginning 1 week prior to and given monthly throughout a standard course of cytotoxic adjuvant or neoadjuvant chemotherapy. In the initial report from this study, use of the LHRHa was associated with significantly decreased rates of treatment-related early menopause, defined as cessation of menses and postmenopausal levels of follicle-stimulating hormone and estradiol at 1 year following completion of chemotherapy.10 The rates of premature menopause were approximately 9% for the group of women treated with triptorelin, compared with 26% for those in the control group. In the current report in this issue of JAMA, the authors present a post hoc extension of the same study focused on long-term resumption of menstrual functioning, with median follow-up of 7.3 years. The 5-year cumulative incidence estimate of resumption of menstrual functioning, defined as having had at least 1 menstrual period, was 73% among 148 women in the LHRHa group compared with 64% among 133 women in the control group. The authors also report a greater number of patients with subsequent pregnancy in the LHRHa group compared with controls (8 vs 3, respectively). Most importantly, disease-free survival was not significantly different between the groups at a median follow-up of more than 7 years (80.5% in the LHRHa group and 83.7% in the control group), regardless of hormone receptor status. This study represents the largest RCT to date testing the use of LHRHa for preservation of menses, ovarian function, Related article page 2632 Opinion