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Importance: Breast cancer (BC) is the most common indication for fertility preservation (FP) in women of reproductive age. Procedures for FP often include hormonal stimulation, but current data are scarce regarding whether using hormonal stimulation for FP is associated with any deterioration in BC prognosis., Objective: To investigate the risk of disease-specific mortality and relapse in women who underwent FP with or without hormonal stimulation compared with women who did not at time of BC diagnosis., Design, Setting, and Participants: This Swedish nationwide prospective cohort study was conducted to assess the safety of hormonal and nonhormonal FP procedures indicated by BC in Sweden from January 1, 1994, through June 30, 2017. Women were identified from any of the regional FP programs located at Swedish university hospitals. A total of 425 women were found to have undergone FP, and 850 population comparators who had not undergone FP were sampled from regional BC registers and matched on age, calendar period of diagnosis, and region. Relapse-free survival was assessed in a subcohort of 241 women who underwent FP and 482 women who had not, with complete data. Nationwide demographic and health care registers provided data on outcome, disease- and treatment-related variables, and socioeconomic characteristics. Data analyses were performed between November 2021 and March 2022 and completed in June 2022., Main Outcomes and Measures: Relapse and disease-specific mortality after a diagnosis of BC., Results: The final study population included 1275 women (mean [SD] age, 32.9 [3.8] years) at the time of BC diagnosis. After stratification by the matching variables age, calendar period, and region, and adjustment for country of birth, education, parity at diagnosis, tumor size, number of lymph node metastases, and estrogen receptor status, disease-specific mortality was similar in women who underwent hormonal FP (adjusted hazard ratio [aHR], 0.59; 95% CI, 0.32-1.09), women who underwent nonhormonal FP (aHR, 0.51; 95% CI, 0.20-1.29), and women who were not exposed to FP (reference). In a subcohort with detailed data on relapse, adjusted rate of disease-specific mortality and relapse were also similar among the groups who underwent hormonal FP (aHR, 0.81; 95% CI, 0.49-1.37), underwent nonhormonal FP (aHR, 0.75; 95% CI, 0.35-1.62), and were not exposed to FP (reference)., Conclusions and Relevance: In this cohort study, FP with or without hormonal stimulation was not associated with any increased risk of relapse or disease-specific mortality in women with BC. Results of this study provide much needed additional evidence on the safety of FP procedures in women with BC and may influence current health care practice to the benefit of young women with BC who wish to preserve their fertility.

Importance: The practice of fertility preservation (FP) in women with breast cancer (BC) is spreading, but long-term reproductive outcomes after FP are largely unknown., Objective: To investigate the long-term reproductive outcomes in women who did or did not undergo FP at the time of BC diagnosis., Design, Setting, and Participants: A Swedish nationwide cohort study was conducted to investigate the long-term reproductive outcomes of women with BC receiving FP at 1 of the regional FP programs from 1994 to 2017 (n = 425). Population comparators with BC but without history of FP (n = 850) were sampled from regional BC registers, matched on age, calendar period of diagnosis, and county. Data on live births, assisted reproductive technology (ART) use, and mortality were retrieved from population-based registers. Data analysis was performed from January to September 2020., Exposures: History of having received FP compared with no history of FP (unexposed)., Main Outcomes and Measures: The primary outcome was hazard ratios (HRs) of live births and ART treatments following BC in women with vs without FP and the cumulative incidence of these events in the presence of the competing risk of death., Results: Women who had undergone FP (n = 425) had lower parity (302 [71.1%] were nulliparous compared with 171 [20.1%] in the unexposed group), were younger (mean [SD] age, 32.1 [4.0] vs 33.3 [3.6] years), more often had estrogen receptor-positive tumors (289 [68.0%] vs 515 [60.6%]), and were more often scheduled for chemotherapy (399 [93.9%] vs 745 [87.7%]). Of 425 women exposed to FP, 97 (22.8%) had at least 1 post-BC live birth (mean follow-up, 4.6 years), compared with 74 of 850 women (8.7%) unexposed to FP (mean follow-up, 4.8 years). Overall, live birth rates after BC were significantly higher among women with FP (adjusted hazard ratio [aHR], 2.3; 95% CI, 1.6-3.3). The 5-year and 10-year cumulative incidence of post-BC live births was 19.4% and 40.7% among FP-exposed women vs 8.6% and 15.8% among comparators, respectively. Rates of ART use were also higher in the FP group (aHR, 4.8; 95% CI, 2.2-10.7). The all-cause mortality rate was lower in women exposed to FP (aHR, 0.4; 95% CI, 0.3-0.7), with 5-year cumulative incidence of death of 5.3% (95% CI, 3.1%-9.0%) vs 11.1% (95% CI, 8.7%-14.1%) for women with vs without FP., Conclusions and Relevance: In this cohort study of Swedish women after a BC diagnosis, successful pregnancy after BC was possible both in women with and without FP at the time of diagnosis, but a significantly higher likelihood of post-BC live births and ART treatments was observed in women who underwent FP, without any negative association with all-cause survival. This information is valuable for health care clinicians responsible for oncologic treatment and reproductive counseling of women diagnosed with breast cancer at reproductive age.

Study Question: How efficacious and safe are the current approaches to controlled ovarian stimulation (COS) aimed at fertility preservation (FP) in women with breast cancer (BC)?, Summary Answer: In women with BC undergoing COS aiming at egg/embryo cryopreservation, letrozole-based protocols and those randomly started were equally effective compared with conventional COS, and the overall survival was similar between the women that proceeded to FP and those who did not., What Is Known Already: Cryopreservation of oocytes and embryos is an established method for FP in women with BC. Recent improvements to COS protocols include concomitant use of letrozole, random-cycle start day of stimulation and the use of GnRHa for the egg maturation trigger. To date, limited sample size of the available studies has not allowed investigation of differences in the efficacy of the different approaches to COS for FP in this patient population., Study Design, Size, Duration: A prospective multicenter study with national coverage including 610 women with BC counseled between 1 January 1995 and 30 June 2017 at six Swedish FP regional programs., Participants/materials, Setting, Methods: After counseling, 401 women elected to undergo COS. Treatments differed in the use or not of concomitant letrozole, a conventional or random-cycle day COS initiation and the use of hCG versus GnRHa trigger for oocyte maturation. Numbers of cryopreserved oocytes and embryos were defined as primary outcome. Pregnancy attempts, reproductive outcomes and long-term survival, investigated by the linking of individuals of the cohort to the total population register of the Swedish Tax Agency (up to 25 November 2018), were evaluated., Main Results and the Role of Chance: Using letrozole or not resulted in similar numbers of oocytes and embryos cryopreserved (meanoocytes = 9.7 versus 10 and meanembryos 4.0 versus 5.3, respectively), similar to COS with random versus conventional start (meanoocytes 9.0 versus 10.6 and meanembryos 4.8 versus 4.8). In COS with letrozole, a GnRHa trigger was associated with a higher number of oocytes retrieved (P < 0.05) and embryos cryopreserved (P < 0.005), compared with conventional hCG trigger. Of 99 women who returned to fertility clinics after cancer treatment, 32 proceeded to thawing of oocytes or embryos and 10 of them had live births. The all-cause survival between the women that underwent COS and those who did not was similar and did not differ between the two groups., Limitations, Reasons for Caution: Data on tumor characteristics and estrogen receptor (ER) status were not known for all women at the time of FP counseling and planning of COS, thus protocols with letrozole have been used for both estrogen-sensitive and non-estrogen-sensitive BC. For the same reason, subsequent adjustment for ERs in the BC or tumor characteristics as potential confounders were not performed as these parameters were not available and did not influence the provision of FP through COS., Wider Implications of the Findings: The results of our study support the premise that recently introduced potential improvements to COS protocols for FP in women with BC are efficacious and safe., Study Funding/competing Interest(s): This study was supported by research grants from the Swedish Cancer Society, the Stockholm County Council, the Percy Falk Stiftelsen, Radiumhemmets Forskningsfonder, The Swedish Breast Cancer Association and Karolinska Institutet to K.A.R.W. J.B. reports grants from Amgen, AstraZeneca, Pfizer, Roche, Sanofi-Aventis and Merck, outside the submitted work, and payment from UpToDate to Asklepios Medicine HB for a chapter on BC prediction and prognostication. All the other authors have no competing interests to report., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)