Efficacy and safety of controlled ovarian stimulation using GnRH antagonist protocols for emergency fertility preservation in young women with breast cancer—a prospective nationwide Swedish multicenter study

Abstract

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.

Reproductive Outcomes After Breast Cancer in Women With vs Without Fertility Preservation

“…Details on FP counseling and FP procedures for women with BC in Sweden have been previously reported. 16,17 Patient consent was obtained at the time of FP, orally until 2008 and thereafter in writing. The Regional Ethics Committee in Stockholm approved the study (Dnr 2011/1758-31/2, amendments 2014/470-32, 2014/1360-32, 2014/1825-32, 2018/275-32 and 2018/1453-32).…”

Fertility preservation for young adults, adolescents, and children with cancer

“…Furthermore, it achieves low systemic oestrogen levels, similar to those found in a normal menstrual cycle, even though multiple follicles develop responding to the exogenous gonadotropins (47). The number of oocytes obtained in cycles with letrozole is similar to that obtained using standard protocols, and their maturity rate does not seem to differ from those obtained with conventional gonadotropin stimulation protocols (46,47). Co-administration of tamoxifen has been also proposed for FP of women with breast cancer.…”

“…The protocols can also be applied with random initiation (random start), that is, regardless of the woman's cycle day. In general, the delay to egg retrieval is shortened to about 2 weeks in most cases (22,(43)(44)(45)(46).…”

“…The safety of hormonal stimulation in women with breast cancer aiming at FP has also been investigated in several studies (46,(49)(50)(51). A systematic review published in 2017 indicated no increased risks (52).…”

Fertility preservation in endocrine responsive breast cancer: data and prejudices

“…A prospective multicentre study conducted by Marklund et al [29] compared different FP strategies among 610 young BC patients who underwent CHT. Of these, 401 performed COS; after a mean follow-up of 6.3 years, no differences in terms of survival were reported between patients who underwent COS and those who did not, between those who used letrozole in the COS protocol or those who used a 'random start' protocol.Hence, all the available data support safety and efficacy of COS in BC patients, whenever it is possible according to their age, ovarian reserve and tumour characteristics [18][19][20][21][22][23][24][25][26][27]29].…”