Breast cancer is the most common malignancy in women and usually presents with biologically aggressive features when presenting at a young age. Hence, chemotherapy is the current standard of care for most young patients but is associated with a high likelihood of inducing ovarian toxicity and infertility after treatment [1, 2].
Infertility induced by cancer treatment is a recognized survivor issue and the practice of fertility preservation is spreading rapidly [3,4,5]. Currently established clinical methods of female fertility preservation include the cryopreservation of embryos and mature oocytes obtained after hormonal stimulation as the ability to thaw and use them successfully in fertility treatments has been demonstrated [4, 6]. However, owing to the biology of breast cancer, concerns have been articulated as hormonal treatment is regarded as being potentially dangerous. There is also the option of ovarian tissue retrieval which does not require hormonal stimulation. Although live births have been reported following the re-transplantation of ovarian tissue, clinical standards have not yet been set and this option is still considered to be experimental .
The main reason for questioning the safety of hormonal stimulation in breast cancer patients is the very high level of circulating estradiol that results from the simultaneous development of multiple ovarian follicles . To overcome fears of hormonal stimulation, less effective treatments have been proposed, such as the retrieval of oocytes in the natural cycle without hormonal stimulation [8, 9] and the cryopreservation of ovarian tissue . However, selected women with estrogen-negative breast cancer have undergone hormonal stimulation using standard gonadotropin-stimulation protocols for the purposes of fertility preservation.
In recent years, potentially safer stimulation protocols have been developed and have involved the addition of tamoxifen or aromatase inhibitors to existing standard gonadotropin-stimulation protocols [10, 11]. As greater efficacy has been reported following treatment with letrozole than that with tamoxifen, the former is preferred and has been used in the USA for several years [11,12,13].
The short-term follow-up of 79 women who elected to undergo letrozole stimulation for fertility preservation  and the following investigation of 120 women for a longer period indicate that this stimulation protocol may not have had a substantial impact on cancer recurrence, and in particular if lymph node involvement was absent . However, the overall safety of these procedures is still not known owing to the lack of comparable groups. Additionally, data on the safety of fertility preservation through the use of standard hormonal stimulation protocols or without hormonal stimulation have not been reported for women with breast cancer.
In Sweden, cancer care and fertility preservation, indicated for medical reasons, are practiced within a public tax-funded healthcare system, whereby equal access by all citizens to health care is ensured. Swedish citizens are also provided with a 12-digit unique identity number that permits the use of national healthcare registers with prospectively collected information gathered on the entire population. The fertility preservation program at Karolinska University Hospital in Stockholm is the largest in the country, serving the entire region of Stockholm–Gotland (with a population of 2.2 million). In general, standard protocols for ovarian stimulation were applied to women without estrogen-sensitive cancer until 2010, when a new protocol was introduced that advocated the use of letrozole, in conjunction with that of gonadotropins . Additional methods, such as egg retrieval in the natural cycle or cryopreservation of the ovarian tissue, are also available and are offered to breast cancer patients and, in particular, to women with estrogen-sensitive disease . A healthcare program for breast cancer has existed in Stockholm–Gotland since the 1970s. Standardized therapy recommendations are provided by the Swedish Breast Cancer Group and have been updated for the past 15 years .
Most young women needing to undergo cancer treatment with the associated risk of infertility express a desire to have children in the future, regardless of their diagnosis, prognosis, or treatment [18,19,20,21]. The objective of our study was to investigate the long-term safety of fertility preservation practiced by women with breast cancer over the years using any of the several available options. As all cancer cases are mandatorily registered in the Swedish Cancer Registry, we designed a matched cohort study that would allow us to compare the incidence of breast cancer relapse within a cohort of women who underwent fertility preservation in Stockholm–Gotland with that of an age-matched control cohort, identified using the Swedish National Quality Register for Breast Cancer in the corresponding healthcare region.