Abstract
Breast cancer is the most common cancer disease in women worldwide, being also the third most common incident cancer overall, with a global estimated of 1.7 million new diagnosed cases per year during 2016 [1]. Fortunately, modern breast cancer treatment achieves a high rate of cure and long-term survival today and improved survival has been continuously observed over the last 50 years, from a 50% 10-year survival in the 1960s up to 80% during the 2010s []. In general, survival of women with a breast cancer treated at early stages 0–1 reaches nearly 100%, whereas it approaches about 80%, 60%, or 20% when the disease is treated in a stages 2, 3, or 4, respectively [2].
Although breast cancer is the most common cancer presenting in women of reproductive age, only 2% of all breast cancers occur in young adult women between 20 and 34 years of age and 11% in women between 35 and 44 years of age [3].
Breast Cancer in Young Women
Breast cancer is the most common cancer disease in women worldwide, being also the third most common incident cancer overall, with a global estimated of 1.7 million new diagnosed cases per year during 2016 [1]. Fortunately, modern breast cancer treatment achieves a high rate of cure and long-term survival today and improved survival has been continuously observed over the last 50 years, from a 50% 10-year survival in the 1960s up to 80% during the 2010s [2]. In general, survival of women with a breast cancer treated at early stages 0–1 reaches nearly 100%, whereas it approaches about 80%, 60%, or 20% when the disease is treated in a stages 2, 3, or 4, respectively [2].
Although breast cancer is the most common cancer presenting in women of reproductive age, only 2% of all breast cancers occur in young adult women between 20 and 34 years of age and 11% in women between 35 and 44 years of age [3]. The incidence of breast cancer, as well as other cancers, increases with age; therefore, delaying childbearing to later in life, which is the current trend in modern societies, results in more female cancer patients who have not yet started to build their families at time of a cancer diagnosis and who express concerns as regards to the impact of cancer treatment in their reproductive health. As most breast cancers are currently diagnosed at an early stage and over 80% of women suffering from breast cancer at reproductive age will be successfully treated today, quality-of-life issues for survivors have become increasingly important.
Current clinical guidelines recommend thus the discussion of fertility aspects with all patients of reproductive age at time of planning a cancer treatment [4]. However, research indicates that among young cancer patients, women in particular do not receive adequate information regarding infertility risks associated to their treatments [5] and that lack of, or poor, fertility-related communication may cause worries among cancer survivors with a negative impact in quality of survival [6].
Impact of Breast Cancer Treatment in Reproductive Health
Young women with breast cancer usually present with tumors having inherent biologically aggressive features, hence, chemotherapy is the current standard of care for most women presenting with breast cancer at reproductive age [7]. In a vast majority of cancer treatments, chemotherapy protocols combine several agents and there is a possibility of a synergistic gonadotoxic effect. In the specific protocols currently used for adjuvant chemotherapy treatment of invasive breast cancer, alkylating agents are combined with anthracyclines and taxanes [8]. These protocols are associated with a high likelihood of inducing ovarian toxicity and infertility after treatment, however, the effect of the taxanes may be variable. Data indicate that using docetaxel in protocols including cyclophosphamide and doxorubicin is associated with a further increased risk of ovarian damage, whereas the use of paclitaxel does not seem to induce such additional risk of infertility [9, 10].
Ovarian failure is common after the chemotherapy recommended for treatment of breast cancer, but the age of the patient is an additional important factor in the development of infertility. Because of a high ovarian reserve with high numbers of follicles in women who are younger at the time of chemotherapy treatment, the risk of developing ovarian failure and permanent infertility after a cancer treatment is smaller in younger than in older women. Younger patients at the time of cancer treatment have thus a higher chance of recovering ovarian function following chemotherapy, nevertheless their fertility window might be reduced, and they should be recommended not to delay childbearing for too long. Women presenting with hormonal-sensitive breast cancer will be nevertheless recommended endocrine adjuvant treatment with tamoxifen for five years or longer, which may importantly delay the timing of attempting a future pregnancy. Considering the naturally age-related decline in ovarian reserve, even women who are not planned to undergo chemotherapy treatment but who are planned for a five-year treatment with tamoxifen should receive information on the impact of this treatment in their fertility [11].
Counseling of Fertility Preservation to Women with Breast Cancer – What Are the Options
The field of fertility preservation is relatively young, but important advances in cryopreservation techniques of embryos, gametes, and gonadal tissue have been reported in the development of effective options for fertility preservation for cancer patients in general. International medical societies currently recommend the use of those methods for fertility preservation [4,12]. However, freezing of embryos and oocytes are recognized as clinically established methods, and the cryopreservation of ovarian tissue is still considered experimental [4,12].
Nevertheless, the safety of fertility preservation procedures that involve hormonal stimulation in women with a breast cancer has been a constant concern. Epidemiological and experimental data have indicated that estrogen plays a central role in the initiation and promotion of breast tumorigenesis. For these reasons, the high estradiol levels that result from conventional ovulation stimulation with gonadotropins have been regarded as unsafe for breast cancer patients, especially because the patients have not yet completed their breast cancer treatment when they undergo fertility preservation. A recent Italian study indicated that only a minor proportion of women younger than 40 years presenting with breast cancer did pursue cryopreservation strategies for fertility preservation. Among the women who accessed fertility counseling, fear of the procedure was the main reason to refuse cryopreservation [13]. In contrast to these data, a report from 14 Nordic university hospitals that had established programs for fertility preservation in five countries found that women with breast cancer have constituted the largest patient group undergoing fertility preservation procedures aiming at cryopreservation in Scandinavian countries for over 20 years [14]. The survey also revealed that, in many cases, ovarian tissue cryopreservation was preferred over methods needing hormonal stimulation, especially if the women presented with hormonally sensitive tumors. However, the trends have changed during the past decade mainly due to the important improvements in the techniques for cryopreservation of oocytes, which have now achieved a clinical standard. Hence, whenever time is available for stimulation and the patient’s clinical condition is permissive, oocyte or embryo cryopreservation after hormonal stimulation are the preferred preservation methods in women with breast cancer [14].
As stated in the recent updated guidelines from the American Society of Clinical Oncology [4], to preserve the full range of options, fertility preservation should be discussed as early as possible with cancer patients, before treatment starts. Early referral has been demonstrated to improve the outcome of embryo and oocyte cryopreservation in women with breast cancer by enabling early initiation of chemotherapy. Early referral for fertility preservation may also improve the likelihood of success by allowing, in some cases, repeated stimulation cycles aiming at obtaining a larger number of oocytes or embryos for cryopreservation before treatment of the cancer. Additional and alternative options should also be included in the information provided, such as third-party reproduction possibilities in the future. Also the possibility to apply Preimplantation Genetic Diagnosis to test for presence of BRCA-1 or BRCA-2 mutation in the embryos of women who would prefer to avoid their future use in fertility treatments should be discussed [11].
Fertility Preservation of Oocytes or Embryos Following Hormonal Stimulation in Women With Breast Cancer
Two approaches that aim to reduce the impact of estrogen on breast tissue during ovarian stimulation with gonadotropins have been proposed as potentially safer for women with breast cancer. Both approaches utilize drugs that are currently used for the endocrine adjuvant treatment of breast cancer, such as tamoxifen and aromatase inhibitors.
The Use of Tamoxifen in Stimulation Cycles for Fertility Preservation
Tamoxifen is a selective estrogen receptor modulator with demonstrated antiestrogenic actions on breast tissue, and these actions inhibit the growth of breast tumors through the competitive antagonism of estrogen at its receptor site. The addition of tamoxifen to either a long gonadotropin-releasing hormone (GnRH) agonist protocol or a GnRH antagonist protocol have been proposed, and both methods have demonstrated efficacy that is comparable to that of conventional gonadotropin stimulation protocols without tamoxifen [15,16]. Irrespective of the induced elevated estradiol levels during gonadotropin stimulation, tamoxifen prevents the binding of estrogen in breast tissue and blocks subsequent DNA transcription at receptor sites.
Tamoxifen also has the property of recruiting and stimulating ovarian follicles until their final maturation because of its nonsteroidal triphenylethylene structure, which is related to that of clomiphene. Thus, tamoxifen has also been used alone for the induction of ovulation or in combination with gonadotropins for the fertility preservation of women with breast cancer. Studies with tamoxifen have demonstrated that its use for ovulation induction does not adversely affect oocyte or embryo development [17].
The Use of Aromatase Inhibitors in Stimulation Cycles for Fertility Preservation
Anastrozole and letrozole, the current third-generation aromatase inhibitors used for the endocrine adjuvant treatment of estrogen-sensitive breast cancer in postmenopausal women, have also been used for ovulation induction in young women. Due to these inhibitors’ competitive binding at the enzyme receptor site, which is a process that highly inhibits the aromatase system, the drugs induce an increase in pituitary gonadotropin production as response to estrogenic negative feedback. Although aromatase inhibitors are contraindicated during pregnancy, data indicate that fertility treatments with letrozole are safe and that use of letrozole for hormone stimulation before conception is not associated with increased risks for the fetus. In a retrospective analysis of data from five centers in Canada, the overall incidence of congenital malformations and chromosomal abnormalities was comparable among children born after fertility treatments with clomiphene (4.8%) and letrozole (2.4%). Furthermore, in that study, the incidence of major malformations was significantly higher after fertility treatments with clomiphene than with letrozole (3% vs. 1.2%, respectively) [18], which has also been confirmed by additional studies [19].
The addition of aromatase inhibitors alongside gonadotropins has been proposed to increase the safety of hormonal stimulation for fertility preservation in women with breast cancer and large studies have been reported over about 15 years. In particular, the use of letrozole is applied in a short protocol using a GnRH antagonist, and the efficacy of treatments aiming at fertility preservation has been reported as similar to that of conventional ovarian stimulation for in vitro fertilization (IVF). An apparent advantage of using letrozole is a decreasing in gonadotropin requirements, which appears to be cost-effective. Thus this protocol has been named as COST-LESS (Controlled Ovarian Stimulation with Letrozole Supplementation) [20] (Figure 10.1). Estradiol levels during these treatments are consistently lower than the levels found in standard stimulation with gonadotropins for IVF, while maintaining similar results in terms of the numbers of oocytes collected during these treatments. Anastrozole has also been investigated in similar fertility preservation cycles, demonstrating comparable results to letrozole in terms of eggs collected; however, significantly higher estradiol levels have been observed with anastrozole. Therefore, protocols using letrozole are currently preferred for women with breast cancer [21].
Figure 10.1 Illustrates the COST-LESS protocol. The treatment starts, if stimulation is initiated during the first menstrual days 2–3, using letrozole orally at a dose of 5 mg/day. After two days of letrozole administration 150–300 IU/day of recombinant FSH or hMG are added, depending on patient’s age and ovarian reserve status. A GnRH antagonist is added when estradiol levels exceed 250 pg/ml (918 pmol/l) or the leading follicle reached 14 mm in diameter to prevent premature LH surge. To obtain a high oocyte maturation rate, oocyte maturation is triggered when at least two leading follicles reach a diameter of 20 mm [22] and oocyte retrieval is performed 36 hours after the trigger. Triggering egg maturation with a GnRH analogue (GnRHa), has shown significantly decreased estradiol levels on the day of retrieval and induces a faster drop of estradiol levels in the subsequent days, further reducing the risk of ovarian hyperstimulation syndrome [23]. Random-start controlled ovarian stimulation has also been described in treatments using letrozole [24]
Fertility Preservation Without Hormonal Stimulation
Obtaining Immature Oocytes for Cryopreservation
Immature oocytes obtained without hormonal stimulation may also be an option for fertility preservation of women with breast cancer when there is a contraindication for hormonal stimulation or time is not available for stimulation, or if it is the patient’s preference. In vitro maturation (IVM) can be attempted or oocytes may be cryopreserved as such. IVM of oocytes clearly needs further development and only few fertility centers worldwide offer treatments using this technique.
The use of IVM methods has also been advocate as an additional tool in stimulated cycles, when oocytes are obtained at immature stages. An increase in the yields of mature oocytes and embryos for cryopreservation has been reported in patients with breast cancer undergoing cycles aimed at fertility preservation [25].
Ovarian Tissue Cryopreservation
The cryopreservation of pieces of ovarian cortex, usually retrieved by laparoscopy, is also a reported method for fertility preservation in women with breast cancer. The surgical retrieval can be planned immediately after the diagnosis of malignant disease and does not require hormonal stimulation, which has been considered safe when applied to women with hormonal-sensitive tumors and some women may prefer to attempt fertility preservation by this method. Given the experimental state of this procedure, both the American Society of Clinical Oncology and the Ethical Committee of the American Society of Reproductive Medicine point out that this method should be offered only as part of an institutional review board–approved research protocol, with full disclosure of risks and uncertainty of benefits to the patient [4,12].
Ovarian tissue transplantation to regain fertility has been reported with success in women with breast cancer and no relapses related to the re-transplantation have been reported [26].
Safety of Fertility Preservation in Women With Breast Cancer
Although potentially safer stimulation protocols have been developed for hormonal stimulation aimed at fertility preservation in women with breast cancer, the main reason for questioning the safety of hormonal stimulation in these patients is the very high level of circulating estradiol that results from the simultaneous development of multiple ovarian follicles. Follow-up studies of women that have elected to undergo hormonal stimulation with protocols using letrozole in the United States indicate that this stimulation protocol may not have had a substantial impact on cancer recurrence, and in particular if lymph node involvement was absent [27, 28]. As many factors can be involved in patient selection bias when aiming at fertility preservation, several variables including disease characteristics are needed to be adjusted to obtain comparable groups and a large patient group as well. 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 healthcare is ensured. We could thus design a large Swedish matched cohort study that allowed us to compare the incidence of breast cancer relapse in women with breast cancer that underwent fertility preservation in the healthcare region of Stockholm and compare them with that of an age-matched control cohort, identified using the Swedish National Quality Register for Breast Cancer in the corresponding healthcare region [29].
Table 10.1 illustrates patient characteristics in the cohort and in each of the groups. In total, 567 women presenting with breast cancer were included in the study, of whom 188 were exposed to a fertility preservation method including 40 women who underwent ovarian tissue cryopreservation and 148 women who underwent oocyte/embryo cryopreservation following ovarian stimulation and 378 aged-matched controls. The mean follow-up time was 6.6 years (range 0.3–17.9 years; median 5.8 years).
Table 10.1 A description of the demographic and tumor characteristics in a matched cohort study of women who had undergone fertility preservation (exposed group) indicated by a diagnosis of breast cancer (n = 188) and control women who did not undergo fertility preservation (n = 378)
| Demographic and tumor characteristics | Women exposed to fertility preservation requiring hormonal stimulation | Women exposed to fertility preservation with no need for hormonal stimulation | Matched comparators (unexposed to fertility preservation) | |||
|---|---|---|---|---|---|---|
| n | Relapses (%) | n | Relapses (%) | n | Relapses (%) | |
| Total | 148 | 16 (10.8) | 40 | 9 (22.5) | 378 | 104 (27.5) |
| 32.7 (21–42) | – | 32.0 (23–38) | – | 34.1 (23–42) | – |
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ER: estrogen receptor
Rodriguez-Wallberg KA, Eloranta S, Krawiec K, Lissmats A, Bergh J, Liljegren A. Safety of fertility preservation in breast cancer patients in a register-based matched cohort study. Breast Cancer Res Treat, 2018 February;167(3):761–769. DOI: 10.1007/s10549-017-4555-3
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