Fertility preservation and pregnancy in women with and without BRCA mutation-positive breast cancer

Abstract

Women with breast cancer face many challenges when considering fertility preservation. Delayed referral results in the limitation of fertility preservation options because most established methods, such as embryo and oocyte cryopreservation, require several weeks to complete. Women with BRCA mutations, on the other hand, may be more aware of fertility issues and motivated to see fertility preservation specialists earlier. Fear of exposure to estrogen limits access to fertility preservation via embryo or oocyte cryopreservation; however, the use of aromatase inhibitors as ovarian stimulants reduces such concern. Ovarian cryopreservation can be used when there is insufficient time to perform ovarian stimulation because this technique does not require hormonal stimulation, but there are safety concerns both in women with BRCA mutations and in patients with hormone receptor-positive disease as well. There does not seem to be a proven ovarian suppression strategy to preserve fertility in women with breast cancer. Pregnancy appears to be safe for breast cancer survivors but studies specific for women with BRCA mutations are lacking. Women with BRCA mutations may elect to use preimplantation genetic diagnosis during in vitro fertilization to avoid transmitting the mutation, but there may be psychosocial difficulties in entertaining this option. Overall, the last decade has brought many options for women with breast cancer considering fertility preservation, but numerous challenges remain. The presence of BRCA mutations further contributes to these challenges.

Figure 1.

Impact of breast cancer chemotherapy on different stages of follicle growth. Based on molecular studies in our laboratory, alkylating agents such as cyclophosphamide and topoisomerase inhibitors such as doxorubicin affect primordial follicle reserve, which results in the shortening of the reproductive life span. These agents are toxic against the nonproliferating population of primordial follicles because they induce apoptotic cell death via induction of breaks in double-strand DNA. The impact of taxanes on the primordial follicle population is unclear from clinical observations and molecular studies are awaited. Regardless of the type of agent, all chemotherapeutics are capable of damaging developing follicles because their granulosa cells are proliferating, and causing at least temporary amenorrhea. Because new follicles will develop from an undamaged primordial follicle population within 3–6 months, this amenorrhea is temporary for non-DNA-damaging agents and hence should not affect future fertility. Antimetabolites such as methotrexate appear to only affect the developing population and hence cause transient amenorrhea without altering ovarian reserve. Abbreviation: FSH, follicle-stimulating hormone.

Figure 2.

Chemotherapy-induced decline in follicle reserve. Our quantitative histological analysis revealed that the primordial ovarian follicle density of chemotherapy-exposed females with a mean age of 26.7 years was similar to that of females of 36.5 years of age with no prior exposure. This suggests that chemotherapy exposure may advance ”ovarian age” by nearly a decade. Adapted from Oktem O, Oktay K. Quantitative assessment of the impact of chemotherapy on ovarian follicle reserve and stromal function. Cancer 2007;110:2222-2229, with permission.

Figure 3.

Approach to candidate for fertility preservation (FP). We use a three-tier approach—triage, physician evaluation, and supportive care—to facilitate and streamline the evaluation of the candidate for FP.

Figure 4.

An individualized strategy for FP in breast cancer patients. Depending on the availability of time, patient's age, whether or not adjuvant chemotherapy and/or tamoxifen treatment is planned, and the candidate's preference in future family size, the FP strategy will vary. Abbreviations: FP, fertility preservation; FSH, follicle-stimulating hormone.

Figure 5.

Controlled Ovarian Stimulation with Letrozole Supplementation Study (COST-LESS) protocol. The aromatase inhibitor letrozole is initiated on the second day of the menstrual cycle, 2 days ahead of starting follicle-stimulating hormone (FSH) stimulation. Gonadotropin-releasing hormone (GnRH) antagonists are added later, when a lead follicle reaches 13 mm in size, to prevent spontaneous ovulation ahead of oocyte retrieval. In the current modification of the protocol, a GnRH analog trigger (1 mg, s.c.) is used to initiate the oocyte maturation process, and oocyte retrieval is performed 35 hours later just prior to ovulation. GnRH analog trigger causes ovarian suppression immediately after oocyte retrieval, further minimizing estrogen exposure in the luteal phase.

Figure 6.

Potential future strategies to use cryopreserved ovarian tissue when ovarian transplantation is not considered safe. When ovarian cryopreservation is the only available option for fertility preservation but the future transplantation of ovarian tissue is not considered safe, such as with ovarian metastasis or a high risk for ovarian cancer development in women with BRCA mutations, experimental strategies such as in vitro follicle growth and xenografting may become available to mature oocytes ex vivo in the future. These options are currently theoretical in the clinical setting.