Quality Oncology Care: Discussing Fertility Preservation for Patients With Breast Cancer

Lindsay Kroener, MD

Fertility preservation practices have evolved in recent years, allowing patients with invasive breast cancer to have more options; however, it also potentially creates more questions to address between providers and patients initiating cancer treatment, according to Lindsay Kroener, MD, an assistant clinical professor in the Department of OB/GYN at UCLA Geffen School of Medicine.¹

Kroener recently presented on the topic during the 39th Annual Miami Breast Cancer Conference. Her presentation, “Answering Your Patient’s Questions About Fertility,” outlined the scope of the fertility preservation in cancer, different treatment options and candidate considerations, and conversations surrounding pregnancy following cancer treatment.

Approximately 1 in 48 women younger than 40 receive an invasive cancer diagnosis, Kroener explained.² Furthermore, as survival rates continue to improve, the issue of posttreatment fertility has become even more prominent. Unfortunately, women who have survived cancer are often at an increased risk of infertility, ovarian insufficiency, and adverse perinatal outcomes. Varying factors such as age, ovarian reserve, and cancer therapy type or dosage can all impact the degree of infertility risk. However, researchers currently lack the correct tools to accurately guess the timing of infertility.

In addition, patients who lose their fertility have demonstrated higher rates of depression and other signs of worsened quality of life compared with other cancer survivors. Therefore, discussions addressing the possibility of infertility and options for fertility preservation should be initiated by health care providers who care for patients of reproductive age.

“It is really important for us, as health care providers, to address the possibility of infertility and discuss options for fertility preservation with reproductive aged patients,” Kroener said. “This is endorsed by many professional societies, including ASCO, National Comprehensive Cancer Network, the American Society for Reproductive Medicine, and the American Academy of Pediatrics. Addressing these issues are really considered to be a measure of quality care in oncologic care.”

Currently, standard-of-care fertility preservation may include embryo or oocyte cryopreservation following controlled ovarian stimulation, gonadal shielding, ovarian transposition, fertility-sparing surgery, and sperm banking in males. Moving forward, other alternative options may include ovarian tissue banking, ovarian suppression with gonadotropin-releasing hormone agonists (GnRH), and in vitro maturation of oocytes. However, Kroener’s primarily discussed ovarian stimulation and GnRH agonists.

Eligibility Criteria

Candidates who should be considered for ovarian stimulation for egg/embryo cryopreservation are women who are both post-pubertal but premenopausal. The urgency for therapy initiation is important to consider, as well as potential complications the patient may be undergoing. For example, patients with thrombocytopenia may experience heightened complications when attempting to preserve their eggs or embryos.

Baseline ovarian reserve is also a relevant factor, she explained. FSH/E2, AMH, and antral follicle counts should be assessed at baseline to determine how many eggs a patient could potentially preserve.

Oocyte and Embryo Cryopreservation

Specialists conduct ovarian stimulation by injecting gonadotropins (FSH/HMG) to stimulate growth in multiple ovarian follicles. These injections are delivered across 8 to 12 days and initiation usually begins on the second or third day of the menstrual cycle. During this time, patients are monitored every other day via an ultrasound and blood work.

When the follicles reach an appropriate size, they receive a trigger shot to induce egg maturation. About 35 to 36 hours later, the eggs are retrieved. This procedure typically occurs in the outpatient setting for about 15 to 20 minutes, and while the patient is under a conscience sedation.

In the case of oocyte cryopreservation, the retrieved eggs are examined microscopically, and the mature ones are cryopreserved. For embryo cryopreservation, oocytes are fertilized with partner sperm on the day they are retrieved and then maintained in a culture for 5 to 7 days. When blastocyst stage occurs (100 cells) the specimen is cryopreserved. Of note, for oocyte cryopreservation, survival rates are currently very high; about 90% of the vitrified oocytes should survive the thaw.^3,4

This is considered a mainstay in treatment, particularly for patients who do not have sperm available, said Kroener.

Previously, when cryopreservation technologies were not as good, only about 50% of oocytes would survive freezing, she continued, and patients were often encouraged to use donor sperm to create an embryo, since they had a higher rate of success with the freezing technology. Luckily that is no longer the case.

Patients can now choose between oocyte and embryo cryopreservation—the benefit to embryo cryopreservation is that the patient will know if their egg is suitable to become an embryo (because not all eggs successfully become embryos), and if they have a long-term partner with whom they wish to create an embryo, they receive a lot more information about the embryo up front and before it is preserved. One of the risks associated with embryo cryopreservation is that once an embryo is created, it is communal property between both partners. If either partner changes their mind about having a child with their other partner, the embryo can no longer be used following cancer treatment.

“I always have this conversation with patients,” said Kroener. “There is no forced parenthood. Basically, both people need to consent to use an embryo; a frank discussion here is important. Some patients even opt to freeze some eggs and some embryos, [and] we are certainly capable of doing both now.”

Safety and Timing Considerations

Traditionally, ovarian stimulation began on cycle 2 or of the menstruation cycle. However, initiation can also begin in the middle of a cycle or in the luteal cycle (second half of the cycle) without changing outcomes. This flexibility has been vital because it has permitted more patients to shorten the delays in cancer treatment initiation, Kroener explained.

One important component to consider is that ovarian stimulation elevates estrogen levels. Therefore, patients with hormonally driven cancers, such as estrogen receptor–positive breast cancer, may experience IVF-related complications like bleeding, infection, and ovarian hyperstimulation.

To mitigate these risks, it is common to administer 5mg of letrozole during stimulation in order to suppress estrogen levels.^5,6

Ovarian Suppression With GnRH Agonists

Many patients may inquire about ovarian suppression with GnRH, noted Kroener noted; however, there are limited data demonstrating that this method is associated with beneficial pregnancy rate outcomes. Furthermore, it may be associated with reduced premature ovarian insufficiency.

Both ASCO and ASRM have expressed that GnRH agonists can be offered to patients with breast cancer, but it should not replace traditional methods for fertility preservation, such as oocyte or embryo cryopreservation. ^7,8

“Basically, ovarian suppression with GnRH agonist is putting patients into a medical menopause for a short period of time,” she said. “This can be administered at the time or immediately preceding the administration of toxic treatments.”

“One of the benefits here is that it is much less invasive, expensive, and intensive, and it can be given right away without any delay. [However], the biologic mechanism by which this may prevent or decrease the chance of ovarian failure is a little bit unclear,” Kroener said.

Pregnancy Following Cancer Treatment

Unfortunately, it can often take months or years after the conclusion of cancer therapy for menses to resume. The timeline for resumption is heavily influenced by age and baseline ovarian reserve. Women younger than 30 years typically resume menses within 1 year, while 2 to 3 years is typical for women 35 or older, and many women older than 50 years do not resume menses after completing cancer treatment. ⁹

Finally, when discussing pregnancy after surviving cancer treatment, Kroener advises incorporating timing and safety into the conversation. She therefore recommends preconception counseling with a high-risk obstetrician. Secondly, if a patient is having difficulty conceiving, utilizing the cryopreserved oocytes or embryos is often a good next step.

Whether or not pregnancy increases the risk of breast cancer recurrence risk is still rather controversial, she noted. Current data do not suggest that pregnancy is linked to worse disease-free survival or overall survival outcomes, but available data are still limited.¹⁰

“The take home on this is that although some of the data we have are reassuring, it is certainly limited and [pregnancy] should be an individualized assessment with the patient and their oncologist,” Kroener summarized.

References

1. Kroener L. Answering your patient’s questions about fertility preservation. Presented at: 39th Annual Miami Breast Cancer Conference®; March 3-6, 2022; Miami Beach, FL.
2. Barton SE, Najita JS, Ginsburg ES, et al. Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol. 2013;14(9):873-881. doi:10.1016/S1470-2045(13)70251-1
3. Schattman GL. CLINICAL PRACTICE. Cryopreservation of oocytes. N Engl J Med. 2015;373(18):1755-1760. doi:10.1056/NEJMcp1307341
4. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Mature oocyte cryopreservation: a guideline. Fertil Steril. 2013;99(1):37-43. doi:10.1016/j.fertnstert.2012.09.028
5. Kim J, Turan V, Oktay K. Long-term safety of letrozole and gonadotropin stimulation for fertility preservation in women with breast cancer. J Clin Endocrinol Metab. 2016;101(4):1364-1371. doi:10.1210/jc.2015-3878
6. 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;167(3):761-769. doi:10.1007/s10549-017-4555-3
7. Oktay K, Harvey BE, Partridge AH, et al. Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2018;36(19):1994-2001. doi:10.1200/JCO.2018.78.1914
8. Practice Committee of the American Society for Reproductive Medicine. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertil Steril. 2019;112(6):1022-1033. doi:10.1016/j.fertnstert.2019.09.013
9. Lambertini M, Kroman N, Ameye L, et al. Long-term safety of pregnancy following breast cancer according to estrogen receptor status. J Natl Cancer Inst. 2018;110(4):426-429. doi:10.1093/jnci/djx206
10. Koga C, Akiyoshi S, Ishida M, Nakamura Y, Ohno S, Tokunaga E. Chemotherapy-induced amenorrhea and the resumption of menstruation in premenopausal women with hormone receptor-positive early breast cancer. Breast Cancer. 2017;24(5):714-719. doi:10.1007/s12282-017-0764-1