More Options for Fertility Preservation for Patients With Cancer

In the article that accompanies this editorial, Oktay et al present the long-term outcomes of the use of high-dose, short-term letrozole for ovarian stimulation and embryo cryopreservation to preserve fertility before chemotherapy in women diagnosed with breast cancer. The methods and results of the study have been published previously. The authors now report on the actual use of the cryopreserved embryos by the women who were treated at their center and the likelihood of having a child as a result of this approach. The feasibility, methods, and success rates for oocyte harvest and cryopreservation of oocytes and embryos have been well established in both cancer and noncancer populations. The use of high-dose, short-term letrozole is tailored to the special needs of patients with cancer in whom exposure to high doses of estrogen to stimulate ovaries is contraindicated. The study enrolled 131 patients with early-stage breast cancer who initially presented with a median age of 36 years. A high number of patients had tumors that expressed estrogen receptor (ER; 69%), and commensurate with hormone receptor expression, 57% of the patients received adjuvant tamoxifen. Notably, 15% of the patients ultimately did not receive chemotherapy. Almost 60% of the referred population had been tested for BRCA mutations, and 18% of the study patients carried a mutated BRCA gene. Enrollment was limited to a single center, and the study did not include a prospectively randomized control group or a prespecified follow-up. Previous reports on the initial success of the method with regard to embryo cryopreservation have been presented with smaller patient numbers. Of the 131 women undergoing embryo cryopreservation, 33 (25%) returned for embryo transfer. Age, tumor stage, treatment history, and BRCA gene mutation status of the returning patients were comparable to those of the patients who did not return. The authors did not offer reasons why 75% of the patients did not return. No data on subsequent spontaneous pregnancies or tumor outcomes were provided for those who did not return. In the returning 33 patients, embryo transfer was attempted at least once in 26 and twice in seven patients. Twenty patients became pregnant, and 17 of 33 women had at least one live birth (52%). The ratio of embryo transfer to live birth was 45% using an average embryo transfer of two. Twinning was common, with seven twin pregnancies. Despite a delay of 5 years, of 131 patients who pursued oocyte harvest before initiating chemotherapy, 17 (13%) had a biologic child from this approach. The success rates of frozen embryo transfer in this study are comparable to outcomes reported in the National Assisted Reproductive Technology Outcomes Report published by the Centers for Disease Control and Prevention. Across fertility clinics nationwide, embryo transfer/live birth ratios are higher for fresh embryos compared with frozen embryos. However, most importantly, this ratio drops considerably for women older than age 35 years. The live birth rate per embryo transfer for women older than 37 years of age was reported to decrease to 29%, and to less than 20% for women older than age 40 years. Albeit a small study and a select group of patients, the implantation, pregnancy, and live birth rate reported for the returning patients is truly encouraging, particularly given a mean age of 41.5 years and the 5-year delay. These data will allow patients to delay pregnancy to complete adjuvant therapy. It further speaks to the feasibility of ovarian stimulation and oocyte harvest before the induction of adjuvant therapy and the benefits of preserving oocytes at a younger age. About 15 of the 33 returning patients opted for a gestational carrier; there were nine deliveries and 14 children born. Women who used a surrogate returned earlier, and frozen embryo transfer was attempted more than once in seven of 15 gestational carriers. The use of gestational carriershasbecomeanacceptedpractice formanywomenwhocannotor should not carry a pregnancy to term. Hence, using embryo cryopreservation before adjuvant therapy and engaging a gestational carrier would allow patients with breast cancer who have ER-positive tumors to increase hormonal therapy to the recommended 10 years, while at the same time starting a family with a biologic child earlier. A considerable number of the patients in this group had been tested for genetic mutations. However, it is not clear whether the mutation status was known at the time of cryopreservation and how a known BRCA status would affect the choices in these patients. Embryo cryopreservation and preimplantation diagnostics may be an important option for mutation carriers with breast cancer, given the strong recommendations for oophorectomies at a young age and the potentially increased vulnerability to DNAdamaging agents and tamoxifen. Alternative options to fertility preservation include the use of gonadotropin-releasing hormone (GNRH) agonists during adjuvant chemotherapy to counteract the determinant impact of chemotherapy on ovarian function. Short-term coadministration of GNRH agonists with chemotherapy has been reported in several randomized JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 22 AUGUST 1 2015