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Controlled Ovarian Hyperstimulation for Fertility Preservation in Women with Breast Cancer: Practical Issues

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Controlled Ovarian Hyperstimulation for Fertility Preservation in Women with Breast Cancer: Practical Issues REVIEW ARTICLE https://doi.org/10.5653/cerm.2020.03594 pISSN 2233-8233 · eISSN 2233-8241 Clin Exp Reprod Med 2021;48(1):1-10 Controlled ovarian hyperstimulation for fertility preservation in women with breast cancer: Practical issues So Yun Park, Kyungah Jeong, Eun Hye Cho, Hye Won Chung Department of Obstetrics and Gynecology, Ewha Womans University College of Medicine, Seoul, Korea In Korean women, a westernized lifestyle is associated with an increased risk of breast cancer. Fertility preservation has become an increas- ingly important issue for women with breast cancer, in accordance with substantial improvements in survival rate after cancer treatment. The methods of controlled ovarian hyperstimulation (COH) for fertility preservation in breast cancer patients have been modified to include aro- matase inhibitors to reduce the potential harm associated with increased estradiol levels. Random-start COH and dual ovarian stimulation are feasible options to reduce the total duration of fertility preservation treatment and to efficiently collect oocytes or embryos. Using a go- nadotropin-releasing hormone agonist as a trigger may improve cycle outcomes in breast cancer patients undergoing COH for fertility pres- ervation. In young breast cancer patients with BRCA mutations, especially BRCA1 mutations, the possibility of diminished ovarian reserve may be considered, although further studies are necessary. Herein, we review the current literature on the practical issues surrounding COH for fertility preservation in women with breast cancer. Keywords: Breast neoplasms; Fertility preservation; Ovarian hyperstimulation Introduction marriage, and having fewer children later in life are all associated with the increasing risk of breast cancer that has been observed Breast cancer is the most common cancer in women, and one in among Korean women. Since 1996, the proportion of early-stage five patients are younger than 45 years old at diagnosis [1]. In light of breast cancers has significantly increased, and the incidence rate of substantial improvements in cancer treatment, fertility preservation female breast cancer was 67.2 cases per 100,000 women in 2010 [5]. has become an increasing priority for women with breast cancer Breast cancer is currently the second most common cancer in Korean [2,3]. In the United States, the overall 5-year survival rate in women women, after thyroid cancer. The current methods of controlled with breast cancer has increased from 74.6% in 1975–1979 to 91.0% ovarian hyperstimulation (COH) for fertility preservation in breast in 2007 [4]. cancer patients have been modified. To reduce the risks associated A westernized diet, early menarche or late menopause, delayed with increased estradiol levels, aromatase inhibitors (AIs) are co-ad- ministered, unlike in other cancers. In contrast to typical infertility Received: February 18, 2020 ∙ Revised: August 10, 2020 ∙ Accepted: August 12, 2020 Corresponding author: Kyungah Jeong treatment, random-start ovarian stimulation is used to minimize the Department of Obstetrics and Gynecology, Ewha Womans University Mokdong time typically required for fertility preservation treatment prior to Hospital, Ewha Womans University College of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul 07985, Korea chemotherapy. Tel: +82-2-2650-2858 Fax: +82-2-2647-9860 E-mail: [email protected] The Korean Society for Fertility Preservation has suggested that an appropriate method of fertility preservation should be decided This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits through individual patient counseling. Methods such as the cryo- unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. preservation of embryos, oocytes, or ovarian tissue and gonadotro- Copyright © 2021. THE KOREAN SOCIETY FOR REPRODUCTIVE MEDICINE www.eCERM.org 1 Clin Exp Reprod Med 2021;48(1):1-10 pin-releasing hormone (GnRH) agonist treatment during chemo- age in comparison with the use of gonadotropins alone in breast therapy may be considered, and patients must consult with experts cancer patients [18]. The triggering of ovulation with a gonadotro- before chemotherapy or any other treatment [6]. Herein, practical pin-releasing hormone agonist (GnRHa) has been suggested to help concerns related to fertility preservation in women with breast can- minimize its negative effect [21], and in vitro maturation is a useful cer will be discussed. With this review, we aim to provide useful clini- strategy to improve the mature oocyte yield in breast cancer patients cal information based on recent studies. undergoing ovarian stimulation for fertility preservation [15]. A recent systematic review identified 1,002 records, of which 15 Letrozole administration during ovarian selected studies were included in the final analysis [22]. No evidence stimulation was found of a decline in relapse-free survival rates in women with breast cancer who received COH with the coadministration of letro- Estrogen exposure is a well-known risk factor for estrogen recep- zole compared with women who did not undergo fertility preserva- tor (ER)-positive breast cancer [7,8]. The role of estrogen in the car- tion procedures. Kim et al. [23] reported the largest long-term study, cinogenesis of ER-negative breast cancer has yet to be elucidated, including over 5 years of safety data, regarding the use of COH with and estrogens are thought to have little effect on breast carcinogen- letrozole supplementation for fertility preservation via embryo or esis in ER-negative breast cancer [9]. However, several studies have oocyte cryopreservation in women with breast cancer. The mean fol- suggested a possible association between estrogen-dependent re- low-up duration after diagnosis was 5.0 years in the fertility preser- productive characteristics such as high parity and the incidence of vation group and 6.9 years among the control patients, who chose ER-negative breast cancer [10,11]. Therefore, treatment with letro- not to undergo fertility preservation. In the fertility preservation zole may be useful even in patients with ER-negative breast cancer. group, the hazard ratio for recurrence after ovarian stimulation was Letrozole is an AI that prevents estrogen production through com- 0.77 (95% confidence interval, 0.28–2.13), and survival was not com- petitive, reversible binding to the heme of the cytochrome P450 unit promised compared with controls (p= 0.61). Neither BRCA gene mu- of aromatase [12]. Clinically, 5 mg/day letrozole (Femara; Novartis, tation status (p= 0.57) nor whether fertility preservation was under- East Hanover, NJ, USA) is administered on day 2 or 3 of the patient’s gone before or after breast surgery (p= 0.44) significantly affected cycle. The administration of letrozole is continued daily during COH survival outcomes in the fertility preservation group. None of the tu- and discontinued on the day of the trigger. After oocyte retrieval, mor characteristics, including ER status, affected the survival rates af- letrozole is continued again for approximately 3 to 6 days until estra- ter COH with letrozole supplementation [23]. COH with concurrent diol levels decrease to < 50 pg/mL [13]. use of AIs appeared to be a safe fertility preservation option for Evidence suggests that the administration of letrozole during COH young women with breast cancer at risk of fertility loss following can significantly reduce peak estradiol concentrations. Peak estradiol chemotherapy. concentrations (337–829 pg/mL) were found to be less than 1,000 Tamoxifen, sold under the brand name Nolvadex among others, is pg/mL when letrozole was commenced on days 2–3 [14-18]. How- a selective ER modulator. It is a nonsteroidal triphenylethylene anti- ever, Azim et al. [19] reported that anastrozole did not suppress es- estrogen. In breast cancer patients, tamoxifen has been proven to tradiol at its maximum tolerated oral dose of 10 mg/day compared have an excellent suppressive effect on cancer cell proliferation and to 5 mg/day of letrozole (2,515.07± 1,368.52 vs. 714± 440.83 pg/mL, tumorigenesis. Tamoxifen is often preferred over other treatments, respectively; p= 0.01), and letrozole was more potent than anastro- as it does not antagonize endometrial development. Oktay et al. [14] zole for the suppression of estrogen. compared tamoxifen and letrozole during COH for embryo cryopres- While it potentially avoids the negative effects of estrogens on tu- ervation in breast cancer patients. They used 60 mg/day of tamoxifen mor growth, letrozole prevents the aromatization of androgens to alone (Tam-in vitro fertilization [IVF]), 60 mg/day of tamoxifen in estrogens, which may induce significant changes in the endocrine combination with low-dose follicle-stimulating hormone (FSH; follicular environment and impact oocyte competence. Several stud- TamFSH-IVF), or 5 mg of letrozole in combination with FSH (letro- ies have investigated whether the co-administration of letrozole has zole-IVF). The combination of low-dose FSH with tamoxifen an impact on oocyte yield. Oktay et al. [16] and Checa Vizcaino et al. (TamFSH-IVF) or letrozole (letrozole-IVF) resulted in higher embryo [20] both reported that oocyte yield was not significantly affected yields than Tam-IVF. The recurrence rates did not appear to be higher, when letrozole was administered. In contrast, Domingo et al. [17]
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