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Fertility Preservation in Breast Cancer Patients Under Special Consideration of Ovarian Stimulation for Fertility Purposes

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Fertility Preservation in Breast Cancer Patients Under Special Consideration of Ovarian Stimulation for Fertility Purposes Invited Commentary Open Access DOI: 10.19187/abc.202073149-154 Fertility Preservation in Breast Cancer Patients Under Special Consideration of Ovarian Stimulation for Fertility Purposes Sebastian Findeklee*a,b, Sebastian Grewec, Klaus Diedrichd a Kinderwunschzentrum Niederrhein, Madrider Straße 6; D-41069 Mönchengladbach, Germany b Department of Gynecology, Obstetrics and Reproductive Medicine, Saarland University Hospital, Kirrberger Straße 100, Building 9, D-66421 Homburg, Germany b Fertility Center Dr. Sebastian Grewe and Dr. Olaf Drost - Bremer Zentrum für Fortpflanzungsmedizin (BZF), Bremen, Germany d Schleswig-Holstein University Medical Center, Lübeck, Germany Importance of fertility preserving methods B. Epidemiologic aspects of breast cancer A. Socio-demographic changes in society Breast cancer is the most common malignancy in In the industrialized countries, two developments women around the world with 1.6 million new breast have been observed over the last few decades that cancer patients being identified each year 6 have shifted the focus of research and reproductive worldwide. Overall, 4-6 % of the women diagnosed medicine to maintaining fertility. With regard to are under the age of 40, and about one out of five 7 social life, there is a trend of postponing the women possesses a premenopausal hormonal status . realization of the desire to have children to an ever Advancement in the adjuvant systemic and later phase of life or a childbirth does not take place locoregional therapy has resulted in a significantly at all due to existing biological limits. In Germany, improved forecast. for example, between 1993 and 2013, the age of The function of the ovaries can be damaged by women at the birth of their first child rose from the therapy resulting in a loss of germ cells and later around 25 to 29.3 years.1 It is well-known for a long on in infertility. The question of maintaining fertility period of time that women’s fertility decreases is of great importance regarding the self- steadily at the age of approximately 30 years.2 determination of the patients. The potential use of However, the optimum fertility is around 25 years. treatments for fertility preservation has to be a At the same time, there is an almost constant increase compromise between risks and costs of the therapy. in life expectancy in cancer patients, especially in The overall forecast, family planning, gonadotoxic women with breast cancer. One reason for this effects of the planned therapy and psychological observation is the progress made in oncologic compounds should be considered before doctors therapy, which is reflected in improved long-term make an indication for fertility preservation. survival in cancer. However, these successes are An interdisciplinary collaboration of an accompanied by a loss of fertility due to premature oncologist, gynecologist, psychologist, radiologist, ovarian insufficiency, triggered by gonadotoxic side radiation therapist and reproductive specialist is effects of chemotherapy and radiation.3, 4 At the same indispensable. time, many women report that they still want to have children despite being diagnosed with cancer. Up to Fertility preserving methods for breast cancer every 7 patient would even be willing to accept a loss patients in oncologic safety if she could still give birth to a A. General considerations child.5 Ovaries contain a limited number of gametes compared to testes with a maximum of 6.000.000 follicles at 20 weeks of gestation. At birth, there are Address for correspondence: only 1,000,000 follicles left, and at entry of puberty Sebastian Findeklee, MD Address: Kinderwunschzentrum Niederrhein, Madrider Straße there are only 300.000 follicles. Finally, the stock of 6, D-41069 Mönchengladbach, Germany follicles is exhausted by entry in the menopause. Tel: +49 6841-1628000 During the stage of fertility only 300–500 oocytes Fax: +49 6841-1628110 Email: [email protected] ovulate. Findeklee, et al. Arch Breast Cancer 2020; Vol. 7, No. 4: 149-154 149 Fertility preservation breast cancer The determining factors in the admission of a The patients were divided into categories with cytotoxic caused amenorrhea include the age of the respect to their age: 20-34 years (n=112), 35-39 woman at the time of the therapy, the ovarian reserve years (n=142) and >40 years (n=212). The and the applied chemotherapy regimen. The probability of amenorrhea was examined as well as gonadotoxic effect of the commonly used the presumption of recurrent menses following chemotherapies is shown in Table 1. As can be seen, amenorrhea. In only 11% of women aged 20-34 there is a correlation between the cumulative dose of amenorrhea was reported six months after the radiation of the pelvis in the case of metastatic completed chemotherapy. Results slightly varied disease and damage of the ovarian function. between different chemotherapy regimens. In relation to recurrence of menstruation following Table 1. Gonadotoxicity of several agents applied secondary amenorrhea the CMF-regimen showed in breast cancer patients worse outcomes than in the other chemotherapy high risk (POI risk >= 80%) Cyclophosphamid schemes. All in all, the risk of premature ovarian Busulfan insufficiency caused by chemotherapy in patients Melphalan suffering from breast cancer appears to be low. However, regarding fertility preservation-especially intermediate risk (POI risk 20-80%) platin derivates Adriamycin in patients suffering from estrogen-sensitive breast cancer-it should be considered that a longer adjuvant low risk (POI risk < 20%) Vincristin endocrine therapy might be necessary. Meanwhile, 5-Fluorouracil Methotrexat the stock of ovarian follicles could be reduced, Actinomycin D particularly if the therapy is initiated in the second half of the fourth life decade. unclear risk Trastuzumab Pertuzumab As the transposition of the ovaries out of the tyrosine kinase inhibitors pelvis prior to radiotherapy as an additional fertility Pembrolizumab preserving technique is not a relevant issue for breast CDK4/6 inhibitors cancer patients we do not report on it in this review PARP inhibitors PDL1 antagonists article. Damage to ovaries caused by oncologic therapy B. Medical protection of ovarian function clinically appears as an ovarian dysfunction In breast cancer patients, GnRH analogues followed by abnormal estrous cycle. If the stock of (GnRHa), such as Leuprorelin, Buserelin or follicles is irreversibly damaged due to adjuvant Goserelin, are used as medicamentous fertility- therapy, a secondary amenorrhea results including protective therapy. A depot injection is carried out the proof of a lack of estrogen, a thin endometrial every 28 or 84 days with a GnRHa during the entire lining in sonography and loss of antral follicles period of chemotherapy (starting shortly before the (ovarian atrophy). Gonadotrophins can be measured initiation of chemotherapy, ending approximately 2 in a hypergonadotropic range and Anti-Mullerian- weeks after completion of chemotherapy). In this Hormone (AMH) is beneath detection limit. case, there might be a downregulation of the ovary The current study situation concerning the with consecutively reduced intake of cytostatics. The duration of amenorrhea with partial damage to the main side effects are climacteric complaints. If the stock of follicles appears inhomogeneous and varies therapy lasts more than 6 months, the so-called add- highly between different authors.8 back therapy with an estrogen and a progestin is Sukuvanich et al. published the first prospective recommended to counteract the serious consequences study examining the effects of different chemotherapy of a sexual hormone deficiency such as regimens evaluating the probability of amenorrhea osteoporosis.10 During the last years there has been a post therapy depending on the women’s age at the start lively debate about the pros and cons of applying of the therapy.9 In the period from 1998 to 2002, 466 GnRH analogues in women with hormone receptor- women aged between 20 and 45 years were examined. positive breast cancer. GnRHa treatment was The rate of amenorrhea was determined at 6, 12 and 24 considered to desensitize the tumor for the following months after termination of therapy. endocrine therapy that is obligatory in hormone Overall, 111 women out of the examined collective receptor-positive diseases, worsening the patient`s received the AC–regimen (Dexorubicin, Cycloph- prognosis. However, in recent years there has been osphamid, Paclitaxel),76 women were treated increasing evidence that GnRHa can in fact reduce the according the CMF–regimen (Cyclophosphamid, risk of premature ovarian insufficiency (POI) without Methotrexat, 5-Fluorouracil) and 143 received the being associated with a deterioration of prognosis - ACT–regimen (Doxorubicin, Cyclophosphamid, regardless of the hormone receptor status. In 2012, a Paclitaxel). Also, 136 women gained other cytostatics meta-analysis of seven randomized studies with (ACR-, FAC-, FACT-, as well as not further defined predominantly breast cancer patients showed that the regimens). administration of a GnRHa during chemotherapy can 150 Findeklee, et al. Arch Breast Cancer 2020; Vol. 7, No. 4: 149-154 Fertility preservation breast cancer significantly reduce the risk of premature ovarian established method for fertility preservation. The insufficiency.11 Therefore, GnRHa as fertility pregnancy rates after fertility preservation using preserving agents are recommended in the guideline cryopreserved 2PN-cells (pronucleus
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