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Breast Cancer and Fertility Preservation
Placenta 29 (2008) S147–S151
Contents lists available at ScienceDirect
Placenta journal homepage: www.elsevier.com/locate/placenta
Breast Cancer and Fertility Preservation G.L. Schattman a, *, J. Navarro b a b
The Center for Reproductive Medicine, Weill Cornell Medical College of Cornell University, 1305 York Avenue, 7th floor, NY 10021, USA Victoria Eugenia Hospital, Operative Unit of Reproductive Medicine, Sevilla, Spain
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 12 August 2008
Many women affected with breast cancer are in their reproductive prime and at the time of their initial diagnosis have not yet started or completed their families. Improvements in outcomes for patients with breast cancer means longer survival times and oftentimes cures. Unfortunately, many of the treatments, while life-saving, are toxic to the finite supply of oocytes and diminish a woman’s chance of future childbearing. After the initial shock of the cancer diagnosis has worn off, women are coming to the realization that their diagnosis is not a death sentence. Women that have not completed their families need to be informed about available options to protect their reproductive organs from the cancer treatments. The currently available options for fertility preservation should be discussed with every patient who is in their reproductive years prior to initiating any treatments. Fertility specialists should work closely with oncologists to counsel patients about the risks, if any, of the recommended treatment on their future fertility and discuss options to preserve potential fertility before starting treatments. Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Fertility preservation Breast cancer
1. Introduction Cancer affects over 625,000 women each year in the USA [1]. Breast cancer, the most common malignancy in women, is newly diagnosed in approximately 180,000 women each year with approximately 15% being diagnosed before age 45 [2]. The overwhelming majority of women with breast cancer have disease localized in the breast. Early breast cancers can be successfully treated in 70% of the cases, showing no evidence of residual disease at 10 years following treatment [3]. Current treatment regimens are effective in treating the primary tumors with 5 year survival rates well above 50% for all but stage IV disease, but these treatment regimens can result in damage to the follicular pool of oocytes or infertility [4]. Chemotherapy, initiated 4–6 weeks following surgery, is often recommended in women with moderate to high risk of recurrence and in pre-menopausal women with tumors lacking estrogen receptors [5]. Chemotherapy will reduce the annual incidence of recurrence by 30–40% and death by 20–30%, however, with the caveat of an increased risk of premature ovarian failure [3]. However, aggressive chemotherapies can damage the ovary with post-chemotherapy ovarian function dependent on the agent and the total dose used. The most potent of these, with respect to ovarian damage are the alkylating agents (e.g. busulfan, carboplatin, cisplatin, chlorambucil, cyclophosphamide, ifosfamide,
* Corresponding author. Tel.: þ1 646 962 3836. E-mail address: [email protected] (G.L. Schattman). 0143-4004/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.placenta.2008.08.012
dacarbazine and thiotepa) usually inducing premature ovarian failure following completion of therapy. The consequences of the proposed therapy with regard to future reproduction as well as options for fertility preservation in patients diagnosed with breast cancer need to be discussed with all patients. The presence of a partner, the disease being treated, the age of the woman, the costs of the treatment and the long-term prognosis all need to be taken into consideration to provide patients with as much information as possible in order to make an informed decision on whether they wish to proceed with efforts to preserve their fertility or go directly to treatment. It is not possible to ascertain an individual’s desire for fertility preservation unless we ask. One report demonstrated that women with early-stage breast cancer might even choose a less toxic regimen of chemotherapy even if it is slightly less effective in preventing recurrence in order to preserve their fertility [6]. Hopefully, women will not have to make that choice in the future if effective means of preserving their future reproductive potential are standardized and perfected. A report by the President’s Cancer Panel recommends that all cancer patients of reproductive age be informed about the possibility of treatmentrelated infertility and fertility preservation options [7]. 2. Risk of gonadal damage The risk of gonadal damage from chemotherapy is variable and depends on the age of the woman and agent used. Since the ovaries are endowed with a finite number of primordial follicles which undergo atresia at a rate proportional to their total number, any insult which diminishes the follicle pool, while not necessarily
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causing permanent amenorrhea unless there is complete destruction of all follicles, will invariably result in a period of amenorrhea and reduced ovarian reserve. The alkylating agents are extremely gonadotoxic as their action is not cell-cycle specific and damage even resting primordial follicles. Patients who receive cyclophosphamide, an alkylating agent commonly used against breast cancer, have a 4–9.3-fold risk for the development of premature ovarian failure than non-exposed controls [8,9]. Approximately 30–50% of women treated in their 30’s and more than half of women treated in their 40’s will experience premature menopause or become infertile after treatment. Anthracycline based regimens also demonstrated an age-dependant effect on amenorrhea rates following completion of therapy. No patients <30 years of age receiving doxorubicin containing regimens experienced amenorrhea during therapy, while 1/3 of women aged 30–39 and almost all women 40 and older did [10]. Even if chemotherapy does not induce permanent amenorrhea, damage to the ovary occurs as evidence by an earlier onset of menopause, on average approximately 5–10 years earlier than anticipated [11,12]. In women with estrogen-receptive positive tumors, the use of adjuvant treatment with tamoxifen for 5 years results in a significant delay in pregnancy and a further worsening of ovarian reserve if complete ovarian failure has not already occurred. Unfortunately, ovarian failure, while absolute as a marker for reduced fertility potential, does not capture the more subtle ovarian damage that occurs with gonadotoxic chemotherapeutic agents. Abnormal levels of markers demonstrating reduced ovarian reserve (FSH and Inhibin B) have been associated with women who resume menses following completion of chemotherapy [13] and fertility preservation should be discussed and considered even for young women who are likely to resume menses following completion of chemotherapy and the 2–5 year delay before attempting pregnancy. Since there is often adequate time from the initial diagnosis of breast cancer and surgery until chemotherapy needs to be initiated before a reduction in benefit in terms of survival is seen, fertility preservation is clearly an option for these women and should be offered prior to initiating chemotherapy. Because of the risk of damage to the developing oocyte from the toxic effects of the chemotherapy, it is not recommended to undergo IVF to either cryopreserve oocytes/embryos or perform a fresh embryo transfer during or soon after receiving chemotherapy [14]. Because follicular development takes up to 6 months until the gonadotropin dependant stage of development, we recommend that women who were not able to perform any fertility preservation prior to initiating chemotherapy delay efforts to preserve fertility until at least 6 months following the completion of chemotherapy and preferably 1 year. Many of these women have either not attempted pregnancy prior to their diagnosis or have not yet completed their family. For these patients, preservation of the possibility of having a child using their own gametes is what provides them with the psychological strength to face the painful therapies they must endure to survive. Ovarian damage can also occur with radiation therapy where the ovaries are affected by direct or scattered exposure to the radiation with resultant destruction of germ cells. Damage to the ovaries occurs in a dose-dependant fashion and the actual dose of radiation required depends on the age of the woman (follicular reserve) and cumulative dose delivered to the gonad. Wallace estimated the LD50 of the human oocyte to be approximately 2 Gy [15]. Permanent ovarian failure requires greater than 16.5 Gy in young women (20 years old) while in women that are still reproductively young (30 years old), 14.5 Gy will induce permanent ovarian failure [16]. Radiation exposure to the uterus of 20–30 Gy will increase the rate of subsequent miscarriage if a pregnancy ensues [17].
2.1. Options for fertility preservation Because the main risk of reduced fertility in these women comes from chemotherapy co-adjuvants, fertility preservation is geared towards reducing the toxic effects of these drugs on the ovary. Options available for fertility preservation in breast cancer patients include attempting to reduce the toxic effects of chemotherapy on the ovaries with the use of a GnRH-analogue, controlled ovarian hyper-stimulation with cryopreservation of oocytes or embryos, recovery of immature oocytes and cryopreservation of immature oocytes or in-vitro maturation and cryopreservation of the matured oocytes or ovarian tissue cryopreservation with either auto-transplantation or in-vitro maturation of follicles. The option chosen will depend on the presence of a partner, the anticipated effects of the chemotherapy on the gonads and the time interval between presentation and the need to initiate adjuvant treatments for the breast cancer. There have been numerous patients we have consulted on who decided not to undergo the process of preserving their gametes prior to treatment after a thorough discussion including the probability of ovarian failure or damage from the chemotherapy and the chances for pregnancy using cryopreserved gametes or tissue. Additionally, alternative treatments such as oocyte donation should be discussed. The appropriate choice depends upon honest counseling and good communication between the physician, the patient and her oncologist.
3. Ovarian suppression Ovarian suppression with a GnRH-a (agonist or antagonist) as a means of diminishing the toxic effects of chemotherapy on the ovarian follicles is a controversial issue. Theoretically, suppression of pituitary gonadotropins with a GnRH-analogue can only suppress follicles that have already entered the gonadotropindependant stage of follicular growth and are destined to ovulate in the next 90–120 days. However, by diminishing ovarian perfusion [18] or activating GnRH receptors on ovarian granulosa cells inhibiting apoptosis [19], the ovary might receive additional protective benefits from the GnRH-a. Evidence to the contrary comes from the fact that more than half of pre-pubertal children who received high-dose chemotherapy had ovarian failure [20]. Most of the studies evaluating the effects of ovarian suppression with GnRH-a are retrospective, with small numbers of patients and have been criticized for insufficient length of follow-up and differences in the gonadal toxicity of regimens used between the two groups [21]. A recent study in Hodgkin lymphoma patients who were retrospectively sorted into three different groups according to the cytotoxicity of the chemotherapy received demonstrated a significant advantage in terms of normal FSH levels in patients receiving ovarian suppression compared to those that did not [22]. In the only prospective, randomized study, 20 men and 8 women were given a GnRH-analogue prior to and during chemotherapy [23]. There was no difference in the rate of amenorrhea 3 years following treatment in the 8 women treated with the GnRH analogue (4/8) compared to the control group (6/9). All men were profoundly oligospermic in both the treatment and control group. This study concluded that there was no evidence for a beneficial effect of GnRH analogue, in the dosage or schedule used, to conserve gonadal function during intensive chemotherapy for advanced Hodgkin’s disease. Larger, clinical trials are needed to determine the overall magnitude of the effect of GnRH analogues on protecting the ovaries from the toxic effects of chemotherapy, if any. Patients should be encouraged to participate in clinical trials, but informed that there is insufficient evidence to support the use of GnRH-a as
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the sole means of preserving fertility in patients anticipating gonadotoxic chemotherapy. 4. Embryo and oocyte cryopreservation Embryo cryopreservation is an established method of fertility preservation and has been routinely used for storing excess embryos created as a result of ovarian stimulation from in vitro fertilization cycles. Success rates will ultimately depend on the age of the female partner. Embryos can be created with the patient’s partner or donor sperm if she has no partner or he is reluctant. The patient and her partner should establish legal ownership of the embryos prior to their creation, and determine what is to be done in the event of dissolution of the relationship. She must be made aware that in the absence of such an agreement, she might not be able to utilize these embryos if the genetic father does not consent to their use. Stimulation of the ovaries is required and will be discussed below. Oocyte cryopreservation avoids many of the issues mentioned previously and ownership of the gametes is not disputable. Unfortunately, despite improvements in cryopreservation techniques using slow-freezing protocols, published success rates are still quite low per oocyte frozen [24]. One of the reasons for the low success rates achieved has been intracellular ice crystal formation during the freezing and thawing process. The metaphase II oocyte is a large cell with a high water content. Damage to the spindle apparatus, which can occur with the formation of ice crystals during freezing and thawing can be lethal to the cell if measures are not taken to limit its occurrence [25,26]. Membrane permeable (ethylene glycol and 1,2-propanediol) and impermeable (mono or disaccharides) cryoprotective agents (CPAs) in a buffered salt solution have been used in various concentrations to extract water from the oocytes in order to limit the osmotic stress as well as different rates of cooling and thawing with variable success rates. Vitrification of oocytes using high concentrations of CPAs with ultra-rapid cooling (several thousand degrees per minute) can vitrify the entire cell without ice-crystal formation, however the cells are exposed to significantly higher concentrations of CPAs and osmotic stress. Additionally, potential exposure to viruses and pathogens in the liquid nitrogen used to plunge the embryos in for vitrification is of concern. In a meta-analysis [24] comparing the results obtained with slow-freezing of oocytes and vitrification, the live-birth rate in young women (mean age 33.7 years) with slow-freeze protocols was 2.3% per oocyte thawed and 4.0% per oocyte injected with an implantation rate of 10.1% using slow-freezing methods. Vitrification gave slightly better results, with a live-birth rate of 6% per thawed oocyte, with an implantation rate of 20.5% in women who had a mean age of 32.3 years of age. Because of the low-success rates of oocyte cryopreservation in peer-reviewed published reports, the American Society of Reproductive Medicine has stated that ‘‘Oocyte cryopreservation presently should be considered an experimental technique only to be performed under investigational protocol under the auspices of an IRB’’ and that ‘‘At the present time, . oocyte cryopreservation should not be marketed or offered as a means to defer reproductive aging’’ [27]. 5. Ovarian stimulation Conventional assisted reproductive techniques (ART) utilize exogenous gonadotropins to recruit multiple follicles with the anticipated recovery of several mature oocytes. Although natural cycle ART without stimulation would be ideal with respect to estrogen sensitive tumors, currently ART programs are not able to guarantee successful implantation and delivery of a healthy child from a single cryopreserved oocyte or embryo. Additionally, in vitro
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maturation techniques are not yet standardized to provide for efficient maturation and developmental competency to offer this as a standard for patients with estrogen-sensitive tumors with either minimal or no stimulation [28]. Fortunately, newer medications and methods of ovarian stimulation have been developed that allow for multi-follicular recruitment and at the same time limit the exposure to supra-physiologic levels of estradiol seen with convention ovarian stimulation protocols [29–36]. Tamoxifen, a non-steroidal tri-phenylethylene anti-estrogen, has been proven effective for the chemoprevention of breast cancer [29]. It has also been effectively used for the induction of ovulation, with success rates similar to clomiphene citrate [30]. Breast cancer patients stimulated with tamoxifen (40–60 mg/day) starting on day 2–3 of a menstrual cycle retrieved an average of 1.6 0.3 mature oocytes per patient, significantly more than the 0.7 0.2 mature oocytes in the natural cycle IVF patients [31]. While peak estradiol levels were also higher in the tamoxifen group (442.4 pg/ml) compared to the natural cycle IVF group (278 pg/ml), the antagonistic effect of tamoxifen on estradiol receptors in breast tissue most likely does not adversely affect prognosis as patients on tamoxifen chronically for 5 years often have elevated estradiol levels [32,33]. Another method for stimulation of ovarian follicles utilizes the action of aromatase inhibitors to block the production of estradiol from the developing follicles. Despite aggressive use of gonadotropins and multifollicular recruitment, estradiol levels can be kept within the physiologic range. Letrozole, a third generation inhibitor, competitively binds the active site of the aromatase enzyme in a highly selective fashion [34]. By blocking the production of estrogens and the negative feedback of estradiol on the pituitary, aromatase inhibitors can stimulate multifollicular growth and enhance the action of gonadotropins [35]. Letrozole in combination with gonadotropins produced significantly more oocytes for cryopreservation than tamoxifen alone (8.5 1.6 vs. 1.5 0.3). Although not statistically different from letrozole and gonadotropins possibly because of the small numbers of patients, tamoxifen with gonadotropins produced only 5.1 1.1 mature oocytes per patient [36]. Peak estradiol levels were lowest in the letrozole with gonadotropin group and tamoxifen group compared to the tamoxifen with gonadotropin group (380 60 pg/ml, 420 40 pg/ml and 1,200 300 pg/ml, respectively). No difference in recurrence rates of breast cancer was observed in patients treated with letrozole compared to controls (patients with breast cancer who elected not to undergo ovarian stimulation for embryo cryopreservation) after almost 2 years of follow-up which should be reassuring to these patients. 6. Ovarian tissue cryopreservation In patients who are either unwilling to undergo ovarian stimulation, do not have the time it might take to adequately stimulate and retrieve mature oocytes, or those that are BRCA-1 or BRCA-2 positive and desire bilateral oophorectomy, ovarian tissue cryopreservation can be offered in programs so equipped under the guidance of an IRB approved protocol [27]. This experimental technique involves the removal of the ovary(ies) with cryopreservation of thin strips of cortical tissue that contain the primordial follicles. This tissue can be thawed and re-transplanted in the ovarian fossa [37], a heterotopic site such as the forearm or abdominal wall [38], or the primordial follicles can potentially, in the future, be isolated and allowed to develop in culture only to be re-frozen when mature or fertilized and cryopreserved. Endocrine function after re-transplantation has been observed [37] and two births have been reported after orthotopic transplantation of frozen-thawed ovarian tissue into the ovarian fossa although definitive proof that the pregnancies originated
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from oocytes that developed from the frozen tissue is lacking as one ovary was not cryopreserved in each of these patients [39,40]. The attraction of freezing ovarian tissue is that the resting stage follicles are less likely to be damaged by the cryopreservation methods. Unfortunately, other obstacles such as difficulties in freezing large pieces of tissue and the lack of current techniques for the in vitro maturation of these primordial follicles currently limit the clinical usefulness of this technology. Improvements in the culture systems and a better understanding of the conditions required to obtain mature, fertilizable oocytes is required. In one recent publication, Telfer and colleagues developed follicles from strips of fresh ovarian tissue and of the minority that survived the entire culture period, 30% cultured with activin A had normal morphology and antrum formation [41]. Additionally, the risk of re-seeding cancer cells with transplantation of thawed tissue poses an additional risk, although the risk of occult ovarian involvement from early stage breast cancer is rare [42]. More concerning would be the BRCA positive patients and the risk of ovarian cancer development in the transplanted ovarian tissue. 7. Summary and conclusions Reproductive aged patients with a recently diagnosed cancer are increasingly seeking options to preserve their fertility. Survival rates are improving and patients should be counseled about options available to them. This will take a great effort on the part of fertility specialists to educate both potential patients as well as oncologists so that the physical and psychological trauma of enduring the side effects of chemotherapy can be lessened by the knowledge that one of the consequences of treatment, loss of reproductive potential, can be limited. All available options along with their risks, limitations and benefits should be thoroughly discussed with patients as soon as the diagnosis is made, and close collaboration between the oncologist and reproductive endocrinologist should be maintained. Treatment plans should be cleared by the patient’s oncologist, and risks to the patient minimized. The most tested and successful option for fertility preservation is embryo cryopreservation using either a partner’s or donor sperm. Oocyte cryopreservation can be offered to single women or even women with a partner who wish to maintain the autonomy of their gametes. Ovarian tissue cryopreservation should be considered only in those situations where either embryo or oocyte cryopreservation is not an option due to logistical reasons or in conjunction with oocyte or embryo cryopreservation. The decision to pursue any of these options can only be made by the patient after appropriate counseling and careful consideration of her disease and longterm expectations, success rates, risks of fertility preservation treatment and the effect of a delay in initiating chemotherapy, as well as the costs involved. All centers offering fertility preservation, additionally, should do so only with adequate IRB oversight using approved consent forms and treatments. 8. Conflict of interest The Authors have no commercial, proprietary, or financial interest in the products or companies described in this article. References [1] American Cancer Society. Cancer facts and figures-2001. Atlanta, GA: American Cancer Society; 2001. [2] Hankey BF, Miller B, Curtis R, Kosary C. Trends in breast cnacer in young women in contrast to older women. J Natl Cancer Inst Monogr 1994;16:7–14. [3] Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005;365:1687–717.
[4] Ries LAG, Percy CL, Bunin GR. Introduction. In: Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, et al., editors. Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995 (NIH pub. No. 99-4649). Bethesda, MD: National Cancer Institute; 1999. p. 1–15. [5] Brown RJ, Davidson NE. Adjuvant hormonal therapy for premenopausal women with breast cancer. Semin Oncol 2006;33:657–63. [6] Partridge AH, Gelber S, Peppercorn J, Sampson E, Knudsen K, Laufer M, et al. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 2004;22:4174–83. [7] Living beyond cancer. Finding a new balance, President’s Cancer Panel 2003–2004 Annual Report, US Department of Health and Human Services, 2004; p. 1–87. [8] Byrne J, Fears TR, Gail MH, Pee D, Connelly RR, Austin DF, et al. Early menopause in long-term survivors of cancer during adolescence. Am J Obstet Gynecol 1992;166:788–93. [9] Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update 2001;7:535–43. [10] Hortobagyi GN, Buzdar AU, Marcus CE, Smith TL. Immediate and long-term toxicity of adjuvant chemotherapy regimens containing doxorubicin in trials at M.D. Anderson Hospital and Tumor Institute. NCI monogr 1986;1:105–9. [11] Walshe JM, Denduluri N, Swain SM. Amenorrhea in pre-menopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 2006;24:5769–79. [12] Ganz PA. Breast cancer, menopause and long-term survivorship: critical issues for the 21st century. Am J Med 2005;118(Suppl. 12B):136–41. [13] Schmidt KL, Andersen CY, Loft A, Byskov AG, Ernst E, Anderson AN. Follow-up of ovarian function post-chemotherapy following ovarian cryopreservation and transplantation. Hum Reprod 2005;20:3539–46. [14] Dolmans MM, Demylle D, Martinez-Madrid B, Donnez J. Efficacy of in vitro fertilization after chemotherapy. Fertil Steril 2005;83:897–901. [15] Wallace WHB, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Hum Reprod 2003;18:117–21. [16] Wallace WH, Thomson AB, Saran F, Kelsey TW. Predicting age of ovarian failure after radiation to a field that includes the ovaries. Int J Radiat Oncol Biol Phys 2005;62:738–44. [17] Urbano MT, Tait DM. Can the irradiated uterus sustain a pregnancy? A literature review. Clin Oncol (R Coll Radiol) 2004;16:24–8. [18] Falcone T, Bedaiwy MA. Fertility preservation and pregnancy outcome after malignancy. Curr Opin Obstet Gynecol 2005;17:21–6. [19] Meduri G, Touraine P, Beau I, Lahuna O, Desroches A, Vacher-Lavenu MC, et al. Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor:clinical, histological and molecular studies. J Clin Endocrinol Metab 2003;88:3491–8. [20] Teinturier C, Hartmann O, Valteau-Coauanet D, Benhamou E, Bougneres PF. Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplant 1998;22:989–94. [21] Sonmezer M, Oktay K. Fertility preservation in female patients. Hum Reprod Update 2004;10:251–66. [22] Huser M, Crha I, Ventruba P, Hudecek R, Zakova J, Smardova L, et al. Prevention of ovarian function damage by a GnRH analogue during chemotherapy in Hodgkin lymphoma patients. Hum Reprod 2008;23:863–8. [23] Waxman JH, Ahmed R, Smith D, Wrigley PFM, Gregory W, Shalet S, et al. Failure to preserve fertility in patients with Hodgkin’s disease. Cancer Chemother Pharmacol 1987;19:159–62. [24] Oktay K, Cil AP, Bang H. Efficiency of oocyte cryopreservation: a meta-analysis. Fertil Steril 2006;86:70–80. [25] Shaw JM, Oranratnachai A, Trounson AO. Fundamental cryobiology of mammalian oocytes and ovarian tissue. Theriogenology 2000;53:59–72. [26] Baka SG, Toth TL, Veeck LL, Jones Jr HW, Muasher SJ, Lazendorf SE. Evaluation of the spindle apparatus of in-vitro matured human oocytes following cryopreservation. Hum Reprod 1995;10:1816–20. [27] The Practice Committee of the American Society of Reproductive Medicine. Ovarian tissue and oocyte cryopreservation. Fertil Steril 2006;86:S142–7. [28] Jurema M, Noguire D. In vitro maturation of human oocytes for assisted reproduction. Fertil Steril 2006;86:1277–91. [29] Prichard RS, Hill AD, Dijkstra B, McDermott EW, O’Higgins NJ. The prevention of breast cancer. Br J Surg 2003;90:772–83. [30] Steiner AZ, Terplan M, Paulson R. Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis. Hum Reprod 2005;20:1511–5. [31] Oktay K, Buyuk E, Davis O, Yermakova I, Veeck L, Rosenwaks Z. Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod 2003;18:90–5. [32] Shushan A, Peretz T, Mor-Yosef S. Therapeutic approaches to ovarian cysts in tamoxifen-treated women with breast cancer. Int J Gynaecol Obstet 1996;52:249–53. [33] Klijn JG, Beex LV, Mauriac L. Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 2000;92:903–11. [34] Pfister CU, Martoni A, Zamagni C, Lelli G, De Braud F, Souppart C, et al. Effects of age and single versus multiple dose pharmacokinetics of letrozole (femara) in breast cancer patients. Biopharm Drug Dispos 2001;22:191–7. [35] Casper RF. Aromatase inhibitors in ovarian stimulation. J Steroid Biochem Mol Biol 2007;106:71–5. [36] Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison with ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol 2005;23:4347–53.
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Contents lists available at ScienceDirect
Placenta journal homepage: www.elsevier.com/locate/placenta
Breast Cancer and Fertility Preservation G.L. Schattman a, *, J. Navarro b a b
The Center for Reproductive Medicine, Weill Cornell Medical College of Cornell University, 1305 York Avenue, 7th floor, NY 10021, USA Victoria Eugenia Hospital, Operative Unit of Reproductive Medicine, Sevilla, Spain
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 12 August 2008
Many women affected with breast cancer are in their reproductive prime and at the time of their initial diagnosis have not yet started or completed their families. Improvements in outcomes for patients with breast cancer means longer survival times and oftentimes cures. Unfortunately, many of the treatments, while life-saving, are toxic to the finite supply of oocytes and diminish a woman’s chance of future childbearing. After the initial shock of the cancer diagnosis has worn off, women are coming to the realization that their diagnosis is not a death sentence. Women that have not completed their families need to be informed about available options to protect their reproductive organs from the cancer treatments. The currently available options for fertility preservation should be discussed with every patient who is in their reproductive years prior to initiating any treatments. Fertility specialists should work closely with oncologists to counsel patients about the risks, if any, of the recommended treatment on their future fertility and discuss options to preserve potential fertility before starting treatments. Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Fertility preservation Breast cancer
1. Introduction Cancer affects over 625,000 women each year in the USA [1]. Breast cancer, the most common malignancy in women, is newly diagnosed in approximately 180,000 women each year with approximately 15% being diagnosed before age 45 [2]. The overwhelming majority of women with breast cancer have disease localized in the breast. Early breast cancers can be successfully treated in 70% of the cases, showing no evidence of residual disease at 10 years following treatment [3]. Current treatment regimens are effective in treating the primary tumors with 5 year survival rates well above 50% for all but stage IV disease, but these treatment regimens can result in damage to the follicular pool of oocytes or infertility [4]. Chemotherapy, initiated 4–6 weeks following surgery, is often recommended in women with moderate to high risk of recurrence and in pre-menopausal women with tumors lacking estrogen receptors [5]. Chemotherapy will reduce the annual incidence of recurrence by 30–40% and death by 20–30%, however, with the caveat of an increased risk of premature ovarian failure [3]. However, aggressive chemotherapies can damage the ovary with post-chemotherapy ovarian function dependent on the agent and the total dose used. The most potent of these, with respect to ovarian damage are the alkylating agents (e.g. busulfan, carboplatin, cisplatin, chlorambucil, cyclophosphamide, ifosfamide,
* Corresponding author. Tel.: þ1 646 962 3836. E-mail address: [email protected] (G.L. Schattman). 0143-4004/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.placenta.2008.08.012
dacarbazine and thiotepa) usually inducing premature ovarian failure following completion of therapy. The consequences of the proposed therapy with regard to future reproduction as well as options for fertility preservation in patients diagnosed with breast cancer need to be discussed with all patients. The presence of a partner, the disease being treated, the age of the woman, the costs of the treatment and the long-term prognosis all need to be taken into consideration to provide patients with as much information as possible in order to make an informed decision on whether they wish to proceed with efforts to preserve their fertility or go directly to treatment. It is not possible to ascertain an individual’s desire for fertility preservation unless we ask. One report demonstrated that women with early-stage breast cancer might even choose a less toxic regimen of chemotherapy even if it is slightly less effective in preventing recurrence in order to preserve their fertility [6]. Hopefully, women will not have to make that choice in the future if effective means of preserving their future reproductive potential are standardized and perfected. A report by the President’s Cancer Panel recommends that all cancer patients of reproductive age be informed about the possibility of treatmentrelated infertility and fertility preservation options [7]. 2. Risk of gonadal damage The risk of gonadal damage from chemotherapy is variable and depends on the age of the woman and agent used. Since the ovaries are endowed with a finite number of primordial follicles which undergo atresia at a rate proportional to their total number, any insult which diminishes the follicle pool, while not necessarily
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causing permanent amenorrhea unless there is complete destruction of all follicles, will invariably result in a period of amenorrhea and reduced ovarian reserve. The alkylating agents are extremely gonadotoxic as their action is not cell-cycle specific and damage even resting primordial follicles. Patients who receive cyclophosphamide, an alkylating agent commonly used against breast cancer, have a 4–9.3-fold risk for the development of premature ovarian failure than non-exposed controls [8,9]. Approximately 30–50% of women treated in their 30’s and more than half of women treated in their 40’s will experience premature menopause or become infertile after treatment. Anthracycline based regimens also demonstrated an age-dependant effect on amenorrhea rates following completion of therapy. No patients <30 years of age receiving doxorubicin containing regimens experienced amenorrhea during therapy, while 1/3 of women aged 30–39 and almost all women 40 and older did [10]. Even if chemotherapy does not induce permanent amenorrhea, damage to the ovary occurs as evidence by an earlier onset of menopause, on average approximately 5–10 years earlier than anticipated [11,12]. In women with estrogen-receptive positive tumors, the use of adjuvant treatment with tamoxifen for 5 years results in a significant delay in pregnancy and a further worsening of ovarian reserve if complete ovarian failure has not already occurred. Unfortunately, ovarian failure, while absolute as a marker for reduced fertility potential, does not capture the more subtle ovarian damage that occurs with gonadotoxic chemotherapeutic agents. Abnormal levels of markers demonstrating reduced ovarian reserve (FSH and Inhibin B) have been associated with women who resume menses following completion of chemotherapy [13] and fertility preservation should be discussed and considered even for young women who are likely to resume menses following completion of chemotherapy and the 2–5 year delay before attempting pregnancy. Since there is often adequate time from the initial diagnosis of breast cancer and surgery until chemotherapy needs to be initiated before a reduction in benefit in terms of survival is seen, fertility preservation is clearly an option for these women and should be offered prior to initiating chemotherapy. Because of the risk of damage to the developing oocyte from the toxic effects of the chemotherapy, it is not recommended to undergo IVF to either cryopreserve oocytes/embryos or perform a fresh embryo transfer during or soon after receiving chemotherapy [14]. Because follicular development takes up to 6 months until the gonadotropin dependant stage of development, we recommend that women who were not able to perform any fertility preservation prior to initiating chemotherapy delay efforts to preserve fertility until at least 6 months following the completion of chemotherapy and preferably 1 year. Many of these women have either not attempted pregnancy prior to their diagnosis or have not yet completed their family. For these patients, preservation of the possibility of having a child using their own gametes is what provides them with the psychological strength to face the painful therapies they must endure to survive. Ovarian damage can also occur with radiation therapy where the ovaries are affected by direct or scattered exposure to the radiation with resultant destruction of germ cells. Damage to the ovaries occurs in a dose-dependant fashion and the actual dose of radiation required depends on the age of the woman (follicular reserve) and cumulative dose delivered to the gonad. Wallace estimated the LD50 of the human oocyte to be approximately 2 Gy [15]. Permanent ovarian failure requires greater than 16.5 Gy in young women (20 years old) while in women that are still reproductively young (30 years old), 14.5 Gy will induce permanent ovarian failure [16]. Radiation exposure to the uterus of 20–30 Gy will increase the rate of subsequent miscarriage if a pregnancy ensues [17].
2.1. Options for fertility preservation Because the main risk of reduced fertility in these women comes from chemotherapy co-adjuvants, fertility preservation is geared towards reducing the toxic effects of these drugs on the ovary. Options available for fertility preservation in breast cancer patients include attempting to reduce the toxic effects of chemotherapy on the ovaries with the use of a GnRH-analogue, controlled ovarian hyper-stimulation with cryopreservation of oocytes or embryos, recovery of immature oocytes and cryopreservation of immature oocytes or in-vitro maturation and cryopreservation of the matured oocytes or ovarian tissue cryopreservation with either auto-transplantation or in-vitro maturation of follicles. The option chosen will depend on the presence of a partner, the anticipated effects of the chemotherapy on the gonads and the time interval between presentation and the need to initiate adjuvant treatments for the breast cancer. There have been numerous patients we have consulted on who decided not to undergo the process of preserving their gametes prior to treatment after a thorough discussion including the probability of ovarian failure or damage from the chemotherapy and the chances for pregnancy using cryopreserved gametes or tissue. Additionally, alternative treatments such as oocyte donation should be discussed. The appropriate choice depends upon honest counseling and good communication between the physician, the patient and her oncologist.
3. Ovarian suppression Ovarian suppression with a GnRH-a (agonist or antagonist) as a means of diminishing the toxic effects of chemotherapy on the ovarian follicles is a controversial issue. Theoretically, suppression of pituitary gonadotropins with a GnRH-analogue can only suppress follicles that have already entered the gonadotropindependant stage of follicular growth and are destined to ovulate in the next 90–120 days. However, by diminishing ovarian perfusion [18] or activating GnRH receptors on ovarian granulosa cells inhibiting apoptosis [19], the ovary might receive additional protective benefits from the GnRH-a. Evidence to the contrary comes from the fact that more than half of pre-pubertal children who received high-dose chemotherapy had ovarian failure [20]. Most of the studies evaluating the effects of ovarian suppression with GnRH-a are retrospective, with small numbers of patients and have been criticized for insufficient length of follow-up and differences in the gonadal toxicity of regimens used between the two groups [21]. A recent study in Hodgkin lymphoma patients who were retrospectively sorted into three different groups according to the cytotoxicity of the chemotherapy received demonstrated a significant advantage in terms of normal FSH levels in patients receiving ovarian suppression compared to those that did not [22]. In the only prospective, randomized study, 20 men and 8 women were given a GnRH-analogue prior to and during chemotherapy [23]. There was no difference in the rate of amenorrhea 3 years following treatment in the 8 women treated with the GnRH analogue (4/8) compared to the control group (6/9). All men were profoundly oligospermic in both the treatment and control group. This study concluded that there was no evidence for a beneficial effect of GnRH analogue, in the dosage or schedule used, to conserve gonadal function during intensive chemotherapy for advanced Hodgkin’s disease. Larger, clinical trials are needed to determine the overall magnitude of the effect of GnRH analogues on protecting the ovaries from the toxic effects of chemotherapy, if any. Patients should be encouraged to participate in clinical trials, but informed that there is insufficient evidence to support the use of GnRH-a as
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the sole means of preserving fertility in patients anticipating gonadotoxic chemotherapy. 4. Embryo and oocyte cryopreservation Embryo cryopreservation is an established method of fertility preservation and has been routinely used for storing excess embryos created as a result of ovarian stimulation from in vitro fertilization cycles. Success rates will ultimately depend on the age of the female partner. Embryos can be created with the patient’s partner or donor sperm if she has no partner or he is reluctant. The patient and her partner should establish legal ownership of the embryos prior to their creation, and determine what is to be done in the event of dissolution of the relationship. She must be made aware that in the absence of such an agreement, she might not be able to utilize these embryos if the genetic father does not consent to their use. Stimulation of the ovaries is required and will be discussed below. Oocyte cryopreservation avoids many of the issues mentioned previously and ownership of the gametes is not disputable. Unfortunately, despite improvements in cryopreservation techniques using slow-freezing protocols, published success rates are still quite low per oocyte frozen [24]. One of the reasons for the low success rates achieved has been intracellular ice crystal formation during the freezing and thawing process. The metaphase II oocyte is a large cell with a high water content. Damage to the spindle apparatus, which can occur with the formation of ice crystals during freezing and thawing can be lethal to the cell if measures are not taken to limit its occurrence [25,26]. Membrane permeable (ethylene glycol and 1,2-propanediol) and impermeable (mono or disaccharides) cryoprotective agents (CPAs) in a buffered salt solution have been used in various concentrations to extract water from the oocytes in order to limit the osmotic stress as well as different rates of cooling and thawing with variable success rates. Vitrification of oocytes using high concentrations of CPAs with ultra-rapid cooling (several thousand degrees per minute) can vitrify the entire cell without ice-crystal formation, however the cells are exposed to significantly higher concentrations of CPAs and osmotic stress. Additionally, potential exposure to viruses and pathogens in the liquid nitrogen used to plunge the embryos in for vitrification is of concern. In a meta-analysis [24] comparing the results obtained with slow-freezing of oocytes and vitrification, the live-birth rate in young women (mean age 33.7 years) with slow-freeze protocols was 2.3% per oocyte thawed and 4.0% per oocyte injected with an implantation rate of 10.1% using slow-freezing methods. Vitrification gave slightly better results, with a live-birth rate of 6% per thawed oocyte, with an implantation rate of 20.5% in women who had a mean age of 32.3 years of age. Because of the low-success rates of oocyte cryopreservation in peer-reviewed published reports, the American Society of Reproductive Medicine has stated that ‘‘Oocyte cryopreservation presently should be considered an experimental technique only to be performed under investigational protocol under the auspices of an IRB’’ and that ‘‘At the present time, . oocyte cryopreservation should not be marketed or offered as a means to defer reproductive aging’’ [27]. 5. Ovarian stimulation Conventional assisted reproductive techniques (ART) utilize exogenous gonadotropins to recruit multiple follicles with the anticipated recovery of several mature oocytes. Although natural cycle ART without stimulation would be ideal with respect to estrogen sensitive tumors, currently ART programs are not able to guarantee successful implantation and delivery of a healthy child from a single cryopreserved oocyte or embryo. Additionally, in vitro
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maturation techniques are not yet standardized to provide for efficient maturation and developmental competency to offer this as a standard for patients with estrogen-sensitive tumors with either minimal or no stimulation [28]. Fortunately, newer medications and methods of ovarian stimulation have been developed that allow for multi-follicular recruitment and at the same time limit the exposure to supra-physiologic levels of estradiol seen with convention ovarian stimulation protocols [29–36]. Tamoxifen, a non-steroidal tri-phenylethylene anti-estrogen, has been proven effective for the chemoprevention of breast cancer [29]. It has also been effectively used for the induction of ovulation, with success rates similar to clomiphene citrate [30]. Breast cancer patients stimulated with tamoxifen (40–60 mg/day) starting on day 2–3 of a menstrual cycle retrieved an average of 1.6 0.3 mature oocytes per patient, significantly more than the 0.7 0.2 mature oocytes in the natural cycle IVF patients [31]. While peak estradiol levels were also higher in the tamoxifen group (442.4 pg/ml) compared to the natural cycle IVF group (278 pg/ml), the antagonistic effect of tamoxifen on estradiol receptors in breast tissue most likely does not adversely affect prognosis as patients on tamoxifen chronically for 5 years often have elevated estradiol levels [32,33]. Another method for stimulation of ovarian follicles utilizes the action of aromatase inhibitors to block the production of estradiol from the developing follicles. Despite aggressive use of gonadotropins and multifollicular recruitment, estradiol levels can be kept within the physiologic range. Letrozole, a third generation inhibitor, competitively binds the active site of the aromatase enzyme in a highly selective fashion [34]. By blocking the production of estrogens and the negative feedback of estradiol on the pituitary, aromatase inhibitors can stimulate multifollicular growth and enhance the action of gonadotropins [35]. Letrozole in combination with gonadotropins produced significantly more oocytes for cryopreservation than tamoxifen alone (8.5 1.6 vs. 1.5 0.3). Although not statistically different from letrozole and gonadotropins possibly because of the small numbers of patients, tamoxifen with gonadotropins produced only 5.1 1.1 mature oocytes per patient [36]. Peak estradiol levels were lowest in the letrozole with gonadotropin group and tamoxifen group compared to the tamoxifen with gonadotropin group (380 60 pg/ml, 420 40 pg/ml and 1,200 300 pg/ml, respectively). No difference in recurrence rates of breast cancer was observed in patients treated with letrozole compared to controls (patients with breast cancer who elected not to undergo ovarian stimulation for embryo cryopreservation) after almost 2 years of follow-up which should be reassuring to these patients. 6. Ovarian tissue cryopreservation In patients who are either unwilling to undergo ovarian stimulation, do not have the time it might take to adequately stimulate and retrieve mature oocytes, or those that are BRCA-1 or BRCA-2 positive and desire bilateral oophorectomy, ovarian tissue cryopreservation can be offered in programs so equipped under the guidance of an IRB approved protocol [27]. This experimental technique involves the removal of the ovary(ies) with cryopreservation of thin strips of cortical tissue that contain the primordial follicles. This tissue can be thawed and re-transplanted in the ovarian fossa [37], a heterotopic site such as the forearm or abdominal wall [38], or the primordial follicles can potentially, in the future, be isolated and allowed to develop in culture only to be re-frozen when mature or fertilized and cryopreserved. Endocrine function after re-transplantation has been observed [37] and two births have been reported after orthotopic transplantation of frozen-thawed ovarian tissue into the ovarian fossa although definitive proof that the pregnancies originated
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from oocytes that developed from the frozen tissue is lacking as one ovary was not cryopreserved in each of these patients [39,40]. The attraction of freezing ovarian tissue is that the resting stage follicles are less likely to be damaged by the cryopreservation methods. Unfortunately, other obstacles such as difficulties in freezing large pieces of tissue and the lack of current techniques for the in vitro maturation of these primordial follicles currently limit the clinical usefulness of this technology. Improvements in the culture systems and a better understanding of the conditions required to obtain mature, fertilizable oocytes is required. In one recent publication, Telfer and colleagues developed follicles from strips of fresh ovarian tissue and of the minority that survived the entire culture period, 30% cultured with activin A had normal morphology and antrum formation [41]. Additionally, the risk of re-seeding cancer cells with transplantation of thawed tissue poses an additional risk, although the risk of occult ovarian involvement from early stage breast cancer is rare [42]. More concerning would be the BRCA positive patients and the risk of ovarian cancer development in the transplanted ovarian tissue. 7. Summary and conclusions Reproductive aged patients with a recently diagnosed cancer are increasingly seeking options to preserve their fertility. Survival rates are improving and patients should be counseled about options available to them. This will take a great effort on the part of fertility specialists to educate both potential patients as well as oncologists so that the physical and psychological trauma of enduring the side effects of chemotherapy can be lessened by the knowledge that one of the consequences of treatment, loss of reproductive potential, can be limited. All available options along with their risks, limitations and benefits should be thoroughly discussed with patients as soon as the diagnosis is made, and close collaboration between the oncologist and reproductive endocrinologist should be maintained. Treatment plans should be cleared by the patient’s oncologist, and risks to the patient minimized. The most tested and successful option for fertility preservation is embryo cryopreservation using either a partner’s or donor sperm. Oocyte cryopreservation can be offered to single women or even women with a partner who wish to maintain the autonomy of their gametes. Ovarian tissue cryopreservation should be considered only in those situations where either embryo or oocyte cryopreservation is not an option due to logistical reasons or in conjunction with oocyte or embryo cryopreservation. The decision to pursue any of these options can only be made by the patient after appropriate counseling and careful consideration of her disease and longterm expectations, success rates, risks of fertility preservation treatment and the effect of a delay in initiating chemotherapy, as well as the costs involved. All centers offering fertility preservation, additionally, should do so only with adequate IRB oversight using approved consent forms and treatments. 8. Conflict of interest The Authors have no commercial, proprietary, or financial interest in the products or companies described in this article. References [1] American Cancer Society. Cancer facts and figures-2001. Atlanta, GA: American Cancer Society; 2001. [2] Hankey BF, Miller B, Curtis R, Kosary C. Trends in breast cnacer in young women in contrast to older women. J Natl Cancer Inst Monogr 1994;16:7–14. [3] Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005;365:1687–717.
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