Fertility preservation in breast cancer with case-based examples for guidance

Abstract

With more young breast cancer survivors, a trend toward having children later in life, and improvements in assisted reproductive technology (ART), fertility preserving techniques are of growing importance prior to initiation of gonadotoxic treatments. The American Society for Clinical Oncology (ASCO) updated their Fertility Preservation in Patients with Cancer guidelines in April of 2018. ASCO continues to recognize oocyte and embryo cryopreservation as standard practice for women interested in preserving fertility and sperm cryopreservation as standard practice for men. ASCO has clarified their statement on ovarian suppression during chemotherapy as an option when standard methods are unavailable but should not be used as the sole method of fertility preservation (FP) due to conflicting evidence. ASCO also updated their statement on ovarian tissue cryopreservation, which is still labeled experimental but ASCO acknowledges that it can restore global ovarian function and could be of use in specific patients. The NCCN’s Version 1.2018 Clinical Practice Guidelines® for treatment of breast cancer include fertility counseling as part of their work-up in all types of breast cancer for premenopausal women.The purpose of this review is to explain the indications and evidence for the different methods of FP for young breast cancer patients in accordance with ASCO and NCCN guidelines. The guidance will then be applied to three theoretical clinical cases in order to highlight actual use in clinical practice.

Introduction

According to American Cancer Society statistics in 2017, the incidence of breast cancer among women under 50 has steadily increased about 0.2% per year since the 1990s [1], and the 5-year survival rate for breast cancer has climbed from 75 to 91% from 1980 to 2010 [2]. With the trend in Western countries to have children at a later age and more young breast cancer survivors, there is increased importance in preserving fertility prior to breast cancer treatment. The American Society for Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) posted updates to their clinical guidelines in managing cancer and fertility [3, 4]. Discussions about the threat of cancer treatment to fertility is stated by both organizations as imperative to be initiated early, even though the patient may not start the conversation, as the focus may be on the new cancer diagnosis. Factors that favor a discussion of infertility from cancer treatment include younger age and nulliparity [5–7], as well as higher educational level [8], although the NCCN states that the topic should be addressed in all women with childbearing potential. Based on these guidelines and current literature, this review will highlight recommended counseling, risk of cancer therapy on fertility, and current techniques for fertility preservation (FP). Three common clinical scenarios, in which patients might benefit from this information, will be presented and discussed at the end of the manuscript.

Clinical case examples

Case 1 is a 33-year-old married female, known to be BRCA2 mutation positive. She was recently diagnosed with invasive ductal carcinoma, confirmed after a recommended mammogram due to her mutation status. While being informed by her surgical oncologist of the gonadotoxic chemotherapies she is about to endure, the patient becomes overwhelmed but states she would like to explore her FP options.

Case 2, a 29-year-old single female, was diagnosed with ER+ invasive lobular carcinoma after feeling a lump in her breast. The diagnosis was made after a mammogram and core needle biopsy. The patient’s medical oncologist asks the patient about her future childbearing plans. She states that she plans on having children in the future. She is sexually active with one partner and is on oral contraceptives.

Case 3, a 39-year-old married male, has recently been diagnosed with invasive ductal carcinoma. He has had his tumor surgically excised and plans to start chemotherapy next week. Upon a visit with his primary care physician, he is informed of the possible gonadotoxic effects of chemotherapy, and the patient states that he has not yet completed his family. He has one child but would like the option for more children. He would like to consider FP.

From the patient’s perspective

Impact of counseling

Unfortunately, the discussion of FP is not always addressed after a cancer diagnosis, and higher reproductive concerns are correlated with moderate to severe depression in young female cancer survivors [9]. In a retrospective survey of 1041 women with cancer between the ages of 18 and 40, there were 560 (61%) who were counseled by their oncology team of infertility risks. Of these women, 223 were breast cancer patients with a mean age at diagnosis of 36.3 (SD = 4.0), and 104 (47%) reported desiring children after treatment. Regardless of age, cancer type, or parity, women who were counseled by an oncologist and saw a fertility specialist were found to have lower decisional regret (P < 0.0001) than those counseled only by their oncology team [10]. Counseling by an oncologist was also shown to improve quality of life, similar to findings in other studies [5, 11].

Although initiation of a discussion on possible infertility has clearly been shown to have psychological benefit, patients may not be ready to explore their options when the novelty of their diagnosis is still sinking in. Feeling too overwhelmed at the time of diagnosis has been reported as a major reason women do not consider their FP options [12]. More interventions to share FP information that do not detract from the patient’s focus and needs regarding their cancer diagnosis could be of value. The use of a decisional aid that can be taken home can increase women’s knowledge of FP options. In a non-randomized trial done with women who received a decisional aid early following breast cancer diagnosis (N = 123) versus women receiving standard care (N = 192), women with the intervention were found to have reduced decisional conflict (P = 0.004) and improved knowledge (P = 0.02) regarding their options in FP [7]. Additionally, an ongoing trial is now evaluating the use of a fertility decisional aid in young breast cancer patients with low health literacy [13]. Although the addition of a decisional aid may be helpful, in a systematic review including 27 publications in oncofertility, most patients preferred a face-to-face consultation about the impact to their fertility [6]. Zero to 85% of patients who underwent cancer treatment reported hearing about the impact of treatment on their fertility; however, a recent study showed a recall rate of about 52% from breast cancer patients with documented conversation in their medical charts [14].

Since the treatment of breast cancer almost always involves adjuvant therapies including surgery, referral to a FP specialist by the breast surgical oncologist may be the most useful stage of referral. In a recent survey of 60 newly diagnosed breast cancer patients of ages 45 and under, 5 had received information on FP before their first visit to a surgical oncologist, indicating a potential opportunity for information at this stage of therapy. Surgical breast tumor excision will not affect a patient’s fertility, but the window between the discussion with the surgical oncologist and medical oncologist can provide the optimal time to visit with a reproductive endocrinologist to discuss options and begin FP prior to gonadotoxic therapy [5].

Reasons women do not undergo FP

Several barriers stand in the way of women and their decisions to pursue FP. Smaller studies in breast cancer patients indicate that women did not feel there was enough time to make FP decisions, or there was a lack of information, and they did not understand their options [15, 16]. In a review examining the decision-making process in women with all cancer types, additional themes emerged. Several perceived risks of FP were reported, including fear that FP will significantly delay treatment, uncertainty about how ovarian stimulation will affect hormone positive tumors, and the safety of pregnancy after treatment. Other themes include non-referral from their oncologist, concerns about the cost of FP, and personal situations. Fertility care is not routinely covered by insurance in the USA, and 8 out of the 11 publications identifying cost as a concern were from the USA. Of these 11 publications, 3 identified cost as the primary concern with pursuing FP [17]. The PREgnancy and FERtility (PREFER) study is a large prospective cohort study currently evaluating both fertility preservation procedures and pregnancy during and after treatment with a 15-year follow-up, specifically in young breast cancer patients. Multiple clinical outcomes with regard to success of FP and pregnancy are being evaluated, including women’s preferences and attitudes toward FP, which will help to expose areas needed for improvement in oncofertility counseling of young breast cancer patients [18].

The cost of assisted reproductive technology (ART) has been a chief concern for women facing the decision to undergo FP. Only about a third of states have insurance mandates for infertility coverage, and Medicaid will not cover ART in any state. Fertility preservation for cancer patients does not fit preexisting definitions of infertility, making FP an elective treatment, although several states are making efforts to mandate insurance coverage for cancer patients. The average in vitro fertilization (IVF) cycle costs about $12,737 nationally, with higher costs per live birth or for multiple cycles [19]. Women pay more on average than men for FP (P < 0.001). In a study of 182 young cancer survivors who underwent FP, 24% of women paid over $15,000 for FP, compared with 2% of men [20].

Pregnancy during and after treatment

Treatment of breast cancer during pregnancy and having a child after treatment come with many concerns and questions from patients who want to ensure that both their baby’s and their own health is not at risk. In a systematic review encompassing patient’s attitudes toward childbearing after breast cancer, some patients were concerned for the risk of cancer recurrence due to pregnancy, while many others believed that childbearing would lead to more fulfillment and happiness in their lives [21]. In survivors of all cancer types, breast cancer was shown to have the lowest posttreatment pregnancy rate, [22] which has been found to be 40% lower than the pregnancy rate in the general population [23]. Nevertheless, providers should be willing to address patient’s concerns pertaining to both treatment during pregnancy and childbearing during survivorship.

Patients may be concerned that pregnancy during breast cancer treatment will pose a risk to their child, but the majority of data show that women treated during pregnancy deliver healthy children. In a clinical trial of 63 breast cancer patients, all were treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) during second and third trimesters. Their children, who were exposed in utero, were a median age of 7 years at the time of responding to a survey. The children were found to be growing well, without any long-term toxicities from chemotherapy [24].

Another study included 413 women with early-stage breast cancer, with varying chemotherapeutic agents used in the second and third trimesters. The primary endpoint measured was neonatal health at 4 weeks, and lower birth weights were found in those exposed to chemotherapy in utero compared to the controls. Any health effects were attributed to lower birth weights than to in utero chemotherapy exposure [25].

Lastly, a group of 40 women who were treated with FAC for breast cancer in the second and third trimester responded to a survey stating that their children were healthy and growing well, without profound developmental issues aside from one child with Down syndrome [26]. Overall, the NCCN Clinical Guidelines state that breast cancer treatment during pregnancy should be similar to treatment in nonpregnant patients and that the rate of fetal birth defects from chemotherapy exposure in utero is about 1.3%, similar to that of the general population. NCCN guidelines also warn to avoid chemotherapy in the first trimester, to monitor fetal health between cycles, and to avoid endocrine and radiation therapy in pregnancy and that there are limited data available on treatment with taxanes, trastuzumab, and lapatinib [3].

Breast cancer patients who are pregnant comprise about 10% of all cases in women under 40. Although the teratogenicity of common breast cancer therapies has shown to be generally safe, breast cancer diagnosed during pregnancy is associated with a lower disease-free survival (DFS) compared with nonpregnant patients [27].

Cancer survivors have been found to have lower pregnancy rates than their age-matched counterparts. In a study of 23,201 women age 39 and younger, cancer survivors were reported as 38% less likely to become pregnant. The babies born to mothers who are cancer survivors were not observed to have any increased risk in infant death rate or miscarriages. Additionally, the proportion of pregnancies ending in live birth was actually higher for cancer survivors, and these women were less likely to terminate pregnancy [28].

Since some breast cancer tumors can be driven by estrogen, it is understandable that many women are hesitant to become pregnant due to fear of recurrence, but fortunately, the evidence does not support any increased risk of recurrence in pregnancy. A recent meta-analysis of 19 studies found increased overall survival in women who become pregnant after breast cancer, as well as a decreased risk of recurrence (although those results were not statistically significant) [27]. Even when comparing outcomes in hormone receptor-positive (HR+) patients, similar results were found in a retrospective cohort study in 333 patients. There were no differences in DFS in patients who became pregnant with a history of HR+ cancer, and variations in the interval between breast cancer and pregnancy did not seem to increase the risk of relapse. Among these women, there was an increase in overall survival in pregnant versus nonpregnant patients [29]. Breast cancer survivors can be reassured that pregnancy does not negatively impact their chance of relapse, regardless of their hormone receptor status.

Considerations for patients with BRCA mutations

Hereditary breast cancer patients, such as BRCA-mutation carriers, experience additional unique fertility-related issues. Further complicating this population is that women may not know their BRCA status by the time they visit a reproductive specialist. Hereditary breast cancer accounts for about 7% of cases [30], and of those, about 80% are thought to be due to BRCA mutations, which also increases the risk for ovarian cancer [31]. By the age of 80, in women with BRCA1 mutations, the risk for breast and ovarian cancer is 72% and 44%, respectively, and 69% and 17% for BRCA2 mutation carriers. Many carriers will be on oral contraceptives to reduce the risk of ovarian cancer [30], and because of its later presentation, the cumulative risk for ovarian cancer is low in BRCA1 mutation carriers under 40 and BRCA2 mutation carriers under 50, normally presenting after childbearing years [32].

Two of the most important fertility concerns in this population will be the decision to perform a bilateral salpingo-oophorectomy to prevent ovarian cancer and the potential to pass on the mutation to their offspring. Because of the later onset of ovarian cancer compared with breast cancer, prophylactic bilateral salpingo-oophorectomy is recommended between the ages of 35–40, after childbearing [30]. Women in this age range face a difficult decision when having to weigh risk-reducing surgery against a desire for pregnancy.

Along with this decision comes the possibility of having a child with a BRCA mutation. Pre-implantation genetic diagnosis (PGD) offers the possibility of determining the BRCA status of an embryo prior to implantation, for women who choose to use this technique. After ovarian stimulation and oocyte collection, on day 5 of embryo development, the trophectoderm is biopsied and genetically analyzed. Frozen embryo transfer is done on day 5 using any embryos without the BRCA mutation. For women not undergoing IVF and conceiving naturally, they may choose to have prenatal diagnosis in their first trimester of pregnancy to know the mutation status of their child [33].

Although there is limited data on pregnancy outcomes after use of FP in BRCA carriers, fertility-sparing options remain the same as those with non-hereditary breast cancer. BRCA1-mutation carriers have been found to have reduced ovarian reserve, but this is not generally seen in BRCA2 carriers. Despite the potentially low ovarian reserve in patients with BRCA1 mutations, they have not been found to have a poor response to hormone stimulation in IVF cycles. However, the effects on ovarian reserve are more pronounced later in life, when women experience earlier onset menopause [34].

Breast cancer in men

According to the American Cancer Society, in 2018, there were expected to be about 2550 cases of invasive breast cancer diagnosed in men, with about 480 deaths [35]. Breast cancer in men accounts for about 1% of breast cancer cases, and treatment is similar to breast cancer in women, with similar gonadotoxic effects. Less is known about breast cancer in males due to the smaller incidence, but known risk factors include BRCA status, family history, hormone imbalances, and environmental exposures. In fact, age of onset in male breast cancer is about 5–10 years older than in women [36].

In the largest study to date involving male breast cancer patients from 1990 to 2010, 7.9% of patients were 41–50 years old, and only 1.6% were under 40 [37]. Nevertheless, providers should be prepared to discuss future family planning goals and FP with male breast cancer patients prior to treatment, which has been shown to occur less often in male versus female cancer patients (P = 0.011) [11]. Sperm cryopreservation is the standard option for men to preserve fertility, and hesitancy for sperm banking is similar to that for FP in women, including fear of delaying treatment, lack of knowledge, and feeling overwhelmed at the time of diagnosis [38].

Effects of breast cancer treatment on amenorrhea and azoospermia

Chemotherapy

The outcomes of gonadotoxicity due to chemotherapy vary and cannot be individually predicted, but age and ovarian reserve are known to greatly influence post-cytotoxic infertility. Different treatments are known to pose different risks on chemotherapy-induced amenorrhea (CIA) (Table 1). Specifically, alkylating agents like cyclophosphamide are known to directly destroy oocytes and deplete follicles, leading to primary ovarian insufficiency (POI), and are unfortunately a usual part of most treatment regimens for breast cancer [43]. Fortunately, chemoprotective agents are being developed to protect follicular ovarian reserve from cyclophosphamide. Both recombinant anti-Müllerian hormone (AMH) and inhibitors of mammalian target of rapamycin (mTOR) significantly prevented primordial follicle loss in murine ovaries among recent studies [44–46]. Anthracyclines such as epirubicin and doxorubicin are generally not used without cyclophosphamide, but an AC (doxorubicin, cyclophosphamide) protocol has shown to be less harmful than CMF (cyclophosphamide, methotrexate, 5-FU) [47], placing AC in the intermediate- or low-risk category depending on age. Trastuzumab, a monoclonal antibody used in HER2+ patients, as well as paclitaxel, part of the taxane family, appear to have no increased effect on CIA in combination with cyclophosphamide-containing regimens [40, 41] (Table 2).

Table 1.

Risk of amenorrhea or azoospermia in breast cancer treatments – modified from [39]

Risk	Breast cancer treatment
High risk of amenorrhea (> 80%)	CMF, CEF, CAF × 6 cycles in women age ≥ 40 (cyclophosphamide, methotrexate/epirubicin/doxorubicin, 5-FU)
Intermediate risk of amenorrhea	CMF, CEF, CAF × 6 cycles in women age 30–39 AC × 4 in women age ≥ 40 (doxorubicin, cyclophosphamide)
Lower risk of amenorrhea (< 20%)	CMF, CEF, CAF × 6 cycles in women < 30 AC × 4 in women < 40
Very low or no risk of amenorrhea	Gonadotropin releasing hormone agonist Methotrexate 5-FU
Prolonged azoospermia	Cyclophosphamide
Temporary reductions in sperm count when used alone, but additive effects are possible	Doxorubicin Epirubicin Methotrexate 5-FU
Unknown	Taxanes (e.g., paclitaxel) * Tamoxifen** Monoclonal antibodies (e.g., trastuzumab) ***

*current evidence is mixed but appears to be low risk [40, 41]

**current evidence suggests no direct effect on ovarian function but lower pregnancy rates [42]

***preliminary findings suggest very low or no risk [40, 41]

Table 2.

Fertility preservation options in breast cancer patients

Standard techniques	Description	Advantages	Disadvantages
Embryo cryopreservation	Ovarian stimulation, oocyte retrieval, in vitro fertilization, embryo banking	Most established and successful method	Estrogen increase from ovarian stimulation* Requires waiting for next menses** Requires a sperm donor Requires surgery
Oocyte cryopreservation	Ovarian stimulation, oocyte retrieval, egg banking	Does not require a sperm donor	Estrogen increase from ovarian stimulation* Requires waiting for next menses** Requires surgery
Sperm cryopreservation	Semen collection, sperm banking	Requires no delay in treatment Most established method in males	N/A
Investigational techniques
Ovarian tissue cryopreservation	Ovarian tissue excision, freezing, reimplantation after cancer treatment	Requires no delay in treatment Restores ovarian function Does not require a sperm donor	Requires surgery Not available at most institutions Requires IRB Potential for reintroduction of cancer cells
Gonadotropin releasing hormone agonists (GnRHa)	Hormone taken to suppress ovarian function during chemotherapy	Potential to maintain ovarian function Widely available	Controversial Inconsistent results in improving pregnancy outcomes

*potential for initiating collection without ovarian stimulation [39, 57, 58]

**potential for random-start ovarian stimulation [59]

There has been, however, data to support a benefit in DFS among patients with CIA. Two recent meta-analyses reported a significantly improved DFS in hormone-receptor positive patients who experienced CIA, indicating an indirect therapeutic endocrine effect in these patients, in addition to the direct cytotoxic effects of chemotherapy. There was not an observed improvement in DFS among hormone-receptor-negative patients, however [48, 49].

Across 74 studies, incidence of CIA was found to be 26%, 39%, and 77% for women with breast cancer ages < 35, 35–40, and > 40, respectively, highlighting the influence of age. Tamoxifen use was also found to be associated with CIA, but without an impact by age of menarche. It is important that these results are interpreted with caution because the definition of CIA is not uniform between studies (although most commonly defined as 12 or more months of amenorrhea after stopping chemotherapy), and the use of menses as a surrogate for fertility is not always reliable [50]. AMH has proven to be a more reliable marker for ovarian function and is more frequently used in clinical studies now for evaluation of ovarian function in breast cancer patients [51]. When compared with age, inhibin B, and FSH, AMH was found to be the best independent predictor of ovarian status (P = 0.005) and amenorrhea (P < 0.0001) 2 years after treatment. The combination of a patient’s age and AMH may aid clinicians in counseling their patients on expected outcomes of FP [52].

Hormone therapy

For women with HR+ tumors, standard adjuvant therapy includes an estrogen receptor antagonist such as tamoxifen, usually taken daily for 5 years. Although these agents greatly decrease breast cancer-related mortality, they are known to be teratogenic, further delaying the opportunity to become pregnant. Few studies have evaluated tamoxifen’s independent effect on fertility. Due to the long window of treatment, variation in follow-up duration, and age of patients at start of treatment, studying tamoxifen’s likelihood of CIA or effect on fertility has shown inconsistent results.

A retrospective cohort study of 397 breast cancer survivors studied tamoxifen’s effect on ovarian reserve and on childbearing. Women in the tamoxifen group were significantly less likely to have a child; however, ovarian reserve was actually higher than the control group, measured by AMH and antral follicle count (AFC). These data suggest that tamoxifen may have no direct effect on fertility. Possible explanations for why women on tamoxifen were less likely to become pregnant may be the 5-year delay during treatment, so they are older when they are trying to conceive, or hesitancy with regard to their HR+ tumor status. The percent of women who desired pregnancy was similar between the two groups, and the median time from the interview to cancer diagnosis was 7 years [42].

The decision to start endocrine therapy is a complex one, and initiation and adherence to tamoxifen have been problematic for women with plans to become pregnant [53]. Further investigation is needed to determine whether stopping tamoxifen to become pregnant has any significant impact on risk of breast cancer recurrence. A current clinical trial (POSITIVE, NCT02308085) is investigating DFS, pregnancy, and neonatal outcomes for women who interrupt endocrine therapy for desire of pregnancy. A 3-month washout period is recommended before trying to conceive, and women must wait until breastfeeding is completed before resuming therapy. In a survey of oncologists’ perspectives on the study, over half stated that they would feel uncomfortable recommending women stop endocrine therapy, but most would recommend trial participation [54]. This clinical trial will give important insights for HR+ patients who do not want to delay childbearing 5 or more years to finish endocrine therapy.

More targeted therapies are being developed for triple-negative breast cancer (TNBC) patients, with special focus on inhibitors of the phosphoinositide 3 (PI3) kinase pathway. Mutations along the PI3 kinase pathway and TP53 mutations occur in in about 25% of TNBC patients, who have mostly been limited to standard chemotherapy. Several of these more targeted therapies are in phase III clinical trials, with no information on the impacts to ovarian reserve, but the use of precision medicine and immunotherapy is thought to be hopeful solutions for the lack of drug development for patients with TNBC [55].

Radiation

Although radiation therapy is a common adjuvant treatment for breast cancer, the amount of radiation reaching the ovaries is insufficient to impact ovarian malignancy or function. Rather, ovarian cancer following breast cancer is more likely attributed to genetic causes [56].

Fertility preservation techniques

Sperm cryopreservation

The only established method of FP in male cancer patients recognized by the ASCO is sperm cryopreservation, followed by use with ART upon thawing. It is important to initiate sperm collection and analysis early, as even one cycle of chemotherapy can affect sperm quality [39]. Collection is generally done at home via masturbation, and multiple vials may need to be frozen depending on the semen analysis. About half of sperm will not survive the freezing process, but methods like intracytoplasmic sperm injection (ICSI) can be used when counts are low [60]. If there are larger numbers of sperm collected, it may be used with simpler and less expensive methods such as intrauterine insemination (IUI). More complex methods of FP in males are being investigated but are scarcely used and have yet to show much benefit in human studies.

The success of using frozen semen in IVF is similar to fresh semen, and studies with large cohorts of male cancer patients reporting on live birth rates are excellent. In a retrospective study of 557 male cancer patients with cryopreserved semen, most (61%) did not return for semen analysis, especially those who experienced more side effects during cancer treatment. Of those who did return, 71.1% were reported to have motile sperm, and many then tried on their own to conceive, resulting in 20 spontaneous pregnancies. Utilization rates of frozen sperm for ART was around 7.5% [61], similar to that reported in another study in male cancer patients [62]. Of the 37 couples who underwent varying methods of ART, 18 live births resulted, and 2 couples were still pregnant at the time of the study’s conclusion. The success rate in achieving pregnancy from cryopreserved sperm varies widely, from 33 to 73%, and in this study was at least 54% [61].

Embryo and oocyte cryopreservation

ASCO clinical guidelines continue to label embryo and, more recently, oocyte cryopreservation as first line methods for pre-treatment FP in cancer patients. This process involves administering gonadotropins or aromatase inhibitors to stimulate multi-follicular growth, retrieval of oocytes and, in the case of embryo cryopreservation, IVF prior to freezing and storage. The success of both techniques is largely based on patient’s age and baseline fertility.

Limited long-term data are available in terms of pregnancy and delivery rates for cancer patients who underwent cryopreservation, but women who choose to freeze oocytes or embryos for any reason have achieved promising results since the 1980s. In fact, pregnancy rates in frozen embryos have surpassed those of fresh embryos. In the CDC’s 2015 Assisted Reproductive Technology National Report Figures, frozen nondonor embryos achieved pregnancies in 54.6% of transfers and live births in 44.3% of transfers (compared to that of fresh nondonor embryos, with rates of 45.0% and 36.7%, respectively) [63]. Higher success rates in frozen versus fresh embryos are thought to be due to the effects of ovarian stimulation leading to a less receptive endometrium, an issue not faced by women who have stored embryos with transfers during their natural cycle. There is potential for a freeze-all strategy in all IVF patients, which has been shown to benefit those with good ovarian response (10–15 oocytes) or for patients at higher risk of ovarian hyperstimulation syndrome [64]. With regard to oocyte cryopreservation, CDC reports show that frozen nondonor eggs with subsequent IVF resulted in a pregnancy rate of 29.3% per cycle and a live birth rate of 22.7% per cycle [63]. Note that these data are not pertaining to cryopreservation specifically in cancer patients.

Although embryo cryopreservation has higher success rates, women may opt for oocyte cryopreservation if they are single and do not want to use donor sperm or if they have ethical oppositions to embryo banking. Objections to both methods may include unwillingness to delay cancer treatment or fear of worsening malignancy by introducing exogenous hormones. And importantly, women over 40 or without an adequate ovarian reserve are not good candidates for these procedures.

The time spent on ovarian stimulation and oocyte retrieval is about 2–5 weeks, depending on when the patient visits a fertility specialist and their next menstrual cycle. Delaying chemotherapy to undergo a cycle of ovarian stimulation and oocyte retrieval has not been found to impact DFS after cancer treatment [65–67], even when accounting for time spent in the OR for surgical excision [68]. For women who want to further minimize delay of treatment, there is strong evidence for random-start ovarian stimulation as opposed to conventional methods, which require a woman to wait for the start of her menstrual cycle. Nineteen publications, most of which pertained to breast cancer, were evaluated in a systematic review comparing random-start versus conventional protocols and concluded that the yield of mature oocytes was comparable in either method [59]. There is also data to suggest that women may be able to safely undergo two rounds of ovarian stimulation, using a random-start protocol, to increase yield of mature oocytes and embryos. In a study of 78 breasts cancer patients, 61 underwent single-cycle stimulation, and 17 underwent two ovarian stimulation cycles. Yield of oocytes harvested was nearly doubled in the two-cycle group (9.1 vs. 16.1, P = 0.008), and the number of days from surgery to chemotherapy was similar between the two groups (63.7 for two-cycle, 58.0 for single-cycle). Although the single-cycle group initiated chemotherapy 5.7 days earlier, this was not a statistically significant difference (P = 0.176). Follow-up 5 years later showed recurrence rates of 0 out of 17 in the two-cycle group and 2 out of 49 in the single-cycle group, which is not a significant difference (P = 0.548) [69]. In another study, 15 oncology patients, 13 of whom had breast cancer, underwent back-to-back random-start ovarian stimulation. Eleven of these patients were able to double their oocyte or embryo yield by undergoing a second round of ovarian stimulation without delaying chemotherapy. Reduced ovarian reserve and dissatisfaction with the first round of oocyte retrieval were stated as the two most common reasons for undergoing a second cycle. For women with these challenges, second stimulation cycles may be offered by clinicians in the future as a means to increase oocyte yield without impacting the timeline of their cancer treatment [70].

Another fear common to patients and physicians is the high estradiol levels during stimulation and their potential effect on tumor growth or recurrence. Ovarian stimulation involves raising blood estradiol levels 10–20 times the level in a woman’s natural cycle for about 2 weeks. Concurrent use of tamoxifen or letrozole during controlled ovarian stimulation is a standard protocol for hormone-receptor positive breast cancer patients, although data in the form of randomized controlled trials supporting the protective effect of the addition of these two drugs is lacking. Standard controlled ovarian stimulation has not been found to adversely affect cancer growth in the setting of FP in breast cancer patients; however, tamoxifen or letrozole continues to be used in order to achieve estradiol levels similar to physiologic levels [71].

An upcoming area of investigation in FP is the use of in vitro maturation (IVM) of immature oocytes, either prior to or after freezing. Since 12–20% of oocytes will likely be immature upon oocyte retrieval, and a patient awaiting chemotherapy may not have time for another cycle of ovarian stimulation and retrieval, IVM of retrieved immature oocytes has shown to be more useful in young cancer patients to maximize the number of embryos or oocytes for storage [72]. Retrieval of immature oocytes followed by IVM would allow women to avoid ovarian stimulation altogether. Some studies report no significant difference in the number of frozen matured oocytes with use of IVM [57, 58]. Multiple recent studies evaluating the addition of epidermal growth factor (EGF)-like peptides in IVM media show an increased yield of mature oocytes in animal models. The EGF network is critical in the ovulatory cascade and oocyte quality [73]. Sphingosine-1-phosphate, an anti-apoptotic agent, has also been proven to increase primordial (P < 0.01) and secondary (P < 0.05) follicle yield when compared to standard culture methods [74]. As a sole method of FP, however, IVM and the use of EGF remain controversial and have not been shown to be beneficial in breast cancer patients over traditional methods [75].

Ovarian tissue cryopreservation

Ovarian tissue cryopreservation (OTC) involves removing part or all of an ovary, slicing the tissue into thin strips and after slow freezing or vitrification, and placing it in storage. The tissue is later thawed, evaluated for malignancy and reproductive function, and transplanted orthotopically, in which natural conception is possible, or heterotopically, in which IVF would be required for pregnancy. Orthotopic sites include the ovary, ovarian fossa, or broad ligament. Heterotopic sites are extra-pelvic, including the sub-peritoneal space or subcutaneous fat of the abdomen or arm. Both options may restore ovarian function in 2–9 months post-transplant. Similar to embryo and oocyte cryopreservation, OTC is not recommended for women over 40 or those with poor ovarian function [76]. First developed in 1996, slow-freezing methods for ovarian tissue have been used in the majority of live births that resulted from OTC. Vitrification methods have shown to be superior in quality of follicles and ease of use when compared with slow freezing, while number of follicles have shown to be similar between the two methods. Still, only two births have resulted from vitrified ovarian tissue. Because there is wide variation in the availability of this procedure and in clinics using this new technology, caution must be exercised when evaluating the clinical outcomes from OTC [77].

ASCO has updated their statement on OTC, acknowledging that it can restore global ovarian function and that it is now a standard option in some countries. They continue to label OTC as experimental, but it could be of use to patients who do not wish to have ovarian-stimulating hormones and for those who do not want to delay treatment. The updated guidelines no longer have a statement warning of the possibility of reintroducing malignant cells, due to no supporting evidence of transplanted ovarian tissue causing recurrence in breast cancer patients [4].

Without an international registry of live births resulting from OTC, it is difficult to track the success of this new technique. As of December 2017, there have been 131 pregnancies reported worldwide resulting from ovarian tissue transplantation (OTT) in 318 women, with 87 live births and 93 children. Out of the 87 live births, 51% were from spontaneous pregnancies, and 84% were menopausal before OTT. From data available on 40 children, their birth weights and gestational ages resembled that of the general population. Reseeding of malignant cells from OTT was not found, but the original cancer relapsed in 9 out of 230 women diagnosed with malignancy, 2 of which experienced recurrence of localized breast cancer. Of the 318 women who underwent OTT, 36 had a second transplant, and 3 had a third transplant, with an average restoration of follicular function of 4.0, 3.9, and 4.5 months, respectively. The majority of women who have undergone OTT do so for breast (24%) or hematological (35%) cancers. About a third of the transplantations were done in Denmark, where OTT is now a standard fertility-sparing option with public reimbursement [78].

Although skepticism remains about OTC, there may be benefits to using it as a dual method with standard techniques, especially when done in conjunction in patients already undergoing an invasive procedure. In a cohort-controlled study, sixteen cancer patients underwent combined OTC followed by ovarian stimulation, oocyte retrieval, and IVF. The number of mature oocytes and good-quality embryos was measured compared to a control group of 100 patients undergoing IVF due to male factor infertility. Metaphase II oocytes (8.3 vs. 8.1) and embryos (4.2 vs. 4.4) were similar in both the treatment and control groups, respectively. Thus, if there is concern that a patient may not have a high enough yield of mature oocytes and there will not be adequate time for a second round of controlled ovarian stimulation, OTC could be used as a backup method in addition to standard techniques in the future. No statistical analysis could be carried out specifically on breast cancer patients in this study since they only comprised 4 of the 16 patients in the treatment group [79]. Another study of 255 cancer patients found that aspiration of immature oocytes from an ovary, along with collection, oocyte aspiration, and cryopreservation of ovarian tissue from the contralateral ovary, increased the yield of mature oocytes (P < 0.001) [80].

Gonadotropin-releasing hormone agonists

ASCO’s 2018 update included a clarification on their statement on ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as an option when standard methods are unavailable, but they should not be used as the sole method of FP due to conflicting evidence [4]. Their mechanism of action has been questioned, since chemotherapy depletes primordial follicles, which do not express gonadotropin or have receptors for GnRH, so adjustment of serum levels of either hormone would, theoretically, have no impact on future fertility. GnRHa have side effects, including potentially irreversible bone loss, and have been criticized for being expensive [81]. However, ovarian suppression with GnRHa (sometimes called luteinizing hormone-releasing hormone agonists) during chemotherapy has the benefits of availability in clinics with scarce resources and non-invasiveness and does not require hormonal stimulation. Overall, it is also less expensive than any other method, except sperm banking.

One of the difficulties in determining the usefulness of GnRHa in FP is that pregnancy outcomes are not always reported. Rather, resumption of menses and biochemical markers are primary outcomes of most RCTs. In a meta-analysis of 12 studies in breast cancer patients, GnRHa were found to lead to a return of menses in 12 months (P < 0.001), demonstrating their efficacy in aiding chemotherapy-induced POI. However, return of menses does not necessarily equate to fertility, and only 5 of the 12 studies reported on pregnancy outcomes. They found that when GnRHa were taken during chemotherapy, more patients became pregnant compared with chemotherapy alone (33 vs. 19, P = 0.04) [82]. However, another meta-analysis showed no benefit with resumption of menses or pregnancy rate [83]. Studies involving use of GnRHa are criticized for a lack of control group; use of self-reported menses rather than more reliable fertility markers, such as AMH, as a surrogate for fertility; using different definitions for chemotherapy-induced POI; and not correcting for desire to conceive [81].

Discussion of cases

Patient A is a BRCA2 positive 33-year-old married female. She was recently diagnosed with invasive ductal carcinoma (HR-, HER2-), confirmed after a screening mammogram. Upon visiting a surgical oncologist, the patient decides to undergo a radical bilateral mastectomy. When discussing the patient’s risk for developing ovarian cancer, the patient and oncologist discuss a risk-reducing bilateral salpingo-oophorectomy due to her BRCA2 status. The patient expresses the importance to her of having a second child, and she decides to have the risk-reducing surgery after cancer treatment. While being informed of the gonadotoxic chemotherapies she is about to endure, the patient becomes overwhelmed but states she would like to explore her options. The surgical oncologist refers the patient to a reproductive endocrinologist and a case worker for evaluation of her psychosocial needs and documents the conversation in her medical record. Upon discussion with the reproductive specialist, the patient decides to undergo embryo cryopreservation. The patient undergoes a GnRH-antagonist protocol for ovarian stimulation and transvaginal aspiration of oocytes. Her husband’s semen is used for traditional IVF, yielding 3 embryos, which are vitrified and stored.

Patient B, a 29-year-old single female, was diagnosed with estrogen receptor-positive, HER2-negative, invasive lobular carcinoma after feeling a lump in her breast, diagnostic mammogram, and core needle biopsy. The patient’s medical oncologist discusses the next steps, including visiting a surgical oncologist, chemotherapy, and radiation. He also recommends a 5-year course of tamoxifen due to the hormone status of her tumor, and he informs her of the teratogenicity and importance of contraception. He asks the patient of her future childbearing plans, and she states that she plans on having children in the future. Her case is discussed by the oncofertility team, including the patient navigator, surgical, medical, and radiation oncologist, as well as the reproductive endocrinologist, who sees the patient to discuss her options. During her post-operative recovery, the patient undergoes controlled ovarian stimulation with letrozole and gonadotropins and transvaginal oocyte retrieval. Eight mature oocytes are vitrified and stored, prior to treatment with chemotherapy and radiation.

Patient C, a 39-year-old married male, has recently been diagnosed with invasive ductal carcinoma. He has had his tumor surgically excised and plans to start chemotherapy next week. Upon a visit with his primary care physician, he is informed of the possible gonadotoxic effects of chemotherapy, and the patient states that he has not yet completed his family. Since the patient lives in a rural area, and he is traveling to a multicenter treatment facility to see a medical oncologist to discuss treatments next week, the oncologist informs the patient of a reproductive specialist in the same facility. The patient arranges to see the reproductive endocrinologist with semen collection at the time of his first visit. Four vials are collected and analyzed, then frozen and stored.

These cases illustrate multiple points. All members of the patient care team can play a role in addressing fertility needs, including the surgical, medical, and radiation oncologists, patient navigator, therapists, reproductive endocrinologists, and primary care physicians. The presence of a multidisciplinary oncofertility team, if available in the patient’s treatment center, can better address the variety of needs that come with a breast cancer diagnosis. Early referral to a reproductive specialist and being able to accommodate visits on short notice are also imperative for oncology patients who may be starting chemotherapy quickly. With this flexibility and communication between patient and healthcare providers, the delay in chemotherapy for FP will not affect the outcome of cancer treatment. Male cancer patients may not initiate the discussion of family planning and are less likely to be informed of the option to preserve fertility [11]. Lastly, documentation of the discussion in the electronic medical record continues to be a part of ASCO’s quality oncology care guidelines.

Conclusion

With more young breast cancer survivors, a trend toward having children later in life, and improvements in ART, fertility-sparing techniques are of growing importance. Many agents used to treat breast cancer, especially alkylating agents, have been shown to be gonadotoxic, although uses of mTOR inhibitors and recombinant AMH are being studied for prevention of primordial follicle loss [43, 45, 46]. Breast cancer patients have been noted to have multiple concerns with pursuing FP, including delaying treatment, exposure to exogenous hormones, and the safety of pregnancy as a cancer survivor [17]. Fortunately, none of the aforementioned issues have posed a risk in DFS for breast cancer patients, regardless of hormone receptor status. In fact, pregnancy after breast cancer has been proven in multiple studies to improve overall survival [29], despite the lower pregnancy rates seen in breast cancer survivors compared with other cancer survivors [22]. Special considerations need to be made for BRCA-mutation carriers, especially regarding gynecologic surgery for avoidance of ovarian cancer, and the concern for passing the mutation onto their child [33]. HR+ patients also face a unique challenge in deciding whether to interrupt long-term hormone therapy for pregnancy or wait until treatment is finished, which may take 5 or more years [42].

In the 2018 update by ASCO on fertility preservation in breast cancer patients, embryo and oocyte cryopreservation continue to be the most reliable methods for FP in women and sperm cryopreservation for FP in men [4]. Embryo cryopreservation has slightly higher success than oocyte cryopreservation in achieving pregnancy but requires IVF with a sperm donor prior to freezing, which may deter some women. Both may delay cancer treatment about 2–5 weeks, which has not shown to impact DFS [65–67]. Ovarian tissue cryopreservation is still not considered a standard treatment by ASCO but, with growing attention, has led to at least 131 pregnancies, and it has the benefits of potentially restoring ovarian function and not requiring ovarian stimulation prior to tissue collection [78]. GnRHa have been studied for several years as a means of ovarian suppression during chemotherapy, but skepticism remains due to inconsistent results among studies. They may have other benefits, including preventing chemotherapy-induced amenorrhea, but have not been reliably shown to increase pregnancy outcomes or live birth rates [81].

Dealing with a new breast cancer diagnosis comes with an array of challenges, and infertility may not be on the forefront of the first discussions with providers following a diagnosis. Patients face a tough decision when deciding to pursue FP, but counseling on the topic has been shown to improve quality of life in cancer patients [10]. ASCO’s patient information website, Cancer.net, provides information on fertility concerns for male and female cancer patients [84]. NCCN also has a resource page titled “Cancer and Fertility” as part of their NCCN Guidelines for Patients® [85]. If looking for a clinic that offers ART, the Society for Assisted Reproductive Technology has a clinic finder by region on their website [86]. Resources will hopefully become more available for breast cancer patients who want to preserve their fertility, as well as a more widespread initiation of the discussion of oncofertility.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest. This research did not receive any specific grant sponsorship from funding agencies in the public, commercial, or not-for-profit sectors. The findings of this project were included in a poster presentation at the UF College of Medicine Celebration of Research on February 19, 2019.