Reproductive Considerations for Patients with Early-Onset Breast Cancer

Abstract

Purpose of Review

Early-onset breast cancer presents various challenges in regard to reproductive health. This review examines the current data pertaining to issues such as fertility preservation, preimplantation genetics, the impact of chemotherapy and endocrine therapy, contraception, and pregnancy in the young breast cancer population.

Recent Findings

Many breast cancer treatments such as chemotherapy and endocrine therapy can be gonadotoxic or teratogenic. Multiple fertility preservation options are now available to young breast cancer patients, including embryo and oocyte preservation, ovarian tissue preservation, and ovarian suppression with GnRH agonists. In patients with known cancer germline mutations, preimplantation genetic testing is an option.

Summary

Fertility preservation and other reproductive services are expanding and offer great promise to the early-onset breast cancer community. Providers must be knowledgeable about the various options in order to better empower patients.

Introduction

Breast cancer represents one of the most commonly diagnosed cancers in the USA [1] and the second leading cause of cancer death. Importantly, it is estimated that approximately 10.3% of all new breast cancer diagnoses are early-onset breast cancer (diagnosed prior to the age of 45) [2]. This population presents with multiple challenges, one of which frequently involves reproductive considerations. Furthermore, with the developement and expansion of genetic testing, patients with known germline mutations are seeking to mitigate breast cancer risk for themselves as well as their offspring. This review explores issues of fertility preservation, preimplantation genetics, and other reproductive considerations for those with an early onset breast cancer diagnosis as well as those of childbearing age with a newly diagnosed high-risk genetic mutation.

Fertility and Breast Cancer

Outcomes and survival after breast cancer treatment have improved significantly in recent years, allowing quality of life issues like reproductive health and fertility to be taken into consideration [3–8] as described in Table 1. While information on potential impact of treatment on fertility can cause emotional and psychological distress, research demonstrates that patients still report wanting to receive information about risk at the time of diagnosis and that quality of life scores improve in patients who consulted with a fertility specialist [6, 7, 9].

Table 1.

Discussion points for early-onset breast cancer

Cancer treatment Options: surgery, chemotherapy, radiation, endocrine therapy Side effects and long-term health impact

Fertility considerations Cancer treatment that may impact fertility Patient’s desire for future fertility Fertility preservation options, side effects, success rates, and available financial resources Necessary delay if endocrine therapy is indicated Pregnancy timing and considerations Contraception options Emphasis on care extending into survivorship

Genetic testing Eligibility Psychosocial preparedness Personal cancer risk and prevention if known mutation Preimplantation genetics and costs

Referrals Reproductive endocrinology and infertility Genetic counseling Mental health professionals Breast cancer support groups Social work for access to services or financial support

Patient goals Personal values Religious beliefs Family considerations

Cancer treatment can impact fertility, reproductive health, and ovarian function, with alkylating chemotherapeutic agents and radiotherapy having the highest risk in a dose-dependent and synergistic manner [7, 10]. These effects on the ovary are twofold, resulting in a decreased chance of having genetically related children as well as increasing the chance of primary ovarian insufficiency (POI) and hypoestrogenemia [11, 12]. Additionally, the acceptable length of time for a patient to pause extended endocrine therapy to attempt pregnancy is controversial and can lead to further delays in family building. Despite concerns over delaying cancer treatment, pursuing fertility preservation prior to cancer therapy does not ultimately affect treatment outcomes [13]. As such, fertility consultation should be offered with every new early-onset cancer diagnosis as well as for survivors of reproductive age [7–9, 14]. Figure 1 outlines fertility management and decision-making for this population.

Fig. 1.

Flowchart for reproductive considerations for early-onset breast cancer

Options for Fertility Preservation

Many clinical factors including age, pubertal status, and ability to delay chemotherapy may play a role in deciding whether to pursue fertility preservation as well as determining the most appropriate options. For premenopausal breast cancer patients, options include ovarian suppression with gonadotropin-releasing hormone (GnRH) agonists such as leuprolide acetate, oocyte stimulation for embryo/mature oocyte cryopreservation, and ovarian tissue cryopreservation [12, 15^••]. It is important to note that the decision to pursue fertility preservation, including oocyte/ovarian cryopreservation, ultimately does not affect long-term cancer outcomes [13, 15^••, 16, 17]. In addition, alternative family building options such as donor gametes/embryos, adoption, and use of a gestational carrier should be discussed during fertility preservation counseling [15^••]. All fertility preservation treatment plans are best managed in a multi-disciplinary fashion involving oncology, nursing, social work, patient navigators, and mental health professionals to ensure all aspects of care are being addressed [12].

Oocyte/Embryo Cryopreservation

In the past, concern for supraphysiologic hormone levels, technological limitations of oocyte cryopreservation, and menstrual cycle timing has been barriers for many patients considering ovarian stimulation before breast cancer treatment. However, new research and technological advancements in this domain have addressed these barriers. A recent systematic review addressing supraphysiologic estrogen levels that results from ovarian stimulation (which could be a concern in hormone-positive breast cancer) reported that when letrozole was added during stimulation, peak estradiol levels were lower without affecting the number of oocytes retrieved [18]. Regarding success rates, techniques for oocyte cryopreservation have now evolved to the point in which pregnancy rates from embryos created from frozen oocytes are essentially equivalent to those from fresh oocytes, allowing patients to wait until they are ready to use the oocytes to attempt pregnancy before determining a sperm source [19]. The fertility preservation treatment that now has the most success is ovarian stimulation with the goal of cryopreservation of either mature oocytes or embryos [12, 15^••]. Additionally, it should be noted that studies have demonstrated that the use of fertility treatments in BRCA1 and BRCA2 mutation carriers did not negatively impact breast cancer risk [20–22].

Concerning timing, ovarian stimulation should ideally occur prior to the initiation of chemotherapy [12]. Some patients opt for oocyte or embryo cryopreservation after biopsy or surgery but prior to the start of chemotherapy or radiation [23, 24]. If it is considered clinically appropriate and there is enough time between the onset of ovarian stimulation and start of chemotherapy, patients can consider doing back-to-back in vitro fertilization (IVF) cycles with a short break of just a few days to maximize the number of oocytes or embryos they are able to cryopreserve. This strategy would ultimately require 4–5 weeks to complete two rounds of stimulation and retrieval, and does not affect long-term cancer outcomes [23, 24].

Furthermore, past stimulation protocols often require several weeks to complete depending on the timing of menses. However, a more recent approach utilizes a random start protocol, regardless of menstrual cycle phase. Random starts result in similar reproductive outcomes and a shorter delay to initiating treatment [15^••, 25]. Though random start protocols decrease the time required for fertility preservation attempts, a 2–3-week delay in initiation of cancer treatment is not acceptable for every patient, such as those with advanced cancer requiring neoadjuvant chemotherapy prior to surgery [15^••, 16, 26]. If a clinically appropriate window is not available or if the patient chooses not to attempt ovarian stimulation prior to chemotherapy start, stimulation can be considered in select patients after chemotherapy is completed.

Ovarian Suppression with GnRH Agonists

Ovarian suppression with GnRH agonists is a strategy aimed at preventing damage to the ovaries to preserve endocrinologic and future reproductive function. This can be considered in combination with cryopreservation of oocytes or embryos, or as an alternative to ovarian stimulation when egg harvesting is not a feasible or immediate option [12, 16, 25]. The “off label” use of GnRH agonists during cancer treatment is aimed at suppressing ovarian function. As a result, the ultimate goal of reducing risk of POI and improving fertility outcomes has significantly increased in recent years [16, 25, 27]. A recent meta-analysis of 5 randomized control trials evaluated neoadjuvant chemotherapy either with or without a GnRH agonist in breast cancer patients. Results demonstrated a significant reduction in POI and improved post treatment pregnancy outcomes for patients who received GnRH agonists with neoadjuvant chemotherapy, with no differences in disease-free survival or overall survival between the two groups [3]. Despite these encouraging data and expert panel recommendations to consider GnRH agonists during chemotherapy, their use remains controversial as results from other recent trials are somewhat mixed [12, 15^••, 16, 26]. While data suggest that GnRH agonists appear to be safe and may exert a protective effect on ovarian function, utilization of additional fertility preservation measures for these patients is still recommended [15^••, 16, 27].

Ovarian Tissue Cryopreservation

Ovarian tissue cryopreservation (OTC) is another possibility for patients who cannot undergo ovarian stimulation [12, 15^••, 16, 25]. The technique involves partial or complete laparoscopic removal of an ovary with the goal of tissue cryopreservation and reimplantation at a later time [15^••, 26]. An added benefit of this strategy is that ovarian tissue has the potential to retain both reproductive and endocrine function after reimplantation. OTC is no longer considered experimental and a recent report describes a 41.6% live birth rate in a group of 60 patients [28]. While this represents a promising technology, reimplantation of ovarian tissue can carry risk if malignant cells were present in the ovary before the tissue was removed. For instance, this is not recommended for BRCA pathogenic variant carriers given the increased risk of cancer, though these patients may consider harvesting of tissue for later use of follicles/ooyctes through an experimental in vitro maturation protocol [15^••]. Developing new technology and novel techniques to mitigate this risk and allow reimplantation of ovarian tissue in a broader group of patients is an active area of research [12, 15^••].

Risk of Gonadotoxicity with Cancer Treatment

Importantly, a patient’s age, clinical characteristics, and baseline ovarian reserve influence the degree of damage inflicted by gonadotoxic treatments [9, 25, 29–31]. Low baseline anti-mullerian hormone (AMH), a measure of ovarian reserve, predicts slower recovery of ovarian reserve after therapy, while both younger age and higher baseline AMH are correlated with higher AMH after breast cancer treatment [31, 32]. As new evidence emerges, it appears that individualized risk may also be related to drug-metabolizing enzyme polymorphisms [25].

While accurate fertility risk assessment is difficult, new methods are available to assist providers in estimating exposure based on treatment regimen [33, 34]. Normalizing doses of different alkylating chemotherapeutic agents with an online cyclophosphamide equivalent dosing (CED) calculator allows the provider to quantify the patient’s exposure to gonadotoxic agents [34]. In addition, there are literature-based risk assessment tools provided by both the Oncofertility Consortium [35] and the Livestrong Fertility Program [36]. These resources allow providers to individualize counseling and assist their patients in the shared decision-making process.

Preimplantation Genetic Testing

The creation of embryos through IVF allows the option of preimplantation genetic testing for aneuploidy (PGT-A) and/or preimplantation genetic testing for monogenic disorders (PGT-M). PGT-A is widely used to prioritize euploid embryos for transfer to increase pregnancy rate and decrease miscarriage rate after embryo transfer. Under certain circumstances, breast cancer survivors may need to undergo IVF and should universally be offered PGT-A as an option, particularly given the increase in aneuploidy in patients 35 and older as childbearing may be delayed to complete cancer treatments. Additionally, as most early-onset breast cancer patients meet criteria for genetic testing, PGT-M should be offered to those who have a known pathogenic germline mutation that increases breast cancer risk. These include pathogenic gene mutations such as BRCA1, BRCA2, ATM, PALB2, CHEK2, BARD1, CDH1, NF1, PTEN, RAD51C, RAD51D, STK11, and TP53 [37]. These genes could be the targets of PGT-M to test embryos and allow for de-selection of positive embryos for transfer [25, 38], ensuring that the pathogenic variant is not present in offspring.

While this option should be discussed and offered to all patients, there are several issues to consider. Many patients are required to pay out-of-pocket costs, which presents a major barrier. Location of services may also be a challenge for those who lack geographic access to specialized clinics. This creates a significant healthcare disparity, which is discussed later in this review. Another point of clarification is that this technology involves testing embryos and not oocytes. Therefore, a sperm source must be selected. This service may also present an ethical dilemma, as it may involve the misuse of this technology for sex selection for some patients or concerns around the concept of “designer babies” [39^•, 40].

Reproductive Considerations with Endocrine Therapy

Options for endocrine therapy for those with hormone receptor-positive breast cancer include selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). A commonly used SERM is tamoxifen, which can be taken either with or without ovarian suppression. Those who still have ovarian function may still ovulate resulting in the possibility of conception during tamoxifen use. While some data show normal fetal development with concurrent tamoxifen use, there is concern for teratogenicity. Reports include infants with craniofacial defects like microtia, cleft palate, micrognathia, and facial asymmetry as seen in conditions such as Goldenhar’s syndrome and Pierre Robin sequence, or ambiguous genitalia [41–45]. While no causal link between tamoxifen and fetal effects has been established, it is still classified as category D. Therefore, reliable contraception is recommended for all premenopausal breast cancer patients while taking tamoxifen.

Regarding subsequent fertility rates following long-term tamoxifen use, there is a dearth of data on the impact of future fertility. Although a recent study suggests breast cancer survivors treated with tamoxifen may be less likely to have children, the authors comment that it may result from reasons other than impaired ovarian function (such as delays due to tamoxifen duration or patients who self-select out of the tamoxifen treatment group) [46]. Furthermore, tamoxifen is known to change the architecture of the endometrium. It classically causes a thickened endometrium with cystic areas [47] or endometrial cystic atrophy [48] that may persist for an unknown period of time. Patients should be informed on the lack of long-term data in this regard. Delaying conception for at least 2–3 months following tamoxifen discontinuation as a washout period could be recommended [49–51], without any significant data that demonstrates any long-term impact on fertility for those with prior tamoxifen use.

While SERMs are commonly used in the early-onset breast cancer population, AIs can also be considered. There is a paucity of data on the long-term fertility effects of 5- and 10-year AI use. Importantly, though, in patients with intact premenopausal ovaries, the hypothalamic-pituitary-ovarian (HPO) axis must be completely suppressed to avoid ovarian estrogen production. Therefore, pharmacologic ovarian suppression through either GnRH agonists such as leuprolide acetate or goserelin, or surgical ovarian ablation through bilateral oopherectomy is required. The goal of GnRH agonists is to prevent ovulation from occurring which makes pregnancy highly unlikely, although still possible [52]. Reliable contraception is still indicated in this instance. Regarding those who have undergone surgical ovarian ablation, pregnancy may be achieved via embryo transfer from prior autologous fertility preservation cycles or through the use of donor oocytes/embryos.

Finally, for patients on any extended endocrine therapy, there are other implications beyond the pharmacologic side effects. One must consider the possibility that a 5- to 10-year hiatus of ovarian function could leave premenopausal patients at an age where they are approaching menopause and when ovarian function may have naturally diminished. This effect may be exacerbated if they have had exposure to alkylating chemotherapeutic agents or radiation potentially shortening their reproductive window [46]. This could create a situation where advanced age poses a challenge and contributes to infertility. For some patients, this may be a deterrent from attempting to conceive after endocrine therapy or, conversely, an impetus to refuse endocrine therapy in order to conceive.

Contraception Options

Contraception should always be addressed as a component of a complete fertility discussion. Reliable contraception in premenopausal breast cancer patients is critical to avoid unintended conception, particularly during administration of chemotherapy, radiation, and endocrine therapy which may be teratogenic to a developing fetus. Furthermore, patients may wish to defer childbearing due to the already significant emotional toll that may accompany a breast cancer diagnosis.

Contraception for this population is limited, as hormonal contraceptive options are contraindicated in the setting of breast cancer. While it may be assumed that this restriction only applies to hormone receptor-positive cancer, some studies have even demonstrated an association between hormone receptor-negative cancer and oral contraceptive use [53–56].

Table 2 outlines contraception options for this population. While barrier methods such as male and female condoms present a widely available option and are the only contraceptive option that offers greater protection against sexually transmitted infections (STI), their failure rate is 13–21% with typical use [57^••]. Spermicide is another option that may be coupled with a cervical cap or diaphragm. The copper intrauterine device (IUD) is a long-acting and reversible option with a failure rate of 0.8% with typical use [57^••]. It can also serve as a method of emergency contraception. Although it requires insertion by a healthcare provider and can carry side effects such as dysmenorrhea and menorrhagia, it represents a highly reliable, hormone-free option that protects against pregnancy for up to 10 years. Non-reversible contraception includes bilateral tubal ligation, bilateral salpingectomy, or vasectomy. While considerations include availability of physicians who perform these procedures as well as anesthesia risks, sterilization is a highly reliable, permanent option [57^••].

Table 2.

Contraception options for breast cancer patients

Method	Failure ratea	Advantages	Disadvantages
Copper IUD	0.8%	Effective for 10 years Not user-dependent Long-acting and reversible Can serve as emergency contraception Highly reliable	May cause heavy bleeding and cramping Must be placed by healthcare provider Does not protect against sexually transmitted infections Risks of insertion and removal (i.e., perforation)
Male and female condoms	13–21%	Protects against most sexually transmitted infections Does not rely on healthcare providers	User-dependent Requires 100% consistent and proper use Single-time use Requires placement before coitus High failure rate
Spermicide	21%	Does not rely on healthcare providers	Requires placement before coitus Does not protect against sexually transmitted infections High failure rate
Diaphragm or cervical cap	17%	Can be used with spermicide Does not rely on healthcare providers (after fitting) Reusable	Requires healthcare provider to initially fit Requires placement before coitus Does not protect against sexually transmitted infections High failure rate
Tubal ligation	0.5%	Permanent contraception May provide some ovarian cancer risk reduction Highly reliable	Possible regret May require general anesthesia Requires trained healthcare provider/facility to perform `Does not protect against sexually transmitted infections
Vasectomy	0.15%	No risk to the breast cancer patient Can be performed outpatient with local anesthesia Highly reliable	Possible regret Not patient-initiated (partner decision) Requires trained healthcare provider/facility to perform Requires barrier method for first 3 months

^aTypical use; from: Trussell J, Aiken ARA, Micks E, Guthrie KA. Efficacy, safety, and personal considerations. In: Hatcher RA, Nelson AL, Trussell J, Cwiak C, Cason P, Policar MS, Edelman A, Aiken ARA, Marrazzo J, Kowal D, eds. Contraceptive technology. 21st ed. New York, NY: Ayer Company Publishers, Inc., 2018

Safety of Pregnancy

Current data suggests that pregnancy in the setting of a history of breast cancer is generally safe for the patient and the neonate, regardless of hormonal receptor status of the cancer and timing of pregnancy. Data also show that pregnancy is generally safe with a history of breast cancer in the setting of a BRCA mutation [58–60]. However, other studies demonstrate increased mortality and decreased disease-free survival in those with pregnancy prior to or with concurrent breast cancer compared to nonpregnant controls, although these outcomes did not apply to pregnancy after breast cancer diagnosis [61]. In addition, some data suggest that pregnancy may increase breast cancer risk specifically in BRCA2 mutation carriers, especially compared to BRCA1 mutation carriers [6]. Although more research in this area is needed, most data generally demonstrate that pregnancy does not affect breast cancer outcomes.

Overall, there is a dearth of data regarding breast cancer and pregnancy in regard to longitudinal outcomes, particularly in light of endocrine therapy which may be indicated up to 10 years after the breast cancer diagnosis. POSITIVE, or Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer (ClinicalTrials.gov Identifier: NCT02308085), is an example of an active prospective clinical trial evaluating the risk of breast cancer recurrence after endocrine therapy interruption for the purposes of pregnancy in a cohort of breast cancer survivors [62]. Such research is necessary to better understand long-term global outcomes of breast cancer survivors and pregnancy.

Health Disparities in Breast Cancer, Genetic Testing, and Fertility Services:

One major barrier to widespread underutilization of fertility preservation is the cost associated with consultation, with treatment varying widely by location and clinic [63]. Current estimated costs are $10,000–15,000 for egg freezing, $11,000–15,000 for embryo freezing, and $10,000–12,000 for ovarian tissue cryopreservation. At present, insurance coverage for fertility preservation is minimal to nonexistent in most cases, but this is becoming an increasingly prioritized focus of legislation across the country. Both the Alliance for Fertility Preservation and Oncofertility Consortium provide information on financial assistance programs available for patients interested in fertility preservation as well as updated information on clinical, scientific, and legislative advancements in the field [64, 65]. Expanding insurance coverage for fertility preservation will increase equity and access to these services [25].

Furthermore, race is a significant consideration when addressing healthcare disparities. While Blacks have a higher incidence of aggressive, early-onset breast cancer and demonstrate higher overall mortality regardless of age [1, 66–71]. Young Black breast cancer survivors are also less likely to undergo genetic counseling and testing even when they meet criteria, which may be due to decreased referral rates to genetic counseling by their healthcare providers as well as socioeconomic barriers [72]. With an already low baseline utilization rate of reproductive endocrinology and fertility services by Black people [73], this is an area that requires national attention and urgent discussion. Purposeful anti-racist efforts to improve outcomes and access for Black communities in this domain are critical.

Conclusions

Early-onset breast cancer presents numerous challenges related to reproductive health. Healthcare providers must be sensitive to these issues and well-versed in options that are available. While most fertility treatments and pregnancy among breast cancer survivors are deemed safe, additional research is required to fully capture long-term outcomes of these interventions on cancer risk in this population. PGD-M should be considered for those with or without a cancer diagnosis who have a newly discovered pathogenic germline mutation. Finally, it is imperative that the future of fertility preservation be more inclusive of those who are socioeconomically disadvantaged or from historically underserved racial minority groups. While there is still much to be done, the recent progress in the field of reproductive medicine for the breast cancer community holds much promise for the future.