BRCA, infertility, and fertility preservation: a review for counseling

Abstract

BRCA mutations as a triggering factor in breast cancer have been reported to result in fertility problems and oocyte aging in young patients with cancer diagnosis. These patients are concerned about fertility problems and family planning before undergoing treatment modalities that may result in infertility. In this review, we conducted analysis of the literature on the association between BRCA mutations and infertility, possible fertility preservation options, and their safety and tried to gather results from different disciplines and points of view on the matter. Our aim is to provide a general summary of recent studies to provide further insight on the matter for counseling BRCA mutation carriers on fertility preservation methods and their implications.

Introduction

Breast cancer is the most commonly diagnosed malignancy in women [1]. The percentage of women diagnosed with breast cancer under the age of 40 is currently at about 6.6 and is increasing [2]. As our understanding of the disease pathogenesis increases, new and improved strategies are uncovered which ultimately turn this previously terminal disease into more of a chronic condition that is subject to personalized patient follow-up and treatment. The patients are given genetic counseling and guided for life planning based on the patient’s clinical status. One of the most prominent aspects of this planning is without a doubt family planning in young patients.

Approximately 10% of breast cancers are hereditary, and the most commonly recognized genetic alterations are found in BRCA1/2 genes [3]. Mutations in these genes have recently been proposed as risk factors for premature ovarian failure which is another potential threat for fertility desires of some patients [4].

BRCA and infertility

Evidence for diminished ovarian reserve in BRCA mutation carriers has been suggested to be explained to occur by different mechanisms. In order to better understand this possible correlation, we must first look into the normal function of the protein.

BRCA1 and BRCA2 genes belong to the family of ataxiatelengiectasia-mutated (ATM)-mediated DNA double-strand break (DSB) repair genes that perform a key role in the preservation of DNA integrity. DNA damage is an especially serious problem for non-dividing or slowly dividing cells, where unrepaired DNA damage will tend to accumulate over time which would explain the connection between BRCA mutations, breast/ovarian malignancies, and oocyte aging [5].

Integrity of DNA is important in normal cell cycle. As the importance of high-fidelity DNA repair for the cell cycle is indisputable, DNA repair mechanisms should be intact and working properly in case of DNA damage. When a double-strand break (DSB) occurs in DNA; the damage is recognized by the MRN complex (MRE11, RAD50, and NBS1) which docks on the damage site to form a platform on which other related proteins cumulate and try to repair the damage. Another protein that plays an essential role in recognition of DNA damage, especially sensitive for changes in chromatin structure, is 53BP1 which also consequently activates ATM, a protein that plays a central role in conducting the DSB repair through homologous recombination (HR). The ɣH2AX protein is activated by ATM with the help of BRCA1 and MDC1 which move the mechanism further downstream where one of two outcomes occurs. The first one is that either the damage cannot be repaired and cell cycle arrests at G2-M checkpoint ensue via CHK2, or the damage is repaired with homologous recombination through a process mediated by BRCA2, RAD51, and DMC1. In germ cells, BRCA2-mediated RAD51 and germ cell-specific DMC1 replacement of RPA initiates HR process [5].

BRCA genes are tumor suppressor genes that are essential for DNA double-strand break repairs via HR which allows for a higher fidelity repair compared to another DNA repair mechanism, non-homologous end joining repair [6]. Any defects in HR system render the DNA susceptible to accumulation of certain mutations, especially deletions. The logic behind BRCA-related ovarian insufficiency has been proposed to be associated with the impaired DSB repair as accumulated DNA damage in the oocytes triggers apoptosis [7]. Oktay et. al. found that BRCA carriers have lower anti-Müllerian hormone (AMH) levels which is the most commonly and practically used parameter for objectively estimating the ovarian reserve along with antral follicle count and progesterone levels [4].

These genes are also thought to have a role in chromatin remodeling, telomere length preservation, and even embryogenesis which may explain their possible association with infertility alongside oncogenesis [8, 9]. BRCA1’s role in embryogenesis through ATM and ATR phosphorylation has been shown in animal models [10]. BRCA1 has also been shown to have a direct function in chromatin remodeling while BRCA2 has been found to have prominent role in chromatin binding and histone acetylation [11, 12]. However, it is worth noting that there are conflicting results regarding telomere length and BRCA status and even telomere length’s association with cancer development [13]. Some studies hypothesize that telomere shortening is related to ovarian aging and reproductive senility [14, 15]. BRCA1 insufficient mice have fewer oocyte yield in response to ovarian stimulation, smaller litter sizes, and defects in mitotic spindle formation [16], and BRCA2 deficient mice have increased nuclear abnormalities and decreased number of germ cells [17]. Histopathological examination of human ovaries suggests that BRCA mutation carriers undergoing risk-reducing oophorectomy have fewer follicles than women undergoing oophorectomy for other reasons [18].

Another mechanism by which these mutations may contribute to premature ovarian failure can be explained with the preliminary findings from another group’s study suggesting that fibrosis starts at an earlier stage in the BRCA mutated ovaries compared to age-matched BRCA-negative cancers. In fact, this increased fibrosis is thought to be an aggravating step towards cancer progression which enables invasiveness [19].

On the other hand, several studies with populations matched for age found no correlation between BRCA mutations and reduced AMH levels [20–22]. However, there are multiple studies and animal models that have found an inverse association between BRCA mutation carrier status and parameters such as AMH levels, ovarian response to stimulation therapies, or ovarian follicle count [23–30].

Counseling a BRCA carrier on fertility preservation

When pathogenic BRCA mutations are recognized at a young age; the patients are left facing a dilemma. They are prone to certain cancers which pose an indirect threat to their fertility due to the organ systems involved, and the mutation itself has been hypothesized to negatively affect the ovarian reserve. To further complicate the matters; the hormonal burden of the techniques used to address infertility may in fact be a triggering environmental factor for the very cancer types that drive the patient to seek fertility preservation treatments in the first place. These reservations are held both by the patients and the doctors; as a survey by Lambertini et al. showed, some oncologists are reluctant in referring their breast cancer survivor patients to the use of assisted reproductive techniques (ART) [31, 32] even though there is a growing number of publications defending the safety of ART [8, 33]. The fertility preservation options presented to the patient are oocyte cryopreservation, ovarian tissue cryopreservation, and oocyte/embryo donation. Of these techniques, oocyte cryopreservation is considered to be the most reliable [34].

Patients who are receiving counseling on BRCA mutations generally fall under one of three main categories: those who are healthy carriers for a deleterious BRCA mutation, those who have a BRCA mutation and have been diagnosed with a related cancer, and those who have survived it. These groups have unique consultation needs and require different approaches explained in the following section.

Healthy BRCA mutation carriers

BRCA mutation carriers who have not yet been diagnosed with cancer stand to gain the most benefit from a consultation regarding their prophylactic treatment strategies and family planning. A multidisciplinary approach is necessary to make sure that main cancer treatment plan and overall survival are not hindered or delayed by the fertility preservation process. While there is ongoing debate on BRCA mutation effects on fertility, some studies suggest that being an unaffected carrier for BRCA mutations associated with decreased primordial follicle density [35] and lower AMH levels compared to age-matched cancer-free women [27, 28]. With that being said, a recent study by Grynberg et al. suggests that BRCA mutations do not prevent in vitro maturation of oocytes collected for fertility preservation purposes [21], so it can be argued that being a BRCA mutation carrier does not render a patient unfit for in vitro fertilization (IVF) treatment in this regard. However, another study investigating the effect of BRCA mutation status on fertility found that BRCA1 mutation carriers had lower oocyte yield of ovarian stimulation compared to BRCA1 wild type women who underwent the similar protocols [36].

The most important issue to be considered when consulting a BRCA carrier who wishes to proceed with fertility preservation methods that rely on hormonal oocyte stimulation is the oncological safety of such an approach. There are two questions to be answered; will there be a significant delay for prophylactic treatments and will the supraphysiological levels of hormones associated with oocyte stimulation have a negative effect on the natural course of the anticipated malignancies associated with BRCA mutations? The latter is an especially important topic as both breast and ovarian cancers are known to commonly express hormone receptors [37]. A case control study with a population of 941 pairs of BRCA1/2 carriers with and without ovarian cancer diagnosis conducted by Gronwald et al. concluded that there is no increased risk for developing ovarian cancer with infertility treatment [38]. A very recent meta-analysis showed that there was no correlation with IVF cycles and breast cancer incidence [39].

With these findings in mind, a personalized approach is necessary when consulting a healthy BRCA mutation carrier on fertility preservation; depending on factors such as the age at which the patient presents, her reproductive status, and most importantly, her oncological evaluation.

BRCA-mutated breast cancer patients

When counseling BRCA-mutated breast cancer patients, one of the most important questions to be discussed is the possible oncological risks of fertility preserving options. Unfortunately, the recognition of BRCA mutation status often comes after the cancer diagnosis, so the time window to decide on fertility preservation is limited. Both timing and safety of fertility preservation should be considered. In a retrospective study carried out by Greer et al., newly diagnosed breast cancer patients who received fertility preservation treatment were compared to those who did not undergo fertility preservation. Fertility preservation did delay beginning treatment by a small amount, but this delay was not associated with a detrimental effect on overall survival and invasive disease-free survival rates [40].

Another controversial topic is the supposed increased negative effect of chemotherapy on ovarian reserve in presence of BRCA mutations [41]. A recent study by Lambertini et al. has shown that in patients that are being treated with FEC (5-fluorouracil, epirubicin, and cyclophosphamide) chemotherapy, adding docetaxel caused the ovarian reserve to diminish further in short-term, but this negative effect was not potentiated by either added endocrine therapy or presence of a pathogenic BRCA mutation [42]. Similar findings were reported with a study carried out on mice; presence of BRCA mutations did not exacerbate the negative effect of chemotherapy on the ovarian reserve [43]. These findings suggest that presence of BRCA mutation does not necessitate that fertility preservation should be prioritized over oncological treatment in anticipation of increased chemotherapy susceptibility of the ovarian reserve.

BRCA-mutated breast cancer survivors

The main concern when counseling breast cancer survivors about fertility treatments is the possible detrimental effects of hormonal therapies may have on disease-free survival. Fertility treatment modalities have been shown to have no correlation with increased breast cancer risk in the general population [44]. However, when a patient has previous history of breast cancer, certain hormonal exposures are generally contraindicated [45]. A multicenter retrospective cohort study by Condorelli et al. compared BRCA mutation positive and negative breast cancer survivors who had post-treatment pregnancies either spontaneously or with assisted reproductive techniques and found no deleterious effect of ART on overall survival [46]. ART seems to be a safe approach for breast cancer survivors even when they harbor pathogenic BRCA mutations together with close monitoring approach and more prudent ovarian stimulation protocols.

Prioritizing either oncological treatment or fertility preservation is likely to show great cultural and individual differences; as such, the patients’ desires should be considered after giving a non-directive consultation. One of the main arguments against certain fertility preservation techniques is the question of whether it will delay the oncological treatment plan or not. Several studies have shown that there is no statistically significant delay when controlled ovarian stimulation is performed for oocyte cryopreservation [47]. To further relieve breast cancer patients during an oncofertility counseling, Greer et al. showed with a population of 272 breast cancer patients that even when there is a statistically significant delay, there appears to be no adverse effects on the long-term survival rates. On average, women who underwent fertility preservation started their initial treatment 6 days later, started neoadjuvant chemotherapy 10 days later, and their adjuvant chemotherapy 8 days later [40]. With that being said, the consultant should make sure that the patient understands that this does not mean there is a long waiting period to decide before starting either treatment. One should also keep in mind that these studies were carried out with BRCA carriers as the main population; other non-BRCA-related breast or ovarian malignancies may be too aggressive to allow for any fertility preservation modalities or delays in initiation of treatment.

Those with BRCA1 mutations have been shown to have decreased ovarian response to ovarian stimulation for IVF cycles which is a very valid indicator of ovarian reserve insufficiency [36]. Possible mechanisms behind this idea are as follows: because BRCA1/2 genes have a prominent role in DSB repair and a very deleterious type of mutation, their absence pushes the cell to use a non-homologous method of repairing the DNA damage which is more prone to errors as it is a non-conservative mechanism [9]. Such mutations are especially problematic for slowly dividing or non-dividing cells because without division, i.e., active cell cycle, mutation detection systems of the cell cannot efficiently function to detect and fix the errors, thus, allowing DNA damage to accumulate which ultimately triggers apoptosis. For the ovaries which have a limited number of follicles most of which are at a state of meiotic arrest, apoptosis means premature ovarian failure [5].

It has also been suggested by Oktay et al. that not only do BRCA mutation carriers have diminished ovarian capacity; they also show increased susceptibility to gonadotoxicity due to chemotherapy [41]. A publication by Arecco et al. however suggests that there is not enough evidence to prove this increased susceptibility [47]. From a different point of clinical view, a retrospective study by Gomez et al. concluded that AMH levels do not predict pregnancy outcomes in patients younger than 35 years of age [48].

Another burning question that needs to be answered and explained to the patient is whether controlled ovarian stimulation used in IVF cycles can trigger certain oncological pathways causing hormone dependent cancers to develop or progress. Evidence from multiple studies shows that there is no increased risk or negative effect on prognosis of BRCA mutation carriers in either breast or ovarian cancer [49]. As for the oncological safety of interrupting ongoing endocrine therapy for conception, the results from POSITIVE trial are expected to give a clearer view on the subject [50].

One of the most crucial topics to be discussed with BRCA carriers is the option to utilize preimplantation genetic diagnosis (PGD) should they choose to initiate an IVF cycle for fertility preservation purposes. PGD application includes ovarian stimulation, egg retrieval, and in vitro fertilization with sperm to form one or more embryos. From these embryos, cells are biopsied at the 8-cell cleavage stage of growth and analyzed for specific genetic mutations; in this case, BRCA [51].

While the European Society of Human Reproduction and Embryology (ESHRE) Ethics Taskforce recognized hereditary breast and ovarian cancer syndromes as valid indications for performing PGD in 2003 [52], there is still a lot of discussion taking place referring to the ethical aspects of this approach. BRCA carriers who do not yet have cancer, also termed “Previvors,” are not certain to develop a malignancy albeit the lifetime risk is calculated to be quite high between 65 and 80% for breast cancer and 20 and 45% for ovarian cancer development [53]. However high these percentages may be, there are still precautions that may be taken and many years to be lived before any measures are needed to be taken such as prophylactic mastectomies, hysterectomies, and salpingo-oophorectomies. Another aspect that further complicates the matter is that BRCA1/2 mutations show incomplete penetrance so the clinical course of the condition cannot be known with certainty even with data from the proband’s family history. On the other hand, even prophylactic surgeries do not completely remove the risk of developing cancer; the risk reduction by mastectomy is found to be about 90% or more for BRCA carriers [54]. As for BRCA2 mutation carriers, organs such as pancreas which are also under risk of malignancy cannot be prophylactically removed. All these problems and considerations could potentially be eliminated with PGD, not only for the patient’s children but also for the generations to follow. Today, owing to the anxiety of inheriting a BRCA mutation to their own child, many patients are showing great interest in practices such as PGD and prenatal diagnosis [55].

A recent survey with 1081 BRCA mutation carriers conducted by Chan et al. concluded that 59% of the patients felt that PGD should be offered in reproductive counseling [56]. However, there are certain caveats to this method as well; pregnancy is not certain as this method utilizes in vitro fertilization and embryo selection which has many factors affecting its success rates. Even if pregnancy is achieved, studies show certain conditions such as congenital heart defects associated with IVF applications [57]. All these points should be relayed to the patient in an unbiased manner to let them make an informed final decision. The common opinion is that BRCA carriers should complete their fertility before the age of 35 if they so desire [8].

Young breast cancer patients who present with BRCA mutations are at a unique position. Because they have a larger reserve of primordial follicles their chance at going home with a baby is greater compared to older BRCA carriers. However, from an oncological perspective, young patients are more likely to be managed more aggressively as they are considered to have poorer prognosis compared to age-matched patients [58]. But this approach is likely to diminish the ovarian reserve they had in the beginning, so it is imperative that each counseling be tailored specific to the patient, her disease, and her personal history. A clear guideline is probably not a realistic option in this regard as it would hinder a personalized approach to an issue that has too many variables and human factors.

Discussion

While there’s a lot of ongoing debate regarding the issue of ovarian insufficiency as a result of BRCA mutation, in most of the publications, there appears to be no mention of the exact mutation of the gene. This gives rise to the following question: can different mutations on the same gene be the reason for these inconsistent results regarding BRCA-infertility association? Future studies should include more specific and systematic data if we are ever to find a more accurate answer to this question. This evaluation could also help some variants of unknown significance be classified as either benign or pathogenic even if this pathology refers to an increased infertility risk and not necessarily an oncological one.

Another subject that requires meticulous research is confirming the safety and determining the window for fertility preservation. Even though there are several studies confirming its safety, the data needs to be larger to comfort both the patients and the healthcare providers because the reservations held about this subject is twofold, possible delay to begin treatment and hormonal consequences of reproductive medicine on the oncological status of notoriously hormone-dependent malignancies.

While examining the relationship between BRCA mutation status and fertility, most studies use variables such as AMH and follicle count. These parameters show the ovarian reserve in theory, but there are studies suggesting that the presence of a BRCA mutation does not make a statistical difference in parity comparisons [59]. In this context, it can be thought that the oocytes affected by the BRCA mutation are perhaps less likely to be successfully fertilized or implanted. Although it is not a sound approach to make assumptions about the quality of the remaining oocytes based on the low reserve, it seems that more comprehensive studies that include oocyte quality in the comparison are required to shed light on this situation. It should not be forgotten that the endpoint is parity rather than ovarian reserve when counseling on fertility, and all data should be examined in detail before initiating treatment processes that may be unnecessary in this context. However, it should be considered by both the physician and the patient that the fertile periods may be shorter. BRCA1 mutation carriers have been suggested to have a tendency to premature menopause [60].

Conclusion

In this paper, we reviewed an increasingly more popular topic in oncofertility counseling for young BRCA mutation carriers. As with many other aspects of medicine today, our approach to such patients must be personalized according to the patient’s disease, age, prognosis, and history and should be managed by a diverse team of specialists on genetics, oncology/gynecooncology, fertility, and psychiatric support. While ART seems to be a safe option, patient’s oncological outcome should always be considered before planning any fertility preservation procedures. While counseling a patient, mentioning the possible relationship between BRCA mutations and infertility would be a comprehensive approach as it may be an early reminder for any other young carriers in the family.

Abbreviations

BRCA

BReast CAncer gene

DNA

Deoxyribonucleic acid

DSB

Double-strand break

MRE

Meiotic recombination 11 homolog A

RAD50/51

Radiation50/51

NSB1

Nijmegen breakage syndrome 1

ATM

Ataxia telangiectasia mutated

ATR

Ataxia telangiectasia and Rad3 related

ɣH2AX

H2A histone family member X

MDC1

Mediator of DNA damage checkpoint 1

CHK2

Checkpoint kinase 2

53BP1

Tumor suppressor p53-binding protein 1

DMC1

DNA meiotic recombinase 1

AMH

Anti-Müllerian hormone

HR

Homologous recombination

NHEJ

Non-homologous end joining

ART

Assisted reproductive techniques

FP

Fertility preservation

IVF

In vitro fertilization

PGD

Pre-implantation genetic diagnosis

Declarations

Conflict of interest

The authors declare no competing interests.