BRCA1– and BRCA2-associated BCs are often diagnosed at an earlier age and at a later stage [23]. Due to elevated breast density, BRCA1/2-associated BCs are also less likely to be detected by mammography and ultrasound screening in young women, and tumors with “pushing margins” are less visible on mammography [24]. BRCA1-associated tumors are more likely to have high histological grade, lack estrogen and progesterone receptors, lack HER2/neu over-expression, and be of triple negative (TN) and medullary subtypes [25–27]. All these factors have an impact on diagnosis and treatment decisions – patients with high grade, endocrine unresponsive tumors more likely to receive chemotherapy.

Several studies have focused on whether prognosis and outcome differ between BRCA-associated BC compared with those in noncarriers. Retrospective studies by Rennert et al. [28] and Huzarski and coworkers both reported no difference in 10-year survival in patients with BRCA1 mutations compared to those without mutations [29]. Several smaller studies reported similar results [25, 30]. Goodwin et al. corroborate these findings, reporting no discernible overall survival benefit among BRCA1 or BRCA2 breast cancer mutation carriers who received adjuvant chemotherapy (n = 164) compared to non-BRCA controls (n = 1,550) [31]. Furthermore, studies that focused on TN BCs also reported no difference in outcome between BRCA1/BRCA2 positive and non-BRCA1/BRCA2 TN cases [32, 33].

Importantly, BRCA1/BRCA2 deficient cells are considered to be more sensitive to chemotherapy because of the underlying deficiency in double-stranded DNA repair [34–36]. Specifically, preclinical models suggested that BRCA mutant cells were more sensitive to chemotherapy that cause double-strand breaks in DNA, such as platinum compounds, anthracyclines, and alkylators [37–40]. When assessing the clinical response of BRCA1/2-mutated breast cancers to therapy, differential response to certain chemotherapy drugs had been proposed [41–43]. Thus, it was suggested that BRCA1 deficient tumors may be more responsive to platinum compounds [44–46] and less responsive to taxanes [41, 47–49]. Byrski et al. reported pathological complete responses to neo-adjuvant cisplatinum as high as 83 % (10/12) in BRCA1 carriers [44, 48]. BRCA1/BRCA2-associated cancers are eligible for targeted biological therapies by PARP (poly-ADP-ribose polymerase) inhibitors that specifically target the DNA repair pathway in BRCA1/BRCA2 deficient cells [36, 50]. Poly (ADP-ribose) polymerase1 (PARP1) plays a key role in the repair of DNA single-strand breaks through base excision repair. The inhibition of PARP1 leads to the accumulation of single-strand breaks in DNA and consequently to double-strand breaks at the replication forks. Normally, these double-strand breaks are repaired by homologous recombination (HR). However, when cancer cells deficient of HR due to absent BRCA are exposed to PARP1 inhibitors they accumulate unrepaired double-strand breaks that result in collapse of the replication forks and cell death. Such synergistic cell death resulting from concomitant inhibition of molecular pathways that are each dispensable when inactivated solely is a concept known as “synthetic lethality.” Since the normal cells of BRCA mutation carriers contain one functional allele of BRCA, they can still use HR and repair DSB, and therefore they are resistant to PARP inhibition. Thus, PARP inhibitors selectively target only the cancer cells and are associated with relatively minor damage to the normal tissues [35]. In recent years, several potent PARP inhibitors were developed and evaluated, alone and in combination with chemotherapy, for the treatment of BRCA-mutated cancers. The pivotal trial assessing PARP inhibitors in a study population enriched for BRCA mutation carriers was published by Fong et al. [51]. Evidence of sustained antitumor activity was limited to patients with BRCA-associated cancers, of whom 63 % experienced clinical benefit. A proof-of-concept study evaluating Olaparib in BRCA-associated advanced BC was next published by Tutt et al. [52]. The first adjuvant trial assessing use of PARP inhibitors in BRCA1/2-associated BC named OLYMPIA opened in 2014, comparing 12 months of adjuvant Olaparib versus placebo following completion of standard neo-adjuvant/adjuvant chemotherapy. The impact of PARP inhibitors on ovarian function is currently unknown.

Hormonal contraception in women with BC is controversial, specifically in BRCA carriers, due to both potential benefits and risks [53]. The literature has focused on the oral contraceptive pill (OCP); however, other forms of hormonal contraception are also debatable.

There is evidence that levonorgestrel-releasing intrauterine system (LNG-IUS) may be effective in protecting the endometrium in women with BC, after tamoxifen therapy [54–56]. Benefits include reduced endometrial hyperplasia and endometrial polyps. Most studies found no evidence of increased BC recurrence or cancer-related deaths in women who used LNG-IUS; however, in one Belgian study, there was an increase in cancer recurrence rate in women diagnosed with BC while using LNG-IUS and continuing to use the device [57]. Another study found a small increased risk of BC recurrence [58]. No studies specifically address BRCA mutation carriers and LNG-IUS.

While until now RRSO has been the gold standard for ovarian cancer risk reduction in this population, more recently, prophylactic bilateral salpingectomy, followed by delayed oophorectomy close to menopause, has been proposed as an alternative approach to reduce ovarian cancer risk [59, 60]. This is yet to be evaluated in a clinical trial setting. Women who are still considering reproduction, or who do not wish to undergo surgical prevention, may be candidates for OCP use in reducing ovarian cancer risk.

The recent long-term follow-up of OCP use in the Nurses Health study [61] demonstrated a trend towards increased premature mortality due to BC (test for trend p < 0.0001) and decreased mortality rates due to ovarian cancer (p = 0.0020) in women who had used OCP. A cohort study of Jewish BRCA1 and BRCA2 mutation carriers [62] showed a significantly increased risk of early onset BC in women who had used the OCP, with average age of onset 6 years earlier than nonusers.

A meta-analysis of studies examining OCP use and BC risk found that although there was a significant increase in BC in women with BRCA mutations in cohort studies, no significantly increased risk was demonstrated in case-control studies [63]. The same analysis showed a significant reduction in the risk of ovarian cancer associated with OCP use. Their conclusion was that OCP may be considered as an alternative to RRSO for prevention of ovarian cancer in women with BRCA1 mutation, although this has not been adopted as a standard practice.

Age of OCP use appears to be important in BC risk. There is evidence that teenage (<20 years) [64] or young adult (<25) [65] OCP use may increase the risk of BC in women with BRCA mutations, especially BRCA1. Other studies demonstrated increased risk in BRCA1 mutation carriers who used the OCP prior to age 30 [66].

The dose of estradiol in the OCP, and the actual formulation, may also be relevant in BC risk. OCP use prior to 1975 (higher dose estrogen) increases the risk of BC in BRCA mutation carriers [67, 68].

Several studies show a small or modest increase in BC risk with OCP use [67, 69, 70], while others show no increased risk with low-dose OCP [71–73]. In BRCA2 carriers, specifically, there appears to be no risk [67]. A meta-analysis of 18 studies assessing association between OCP use and breast and ovarian cancer in women carrying BRCA1/2 mutations [68] demonstrated significantly reduced risk of ovarian cancer and no increased risk in BC with newer OCPs.

Duration of OCP use may be associated with BC risk, with increased risk demonstrated for over 5 years of use [67]. Kostopolous [65] showed increased risk for each year of use when OCP was commenced prior to age 20. A meta-analysis showed no consistent trends of increasing risk with longer duration use of OCP for either BRCA1 or BRCA2 carriers [69].

A recent meta-analysis [69] found that the association between OCP use and ovarian and breast cancer risk in women with BRCA mutation were comparable to risks in the general population, with a nonstatistically significant association with BC, and inverse association with ovarian cancer.

Healthy Women carrying BRCA1 and BRCA2 mutations should be carefully counseled regarding OCP use. Younger women specifically, aged less than 30, should be aware of the potential additional risks of early onset BC. Women aged 30 years and older, who are not yet ready for RRSO, and who are desiring contraception, may be cautiously offered OCP, after discussion of risks and benefits.

BRCA1 and BRCA2 mutation carriers conventionally undergo RRSO at the completion of childbearing, in order to reduce their risk of both ovarian and breast cancer [88]. These women experience induced surgical menopause, and thus determination of their expected fertility or ovarian reserve, or assessment of early menopause, is not possible. However, it has been hypothesized that BRCA mutations, in particular BRCA1, may be associated with reduced fertility. This is expressed by increased chemotherapy-induced amenorrhea [89], premature menopause [90–93], primary occult ovarian insufficiency [94], reduced ovarian reserve [95], and infertility [96–98].

The proposed link between BRCA mutation and fertility is suggested by several possible theories. BRCA 1 is a tumor suppressor, associated with telomere length [99, 100]. It is important in maintaining stability of the genome, as well as playing a role in DNA repair [101, 102]. BRCA1 may also have a role in protecting cells against oxidative stress [103]. Mutations in BRCA1 may lead to compromised genome integrity and deficiencies in double-stranded DNA repair [10]. Primordial follicles may be particularly sensitive to incidental DNA damage. Accumulation of DNA damage then results in oocyte apoptosis. This is turn would cause reduced ovarian reserve, decreased fertility, and earlier menopause.

Titus et al. [104] analyzed expression of DNA repair genes in human oocytes, including BRCA1. They proposed that in women with BRCA1 mutation, two processes occur concurrently during reproductive aging. As the DNA repair efficiency undergoes natural decline, double-stranded DNA breaks (DSDs) accumulate and thus more oocytes undergo apoptosis. In women with BRCA1 mutations, oocyte aneuploidy is augmented, probably due to reduced function of BRCA1 and resultant accumulation of DSDs, as well as other possible effects of BRCA1 mutation. The age-related decline in BRCA1 carriers is thus linked to earlier menopause, diminished ovarian reserve, and increased vulnerability to chemotherapy-induced amenorrhea [98]. This decline may be not be clinically apparent before age 35, when the age-related decline becomes more important.

BRCA1 appears to be upregulated in human male and female germ cells and in preimplantation embryos [105], which may support another possible mechanism involving BRCA1 dysfunction and altered human embryogenesis.

A potential link between BRCA mutation and FMR1 mutation, which is known to be associated with primary ovarian insufficiency [106] has also been proposed, suggesting that the diminished ovarian reserve in women with BRCA mutations may be FMR1 mediated. An initial study revealed a different distribution of constitutional FMR1 genotypes in BRCA mutation carriers compared with female controls [90]. BRCA mutation carriers almost uniformly expressed het-norm/low FMR1 sub-genotype. The same study group showed a trend towards earlier menopause in the BRCA1/2 carriers [90]. A subsequent study [107] found no association between low FMR1 sub-genotypes and BRCA1 mutation carriers.

Menopause is defined as commencing 12 months after the last menstrual period. Menopause occurs when the remaining follicle count reaches 1,000 or below. The years preceding menopause represent the decreasing number of follicles, but also reduced quality of oocytes, with increased risk of aneuploidy, increased risk of spontaneous miscarriage, and infertility. Evidence of earlier menopause in BRCA mutation carriers would imply reduced fertility at an earlier age, with lower ovarian reserve.

Age at menopause is multifactorial, and includes hereditary and environmental factors, including smoking. Ninety percent of women undergo menopause between the ages of 45–55, average age 51 [108]. Premature menopause, or primary ovarian insufficiency, which occurs in approximately 1 % of women, has a strong hereditary component, with over 15 % having a first-degree relative with premature menopause [109]. The commonest genetic causes are Fragile X mutation, with a mutation of the FMR1 gene, and Turner syndrome (monosomy X). Premature menopause can also be associated with autoimmune disease. Iatrogenic causes include gonadotoxic chemotherapy and radiotherapy, and surgical menopause.

Several studies have compared age at menopause between BRCA carriers and various control groups. Lin et al. [93] assessed age at natural menopause in women who were BRCA mutation carriers and women in the general population in San Francisco. Risks were adjusted for known risk factors including smoking, oral contraceptive use, and parity. The median age at the time of natural menopause in the BRCA1/2 carriers was significantly younger than in controls (50 years vs 53 years; p < 0.001). In women defined as current heavy smokers (more than 1 pack per day), the median age was 46 in BRCA carriers compared with 49 in controls (p < 0.027). No difference in age was observed in BRCA 1 and BRCA 2 carriers.

A recent large study compared the rate of premature menopause in BRCA mutation carriers and age-matched controls who were not carriers. Controls were either family members of known mutation carriers who tested negative, or women with a family or personal history of breast or ovarian cancer, who were found not to be carriers of known mutations. There were no significant differences between the groups for parity, age at first birth, or age at last birth. Age at menopause was significantly younger in BRCA mutation carriers (49.0 vs. 50.3 years; p < 0.001). The difference was also observed for both BRCA1 (48.8 vs. 49.9 years; p < 0.06) and BRCA 2 carriers (49.2 vs. 50.8 years; p < 0.006). Twelve women (4.7 %) with a BRCA mutation experienced menopause before age 40 compared with three women (1.4 %) in the control group (p  < 0.04). The observed rate of premature menopause, which is defined as menopause before age 40, is 1 % [110]. There were no differences in reported fertility problems or use of fertility medications.

Collins et al. [111] analyzed BRCA mutation carriers (n = 829) and family members who were negative for BRCA mutation (n = 1,021), for the risk of natural menopause at given ages. They included covariates of smoking, BMI, parity, age at first birth, alcohol, and fertility medications. Nineteen percent of women in the study had undergone menopause; however, no difference was observed for age-specific incidence of natural menopause between BRCA mutation carriers and noncarriers.

A study of ovarian morphology in postmenopausal women who underwent oophorectomy, assessed “signs of estrogenization” as part of the histopathological examination, in women with and without BRCA1 mutation [112]. Women with BRCA1 mutation had absent signs of estrogenization in their ovaries compared to other women. Over 50 % of ovaries from women who were not BRCA1 mutation carriers had signs of estrogenization. The authors proposed that premature menopause is associated with loss of estrogen, which may lead to increased gonadotropin release via negative feedback. This in turn may promote carcinogenesis. Earlier menopause in BRCA1 mutation carriers was also observed, with mean age in BRCA carriers of 45.5 compared with 48.2 in noncarriers (p < 0.05).

The link between diminished ovarian reserve in BRCA mutation carriers has been investigated in several studies, ranging from observation of ovarian reserve tests [95, 115], response and outcomes in in vitro fertilization (IVF) treatments [94, 116], patient-reported fertility [91, 97], and natural fertility in the absence of contraception [117].

A multicenter study examined parity and fertility in BRCA mutation carriers and noncarrier relatives [91]. No differences were observed in age at first birth, age at last birth, parity, or infertility. In a study of women of Ashkenazi Jewish descent with ovarian cancer, and without ovarian cancer, the association between BRCA mutation status and self-reported fertility, pregnancy rate, and pregnancy success was compared [91]. The study also examined sex ratio in the children born to these women. No difference was observed regarding fertility.

Conception and fertility in the context of “natural fertility conditions” was explored in a case-control study of woman in Utah [118]. The original BRCA mutation carriers served as probands to trace additional presumed carriers in their ancestors, based on the family pedigree as recorded in comprehensive state health records. Controls were identified as women who had no familial connection to the BRCA carriers and presumed to be BRCA negative. According to their analysis, putative BRCA mutation carriers born prior to 1930 had significantly larger families, shorter spaces between births, and later age at last birth. These findings are similar, but not statistically significant, in women born after 1930.

Several recently published studies of ovarian reserve in BRCA mutation carriers presented conflicting results. Wang et al. [95] compared BRCA1 carriers, BRCA2 carriers and controls who were not carriers of a mutation, for Anti-Mullerian Hormone (AMH), considered the best single test for ovarian reserve testing [119]. Results were adjusted for age and BMI. BRCA1 mutation carriers had significantly lower AMH levels compared with controls (0.53 ng/mL [95 % confidence interval (CI) 0.33–0.77 ng/mL] vs. 1.05 ng/mL [95 % CI 0.76–1.40 ng/mL]). Logistic regression validated this finding: BRCA1 carriers had a fourfold increased odds of having AMH <1 ng/mL compared with controls (odds ratio 4.22, 95 % CI 1.48–12.0). No difference was observed in AMH levels between BRCA2 carriers and controls.

Conversely, Michaelson-Cohen et al. [115] tested BRCA1 and BRCA2 mutation carriers for AMH and found no significant difference in results compared with general population controls. This study did not examine BRCA1 and BRCA2 mutation carriers as distinct groups, and controls were from the general population, with no family history of BC.

Oktay et al. [94] reported their results of women with BC undergoing the COSTLESS protocol (Letrozole and Gonadotropin) for fertility preservation [120]. BRCA mutation testing was performed parallel to the treatment cycle, but results were only available after treatment was completed. Low ovarian response was defined as four or less oocytes retrieved in women younger than 38 years. Low ovarian response was significantly higher in women with BRCA mutation compared with no mutation (33.3 % vs 3.3 %; p = 0.014) and BRCA-untested women (2.9 % p = 0.012). Mean oocyte numbers were also significantly lower in women with BRCA mutation compared with BRCA mutation–negative women. BRCA1, but not BRCA2, mutations were associated with low response with an OR of 38.3 (95 % CI, 4.1–353.4; p < 0.001).

A recent multicenter study [116] analyzed two groups of women with BRCA undergoing IVF. BRCA mutation–positive BC patients undergoing fertility preservation were compared with BRCA mutation negative or unknown breast cancer patients. BRCA mutation carriers undergoing IVF-PGD were compared with women undergoing IVF for male factor infertility, as well as women undergoing IVF-PGD for other reasons (not affecting ovarian reserve). Low response was defined as four or less oocytes retrieved. There was no significant difference in low response rate (8.77 % vs 8.46 %, p = 1), number of oocytes retrieved (15.00 ± 8.06 vs. 14 ± 8.24, p = 0.44), or number of 2PN embryos (9.61 ± 5.91 vs. 8.17 ± 5.55, p = 0.077). Subgroup analysis according to age was also performed, with no observed differences. This study refutes the concept of diminished ovarian reserve, poorer response to treatment in BRCA mutation carriers, and BRCA positive women with BC.

Carriers of BRCA1/2 mutations have a 50 % chance of transmitting the mutation with each pregnancy, assuming their partner is BRCA mutation negative. Women who prefer to have children who will not be carriers of BRCA mutations may choose diagnosis during preimplantation and prenatal stages.

Prenatal diagnosis involves invasive tests which sample either the chorionic villi (CVS) or amniotic fluid (amniocentesis) in order to test karyotype abnormalities, or the presence or absence of single gene disorders. BRCA mutations may be tested by CVS or amniocentesis. A newer alternative is noninvasive prenatal testing, which tests cell-free DNA in maternal blood; however, this method is not yet available for BRCA mutation detection. Prenatal testing assists parents who may be considering termination of pregnancy for an affected fetus.

PGD is a technique offered to test embryos, usually on the third day following in vitro fertilization (IVF) [126]. Testing is performed on 1–2 cells of the developing embryo, usually at the blastomere stage. This allows for the selection of a healthy embryo for transfer. PGD was initially used for lethal or very severe genetic illnesses, but its use has been expanded to include disease carrier states. PGD is offered in many centers worldwide for BRCA1/2 mutations [127–129].