Risk Management for BRCA1/BRCA2 mutation carriers without and with breast cancer

Abstract

Purpose of review:

We review the management for unaffected BRCA1/2 mutation carriers and the local management of early stage breast cancer.

Recent findings:

For unaffected BRCA1/2 mutation carriers, surveillance includes annual magnetic resonance imaging (MRI) and mammogram (MG). Novel imaging modalities, including abbreviated protocol MRI, ultrafast/accelerated MRI, and contrast-enhanced digital mammography are being investigated. Risk reducing mastectomy (RRM) should be considered, and nipple-areolar sparing mastectomy (NSM) is now an option. Additionally, risk reducing salpingo-oophorectomy (RRSO) is strongly recommended as it reduces mortality.

In BRCA1/2 mutation carriers with breast cancer, BCT is an appropriate treatment option but to reduce risk of second primary, mastectomy and contralateral risk-reducing mastectomy should be considered.

Summary:

Breast and ovarian cancer screening and prevention options result in improved outcomes and decreased mortality in BRCA1/2 mutation carriers. In women with BRCA1/2 mutations who have BC, local management of the BC and secondary surgical prevention measures are different than women with sporadic disease.

Introduction

Breast cancer (BC) is the most common malignancy diagnosed in women. In 2019, there will be approximately 268,000 cases in the United States (US) (1). A woman’s lifetime risk of developing BC is about 12%. This risk increases based on a variety of factors including the presence of genetic mutations, particularly mutations in the breast cancer type 1 or 2 genes (BRCA1 or BRCA2). Women who inherit a deleterious BRCA1 or BRCA2 germline mutation have an elevated risk of developing BC, with an estimated lifetime risk of 72% and 69%, respectively (2). The risk of ovarian cancer is also elevated in BRCA1 or BRCA2 carriers, with an estimated lifetime risk of 44% and 17% respectively (2). Overall, the prevalence of these mutations are rare in the general US population, but occur at a frequency of 2.5% in women of Ashkenazi Jewish ethnicity (3).

Breast cancers related to deleterious BRCA1/BRCA2 mutations account for less than 10% of all BC cases (4). The peak incidence of BC in BRCA1 and BRCA2 carriers occurs in the 41–50 age group and 51–60 age group, respectively (2). Ovarian cancers related to deleterious BRCA1/BRCA2 mutations account for 13–15% of ovarian cancer cases (5).

In addition to epidemiological factors, the histopathology of breast cancers associated with BRCA1/2 mutations have been well characterized. Breast cancers associated with BRCA1 mutations tend to be poorly differentiated, high grade-invasive ductal carcinomas (6). BRCA1 mutated BC is more often triple negative (negative for estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]), and P53 positive (7). In contrast, the frequency of ER and PR positivity in BRCA2 mutated BC is similar to sporadic cases of BC, and the frequency of HER2 overexpression in BRCA2 mutated BC is similar to BRCA1 mutated BC (7). In addition, in those with hormone receptor positive HER2 negative disease, high Oncotype DX score is associated with BRCA1/BRCA2 mutations (8). For ovarian cancer, the most common histology associated with BRCA1/2 mutation carriers is high-grade serous carcinomas, which tend to overexpress p53 (9).

It is important to identify carriers of BRCA1/2 mutations because they are at increased risk for developing breast and ovarian cancer. It is therefore necessary to have a thorough understanding of available options that can mitigate that risk. In addition, women with BRCA1/2 mutation associated BC are at increased risk of developing a new ipsilateral primary malignancy and contralateral BC. It is therefore necessary to be familiar with therapies that can decrease this risk. In this article, we review the risk of breast and ovarian cancer, screening recommendations and cancer prevention options for BRCA1/2 mutation carriers without breast or ovarian cancer. We also review the local therapy options for women with BRCA1/2 mutated breast cancers and the local options available for secondary BC prevention. This review does not include systemic therapy options for the treatment of early or advanced BRCA1/2 mutation associated BC. The systemic therapies for BRCA1/2 mutation carriers with BC are discussed in a separate chapter.

Management of BRCA1/2 mutation carriers without BC

Breast Cancer Screening

For patients with BRCA1/2 mutations without BC, current recommendations from the National Comprehensive Cancer Network (NCCN) include breast awareness starting at age 18 and clinical breast exams every 6–12 months starting at age 25 yrs. Breast MRI is recommended annually ages 25–75yrs. A mammogram (consideration of tomosynthesis) and breast MRI is recommended annually for patients ages 30–75yrs. For women greater than 75 years of age, the management is on an individual basis taking into account the patient’s health status and concomitant comorbidities (10).

An alternating screening schedule with both mammogram and breast MRI is recommended for BRCA1/2 mutation carriers. Two large prospective cohort studies supporting this practice were completed in Canada and the Netherlands. Warner et al completed a prospective screening trial in which 445 women who underwent MRI-screening were compared to 830 women who underwent conventional screening. They reported that in the MRI-screening group, breast cancers were detected at an earlier stage than the women who underwent conventional screening, resulting in a reduction in the incidence of stage II-IV invasive breast cancers (HR 0.30 [95% CI, 0.12 to 0.72]) (11). Similarly, Kriege et al completed a prospective study investigating the efficacy of MRI and MG for BC screening in women with a familial or genetic predisposition. In this study, 1909 woman, 276 with BRCA1 mutations and 77 with BRCA2 mutations, underwent clinical breast exam every 6 months and annual imaging including MG and breast MRI. This study reported that MRI had a higher sensitivity compared to MG, but lower specificity and positive predictive value (PPV) (12). MRI and MG, taken together, have a sensitivity of 94% vs 39% compared to mammography alone (13).

While these studies show that cancers detected using MRI in addition to mammography are diagnosed at earlier stages, it is unclear if this strategy results in improved survival. A recent Dutch prospective cohort study comparing the efficacy of MG with MRI in 2308 women with genetic and familial predisposition (including BRCA mutations and women with cumulative lifetime risk ≥15%) versus controls (women screened with MG if ≥ 50) found that breast cancer metastases free survival was improved for the group of women who underwent MRI in addition to MG. For BRCA1 mutation carriers, the HR was 0.30 (95% CI, 0.08–1.13, p=0.055) and for BRCA2 mutation carriers, HR was 0.74 (95% CI 0.12–4.45, p=0.739), suggesting that MRI screening may result in better BC outcome (14).

Other modalities, including breast ultrasound (US) have been evaluated to see if it can offer an additional benefit to MG and MRI. A prospective, nonrandomized comparison study of MG, US, and MRI as screening modalities in 559 women, 28% of whom were BRCA1/2 mutation carriers found that US did not detect any additional cancers (15). Additionally, US significantly increases the number of false-positive results (16, 17). Thus, breast ultrasound is not recommended as a screening tool in mutation carriers.

Traditional breast MRI can be time consuming for both the patient and health-care providers. Therefore, multiple groups have tried to evaluate if abbreviated protocol MRI is appropriate for breast cancer screening. Kuhl et al, was the first to evaluate abbreviated protocol MRI. In their prospective observational study of 443 women at mild to moderate increased risk of breast cancer (the BRCA1/2 mutation status was not known, but the women were categorized based on the BRCAPRO model), they sought to evaluate if one pre-contrast image, one post-contrast image, and their derived images were appropriate to use for BC screening. They reported that the specificity and PPV were equivalent with the abbreviated protocol compared to the standard MRI protocol (18). Other groups have since evaluated this imaging modality, and most studies have reported that the sensitivity is similar to standard breast MRI. One potential drawback to abbreviated protocol MRI is that it does not allow for kinetics to be assessed. Some groups have therefore evaluated ultrafast/accelerated breast MRI protocols to assess morphology and kinetics of breast lesions using time-resolved angiography with stochastic trajectories (TWIST) acquisitions (19). In 2014, Mann et al reported that the maximum slope (MS) of contrast enhancement better characterized lesions compared to BIRADS curves (20). These techniques are still investigational and not included in the standard of care.

Additionally, Contrast-Enhanced Digital Mammogram (CEDM) is another novel imaging modality. This technique combines an iodinated contrast agent with mammography. A retrospective study of 904 patients, 82 of which had a BRCA mutation, that underwent CEDM for breast cancer screening, showed that CEDM had a greater sensitivity compared to 2D mammography, 87.5% vs. 50% (P=.03) and specificity of 93.7% (21). The PPV of the recommended biopsy and of the performed biopsy were reported as 29.4%, which the authors state are within the range expected for mammography and breast MRI (21). CEDM is currently not standard of care but may be used in the future.

Ovarian Cancer Screening

Current recommendations from NCCN are to consider transvaginal ultrasound (TVUS) and serum CA-125 starting at age 30–35 years of age (10). A prospective study by Cancer Genetics Network and Gynecology Oncology Group trials used serum CA 125 collected every 3 months, and a risk of ovarian cancer algorithm (ROCA) to order TVUS. This method incorporates not only the CA-125 value, but the slope of change over time and had better sensitivity at a specificity of 92%, but a low PPV at 4.6% (22). Notably, among incident cases, 50% were stage I/II compared to 10% historical for BRCA1 controls (22). Currently, standard of care does not include routine screening, but it should be offered in carriers who have not undergone rrBSO.

Prevention strategies for BRCA1/2 mutation carriers without BC

Breast Cancer Prevention with Risk-Reducing Mastectomy (RRM)

National guidelines recommend that risk-reducing mastectomy (RRM) be discussed with BRCA1/2 mutation carriers, as RRM has been shown in numerous studies to reduce the risk of breast cancer by about 90% (23). For example, a prospective cohort study of 2482 carriers from 22 clinical sites in Europe and North America with 3 years of follow-up, no breast cancers were observed in the RRM group compared to 7% in the group who had not undergone RRM (24).

Even with such large reductions in breast cancer diagnoses, it remains unclear if RRM results in a survival benefit. A recently reported Dutch cohort study with 2857 BRCA1/2 mutation carriers who underwent RRM versus surveillance reported decreased mortality (0.40 [95% CI 0.20–0.90) and lower breast specific mortality (0.06 [95% CI 0.01–0.46) for BRCA1 carriers. In BRCA2 mutation carriers, decreased mortality (0.45 [95% CI 0.15–1.36), but not BC-specific mortality was observed at a mean follow up of 10.3 years (25). For BRCA1 carriers the probability of not having succumbed to BC by age 65 was estimated to be 99.7% for the RRM group versus 93% for the surveillance group. For BRCA2 carriers, the probability was 100% in the RRM versus 98% in the surveillance group. There were limitations to the above study, including lack of data on the screening practices of the carriers as well as data on their comorbidities. It is important to note that the decision to pursue RRM and its timing is a personal one and may change over time. It is helpful to provide carriers with decade specific risks so that they can balance the pros and cons of screening versus mastectomy, within the setting of their current life choices.

Increasingly, when undergoing RRM, more women are choosing skin-sparing mastectomy, including nipple-areolar sparing (NSM) procedures, as it offers superior cosmetic outcomes. Jakub et al, retrospectively assessed the rate of new breast cancers after risk reducing NSM at 9 institutions in the Unites States. This study included 201 patients with BRCA1 and 145 patients with BRCA2 mutations. Although there was a short follow up time, median of 34 months and mean of 56 months, they reported no ipsilateral BC after NSM, and no BC in patients who underwent bilateral NSM (26). In addition, Grobmyer et al, completed a study of 136 patients (most of which had mutations in breast cancer associated genes), who had undergone NSM for cancer risk reduction. They reported, at a mean follow up of 53 months, no breast cancers (27).

Risk-Reducing Salpingo-oophorectomy (RRSO)

There is debate regarding the role of RRSO for breast cancer risk reduction in patients with BRCA1/2 mutations. Previous studies reported that RRSO reduces the risk of breast cancer in women with BRCA1/2 mutations (28), however, more recent studies treating RRSO as a time dependent covariate, found no association with RRSO and breast cancer reduction (29). One recent study, of 3722 mutation carriers found that RRSO prior to age 50 may be associated with decreased risk of breast cancer in BRCA2 mutation carriers but not BRCA1 carriers (30). In a recent report by Terry et al, during a median follow up of 10.7 years, there was no association between RRSO and breast cancer risk in a cohort of 17917 women at familial risk of BC (7.2% of the cohort had known BRCA1/2 mutations) (31).

Is there a role for chemoprevention with Tamoxifen?

In women with BRCA2 mutations who defer prophylactic surgery, tamoxifen or an aromatase inhibitor can be offered, although data is very limited(32). An analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1 trial), revealed that tamoxifen reduced the breast cancer risk by 62% in BRCA2 carriers, but not BRCA1 carriers (33). Tamoxifen is not generally offered to BRCA1 carriers because BRCA1 associated tumors are often ER negative.

Ovarian Cancer Prevention

Risk-Reducing Salpingo-oophorectomy (RRSO)

As risk-reducing salpingo-oophorectomy (RRSO) reduces mortality, it is strongly recommended for BRCA1 carriers between the ages of 35 and 40, after child bearing is completed (10), and can be delayed until age 40 to 45 in women with BRCA2 mutations. In a study of 2482 carriers, RRSO decreased ovarian cancer-specific mortality (3% vs. 0.4%; HR 0.21 [95% CI, 0.06–0.80) and all-cause mortality, (10% vs. 3%; HR 0.40 [95% CI 0.26–0.61) compared to women who did not undergo RRSO (24). In addition, an international prospective study of 5783 women with BRCA1/2 mutations reported a significant risk reduction for ovarian, fallopian, or peritoneal cancer with RRSO with HR 0.20 (95% CI, 0.13 to 0.30; P<0.001) (34). In addition, there was a 77% reduction in all-cause mortality to age 70 associated with RRSO with an HR of 0.23 (95% CI, 0.13 to 0.39; P<.001) (34).

There is ongoing debate about uterine cancer risk in mutation carriers. Shu et al published a prospective cohort study in over 1000 women with BRCA1/2 mutations in the US and UK who underwent a RRSO without hysterectomy. With 5.1 years followed, 8 cases of uterine cancers were observed including 5 cases of serous/serous-like carcinomas (4 in BRCA1 carriers - corresponded to a 0.6% incidence) (35). No excess risk of uterine sarcomas or endometrioid CAs were noted. The author estimated that this would result in a 2.6% likelihood of a BRCA1 mutation carriers’ of developing serous/serous-like carcinoma, through age 70 (95% CI, 0.7%−6.8%) (35). Overall, the risk of uterine cancer is felt to be low and thus hysterectomy is not routinely recommended only for prevention. As discussed below, hysterectomy may be considered to allow for us of unopposed estrogen replacement post RRSO.

As it is hypothesized that the fallopian tube is the site of origin for ovarian carcinomas in mutation carriers, there is interest in evaluating if risk-reducing salpingectomy would confer the same beneficial risk reduction as RRSO in women at high risk, while obviating the side effects and risks of early menopause. The Women Choosing Surgical Prevention (WISP) Trial, is a prospective, two-arm, nonrandomized trial evaluating RRSO and Interval salpingectomy with delayed oophorectomy (ISDO). Recently, an early report revealed that there is a significant difference in quality of life physical scores between the two groups, but no difference in quality of life mental scores. In addition, there was a significantly increased level of decisional regret in the group that underwent RRSO (36). Overall, this method is investigational, and not currently offered as standard of care for this cohort of women.

Hormone replacement therapy after RRSO

RRSO reduces the risk of developing ovarian cancer and decreases all cause-mortality, but it does place a woman into menopauses, which increases the risk of osteoporosis, vasomotor symptoms and cardiovascular disease. Nonhormonal options to manage menopausal symptoms and osteoporosis prevention should be considered before hormone replacement therapy (HRT) is offered to BRCA mutation carriers who have undergone RRSO. If a patient’s symptoms are not controlled with nonhormone approaches, then HRT should be offered but BRCA mutation carriers who do not undergo a risk reducing mastectomy, should be informed about the theoretical risk of increased BC (32). The data for the association with HRT and breast cancer risk consist mostly of observational studies. Kotsopoulos et al completed a prospective, longitudinal cohort study of BRCA1/2 mutation carriers to evaluate the relationship between HRT and BRCA1 associated BC. In this study, 872 BRCA1 mutation carriers who had undergone bilateral oophorectomy completed questionnaires about HRT use after oophorectomy. At a mean follow up of 7.6 years, it was reported that HRT use did not contribute to an increase risk for BC, HR 0.97 (95% CI, 0.62–1.52, p=.89). While there was no increased of BC in women using estrogen alone, the 10 year cumulative incidence of BC was 12% vs. 22% (p=.04), in women who used unopposed estrogen vs combination estrogen and progesterone (37). Although, there is a paucity of data, if patients want to pursue HRT use, then clinicians will need to counsel on ways to mitigate the theoretical risk including limiting the duration of HRT, consideration of prophylactic mastectomy, and/or a hysterectomy (unopposed estrogen therapy in women can cause endometrial cancer) (32).

For BRCA mutation carriers with symptomatic vaginal atrophy, non-hormonal options should be utilized. If these do not control a patient’s symptoms, then vaginal estrogen therapy can be used. Low dose vaginal estrogen does not increase the serum estrogen concentration about average level after natural menopause (32).

Genetic counseling for family members

One of the key components of the genetic testing process is to strongly encourage cascade-testing, or genetic testing in disease-free family members of individuals with a pathogenic variant in BRCA1/2. Such testing allows family members identified as carriers to begin appropriate screening and preventive interventions, with the hope of reducing cancer incidence and burden.

Management of localized breast cancer in patients with BRCA1/2 mutations

BRCA mutated BC

As previously stated, this review will only focus on local therapies for BRCA1/2 mutation associated BC. While the standard of care for early breast cancer is breast conserving therapy (BCT) as it results in equivalent survival as mastectomy (38), there is controversy surrounding the optimal local therapy for women with BC and germline BRCA mutations. In mutation carriers, questions have arisen regarding whether BCT is effective treatment for the index breast cancer, whether radiation is safe, and how to appropriately address the risk of second breast primaries.

Treatment of Breast Cancer in BRCA1/2 mutation carriers.

Risk of Ipsilateral BC and Survival in BRCA mutated BC patients undergoing BCT

Over the last two decades, there have been inconsistent reports about the risk of ipsilateral breast cancer recurrence in patients with BRCA1/2 mutation associated BC treated with BCT. Some studies have reported an increased risk of ipsilateral recurrence, while others reported no increased risk (39–42). In addition, most of these reports suggest the ipsilateral tumors were new primary tumors. One study by Pierce and colleagues compared local failure rates between BCT and mastectomy in this specific patient population. They reported the risk of local failure as 23.5% vs. 5.5% at 15 years (p<0.0001) (43), but noted that the majority of ipsilateral recurrences were in a different quadrant and had different histology compared to the original tumor (43). These findings suggest that these are second primary tumors and not true disease recurrence. In a meta-analysis of 10 studies, an increased frequency of Ipsilateral breast recurrence was noted with longer follow up (≥7 years), RR 1.51 (95% CI 1.15–1.98) (44).

A recent cohort study from Dutch hospitals of women diagnosed with BC at age less than 50 found no differences in survival in BRCA1 carriers with BCT versus mastectomy (45). In previous reports, Pierce and colleagues reported no difference in breast-cancer specific or overall survival in patients who underwent BCT versus mastectomy at 15 years follow up (43). Pierce et al reported an increased risk for local failure at 15 years, but no difference in overall survival (46). Nilsson et al compared endpoints including first recurrence, overall survival, breast cancer death and distant recurrence between BCT and mastectomy in BRCA1/2 mutation carriers. They reported an increased risk of local recurrence (HR 4.0; 95% CI 1.6–9.8), but no difference in distant recurrence, breast cancer death, or overall survival (47).

In summary, these studies indicate that BCT is a safe and effective treatment option for women with BRCA1/2 mutation associated early breast cancer. However, many carriers will choose to have a mastectomy to not only treat the index BC but to also reduce the risk of a new primary ipsilateral BC. They may also choose to have a contralateral mastectomy, as discussed further in the sections below, to help reduce the risk of a contralateral BC. As Nipple-sparing mastectomy (NSM) has improved cosmesis, there have been studies to evaluate its role in this patient population. Manning et al evaluated outcomes for BRCA carriers who underwent NSM for early stage breast cancer. They reported no local or regional recurrences at short term follow up of 2.34 years (48). Thus, this can be offered to appropriate patients with BRCA1/2 mutations as a treatment option.

The safety of radiation therapy in patients with early stage BRCA1/2 associated BC

Over twenty years ago, it was hypothesized that tumors in women with BRCA1 or BRCA2 mutations would have increased sensitivity to radiation. It was also thought that these women may be at increased risk of contralateral breast (CBC) cancers due to radiation scatter, in addition to, being at increased risk for radiation related toxicities. Drooger et al, completed a retrospective cohort study including 691 BC patients with BRCA1/2 mutations. At a median follow up time of 8.6 years, there was no association between radiation therapy for the index breast cancer and risk of CBC. This conclusion was true in the total population (HR 0.82, 95% CI 0.45–1.49) and in the population of women younger than 40 years of age (HR 1.36, 95% CI 0.60–3.09) (49). Other noted similar findings (50). Pierce et all completed a retrospective cohort study looking at treatment toxicity in 71 women from 9 institutions in North America who had BRCA1/2 germline mutations and who were treated with BCT and reported no significant differences in radiation related toxicity including, pain in the breast and skin/lung symptoms (51). Other studies looking specifically at toxicities related to radiation therapy include a retrospective study of 55 BRCA1/2 mutation carriers treated with radiotherapy in the UK. In their study, there was no significant increase in late toxicity including rib fractures, lung fibrosis, necrosis of bone/soft tissue, or pericarditis, related to radiation therapy in BRCA1/2 mutation carriers (52).

Of note, while accelerated partial breast irradiation is now an appropriate option for some BC patients, the National Comprehensive Cancer Network does not recommend accelerated partial breast irradiation (APBI) for BRCA positive patients. Interestingly, a recent retrospective review of 341 woman, 11 which had a BRCA1/2 mutation, who were treated with APBI, reported no ipsilateral or contralateral breast recurrence for the BRCA1/2 group at a median of 8.8 years follow up (53). This report included a very small number of patients, and as such APBI is not routinely used for BRCA1/2 associated tumors. Overall, patients with BRCA1/2 mutation associated BC are candidates for radiation therapy.

Secondary Prevention of malignancy

Risk of Contralateral BC in BRCA mutated BC and the role for Contralateral risk reducing mastectomy (CRRM)

It is widely accepted that the risk of contralateral breast cancer is increased in germline BRCA1/2 mutation carriers and thus CRRM should be considered at the time of initial BC diagnosis. More recently studies have shown that this risk varies by the age at first diagnosis. In a retrospective cohort study of 2020 women with BC who were members of families with BRCA1/2 mutations, the 25 year risk of CBC was 62.9% (95% CI 50.4% to 75.4%)in BRCA1 carriers whose age at first cancer was younger than 40, compared with 19.6% (95% CI 5.3% to 33.9%) of patients whose first cancer occurred older than age 50 (54). Similarly, Malone, in a nested case-control study which included 181 carriers, found that the relative risk for developing CBC decreased with older age at first diagnosis. For women with a BRCA1 mutation diagnosed before age 35, there was an 11-fold increase risk, for women diagnosed between 35–44 years, there was a 4-fold increase, and for woman diagnosed between 45–54, there was a 2.6 fold increase in risk (55). Lastly, Van Den Broek et al reported on the risk of CBC for 6294 young patients with BC with or without BRCA1/2 mutations. For BRCA1 patients diagnosed before age 41, the 10 year cumulative risk of CBC was 25.5% and for those diagnosed at 41–49 years of age, it was 15.6%. For BRCA2 patients diagnosed before age 41, the 10 year cumulative risk was it was 17.2% and for those diagnosed age 41–49 years, the risk was 7.2% (56) Graeser et al also reported a higher risk of CBC for BRCA1 than BRCA2 carriers (54).

Thus, based on the above data, CRRM should be offered to BRCA½ carriers with newly diagnosed BC, but recommendations should be influenced by the age at initial diagnosis, the underlying prognosis related to the breast primary, and patient preference. It is also important to note that findings regarding the survival benefit of a contralateral mastectomy have yielded conflicting results, with some reporting a survival advantage and others not (29, 57–59). Thus, currently there is not definitive evidence to conclude that CRRM confers a survival advantage.

Screening procedure if patient does not choose CRRM.

Extrapolating from the screening for BRCA1/2 mutation carriers without BC, patients who undergo BCT should resume surveillance screening with annual mammogram and breast MRI staggered at 6-month intervals.

What is the role of RRSO in patients with BRCA1/2 mutation associated BC?

In patients with prior BC, RRSO confers a significantly decreased risk ( HR=0.14 95% CI 0.04–0.59) of ovarian cancer in BRCA1/2 mutation carriers and a lower all-cause mortality (HR 0.30 [95% CI 0.17 −0.52] (24). In addition, a large, international prospective study of women with BRCA1/2 mutations reported a decreased all-cause mortality, HR 0.32(95% CI 0.26–0.39 p=.001) in patients with previous BC (34). Metcalfe et al reported also found that RRSO was associated with a decrease in all-cause mortality (HR 0.35 [95% CI 0.22–0.56; P=.001) (60). Additionally, data have suggested that RRSO may confer a benefit in terms of breast cancer specific mortality (24, 60). Based on these findings, RRSO is strongly recommended in mutation carriers with a BC diagnosis, with similar age guidelines as in unaffected mutation carriers.

Conclusions:

We have reviewed the screening for BRCA1/2 mutation carriers without cancer. For BRCA1/2 mutation carriers without BC, surveillance imaging with annual MRI and mammogram staggered every 6 months is recommended because of the increased sensitivity observed with dual modality imaging. Novel imaging techniques including abbreviated protocol MRI, ultrafast/accelerated breast MRI, and Contrast-Enhanced Digital Mammography, are being investigated to evaluate if they will have a role in BC screening for this high risk population. Prevention strategies for BRCA1/2 mutation carriers without BC include RRM. Recent studies suggest that NSM is an appropriate surgical approach. While prior studies suggested that RRSO reduces the risk of breast cancer, more recent data call this finding into question. Currently, there is a very limited role for systemic chemoprevention with tamoxifen or aromatase inhibitors.

For BRCA1/2 mutation carriers without ovarian cancer, clinicians can consider offering surveillance with transvaginal ultrasound and serum CA 125 testing. Most important, RRSO is strongly recommended at age 35–40 in BRCA1 carriers and age 40–45 in BRCA2 carriers and once childbearing is complete as it decreases the risk of ovarian cancer, reduces ovarian-specific mortality, and reduces all-cause mortality. This procedure will result in early menopause. If necessary, after shared decision making, HRT may have to be used to treat the patient’s symptoms.

In women with BRCA1/2 mutations who have been diagnosed with breast cancer, there is an increased risk of new ipsilateral breast cancer and an increased risk of contralateral BC, that is age dependent. In women with BRCA1/2 mutation associated BC, BCT has similar survival outcomes compared to mastectomy, and radiation therapy has not been shown to be associated with an increased risk for toxicity or likelihood of developing a secondary malignancy in the radiation field. For women who opt for mastectomy, NSM does not appear to result in increased recurrence, and therefore, can be offered after careful patient selection. As a result of the increased risk for contralateral BC, CRRM should be offered to these patients, but this discussion should be individualized based on the patients age at diagnosis, the underlying prognosis associated with her primary cancer, and her preferences. For women with BRCA1/2 mutation associated BC, RRSO decreases the risk of ovarian cancer, ovarian specific mortality, and all-cause mortality and thus should be recommended at the ages outlined above.