Managing hereditary breast cancer risk in women with and without ovarian cancer

YGYNO-976714; No. of pages: 10; 4C: Gynecologic Oncology xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Review Article

Managing hereditary breast cancer risk in women with and without ovarian cancer Mary Linton Peters a,⁎, Judy E. Garber b, Nadine Tung a a b

Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA, United States Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States

H I G H L I G H T S • • • • •

Most women with ovarian cancer use genetic testing that informs breast cancer risk For BRCA1/2 carriers, breast cancer screening depends on ovarian cancer prognosis For early-stage or favorable advanced stage, screening is reasonable For unfavorable advanced stage, screening is appropriate if disease-free 2 years Prophylactic mastectomy can be considered for carriers in remission after 5 years

a r t i c l e

i n f o

Article history: Received 23 February 2017 Received in revised form 16 April 2017 Accepted 19 April 2017 Available online xxxx Keywords: Breast cancer Ovarian cancer Genetic testing Surveillance

a b s t r a c t Current guidelines recommend that all women with ovarian cancer undergo germline genetic testing for BRCA1/2. Increasingly, genetic testing is being performed via panels that include other genes that confer a high or moderate risk of breast cancer. In addition, many women with a family history of breast or ovarian cancer are not found to have a mutation, but may have increased risk of breast cancer for which surveillance and risk reduction strategies are indicated. This review discusses how to assess and manage an increased risk of breast cancer through surveillance, preventive medications, and risk-reducing surgery. Assessing and managing the increased risk of breast cancer in BRCA1/2 mutation carriers after a diagnosis of ovarian cancer can be challenging. For the first few years after an ovarian cancer diagnosis, BRCA1/2 mutation carriers have a relatively low risk of breast cancer, and their prognosis is largely determined by the ovarian cancer. However, if these women remain in remission after two years, the risk of breast cancer becomes comparable with, and in some cases exceeds, their risk of ovarian cancer recurrence. For these women, breast cancer surveillance and risk reduction becomes important to their overall health. Specifically, for BRCA1/2 carriers who are diagnosed with early-stage ovarian cancer, we recommend regular breast cancer surveillance and consideration of risk reduction with medication and/or prophylactic mastectomy. For women with advanced ovarian cancer who do not achieve remission, breast cancer surveillance or prophylaxis is not of value. However, among carriers with more favorable advanced disease, it is reasonable to initiate breast cancer surveillance. Patients with less favorable advanced stage disease who achieve sustained remission (N 2–5 years) should also consider more aggressive strategies for breast cancer screening and prevention. For mutation carriers who remain in remission after five years, prophylactic mastectomy can be considered. © 2017 Elsevier Inc. All rights reserved.

Contents 1. 2. 3. 4.

Genetic testing for hereditary breast cancer . . . . . . . Breast cancer risk assessment in the absence of a mutation Breast cancer screening . . . . . . . . . . . . . . . . Breast cancer risk-reducing medications . . . . . . . .

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⁎ Corresponding author at: Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, RW4-T1, Boston, MA 02215, United States. E-mail address: [email protected] (M.L. Peters).

http://dx.doi.org/10.1016/j.ygyno.2017.04.013 0090-8258/© 2017 Elsevier Inc. All rights reserved.

Please cite this article as: M.L. Peters, et al., Managing hereditary breast cancer risk in women with and without ovarian cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.04.013

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M.L. Peters et al. / Gynecologic Oncology xxx (2017) xxx–xxx

5. 6.

Risk-reducing surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Breast cancer risk management in BRCA1/2 carriers after ovarian cancer diagnosis . . . . . . . . . 6.1. Ovarian cancer prognosis in BRCA1/2 carriers . . . . . . . . . . . . . . . . . . . . . . 6.2. Risk of breast cancer after ovarian cancer in BRCA1/2 carriers . . . . . . . . . . . . . . . 6.3. Breast cancer risk management after ovarian cancer in BRCA1/2 carriers after ovarian cancer . 6.3.1. Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2. Risk-reducing medications . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.3. Prophylactic mastectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Other breast cancer gene mutation carriers . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Epidemiologic studies have demonstrated that 14.1% of women with non-mucinous ovarian cancer and 22.6% of women with high-grade serous ovarian cancer have a germline BRCA1 or BRCA2 (BRCA1/2) mutation. Of these, 44% have no family history [1]. Based on these data, the National Comprehensive Cancer Network (NCCN) now recommends that all women with ovarian cancer be tested for germline mutations in BRCA1 and BRCA2 [2]. Next generation sequencing panels that assess mutations in many cancer susceptibility genes simultaneously are now in wide use. As a result, many other inherited mutations that confer a moderate risk of developing breast and ovarian cancer are now being identified. The goal of this review is to discuss how to manage women with an increased risk of breast cancer, including those with hereditary breast cancer risk, through screening, preventive medications, and riskreducing surgery. In addition, we will discuss how to assess and manage the increased risk of breast cancer in BRCA1/2 mutation carriers after a diagnosis of ovarian cancer.

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1. Genetic testing for hereditary breast cancer There are a number of identified high-risk breast cancer susceptibility genes, including BRCA1, BRCA2, PALB2, TP53, CDH1, and PTEN. The cumulative breast cancer risk associated with mutations in these genes is at least 5-fold the population risk. Mutations in moderate-risk breast cancer susceptibility genes have also been identified and confer a twoto five-fold increased breast cancer risk, with ATM and CHEK2 mutations most common [3]. Several other candidate moderate-risk breast cancer susceptibility genes have been proposed. We are in a period in which the specific cancer risks associated with mutations in these genes are still being fully defined. It is notable that three of the genes on most panels are ovarian cancer susceptibility genes, BRIP1 [4], RAD51C [5] and RAD51D [5] that may not be associated with breast cancer risk. The overall lifetime risks of breast and ovarian cancers associated with mutations in each susceptibility gene are shown in Table 1.

Table 1 Breast cancer risk susceptibility genes.a

BRCA1 BRCA2

Lifetime breast cancer risk (age 80)b

Lifetime ovarian cancer risk

References

67%–75% RR 11.4 66%–76% RR 11.7

45%

[3,81]

12%

[3,81]

Genes other than BRCA1/2: high risk CDH1 53% RR 6.6 (2.2–19.9) PALB2 45% RR 5.3 (3.0–9.4) PTEN RR 25–39d TP53 RR 105 (62–165)

No increase

[3]

OR 2.3–10.2 Inconsistent data No increase Risk increased for many cancers. No specific risk estimate for ovarian cancer

[3,12,82] [3] [3]

Moderate risk ATM

No increase

[3]

No increase

[3,13,83]

No increase

[3]

STK11

27% RR 2.8 (2.2–3.7) 20–29% RR 2.3–3.0 23% RR 2.7 (1.9–3.7) 31–45%e

Average risk BRIP1

No increase

RAD51C

No increase

RAD51D

No increase

CHEK2 NBNc

f

[3,84]

4.1–12.7% RR 3.4–11.2 6.1% OR 5.2 13.6% OR 12

[4,82]

RR 27

0 0 0 0 0 0 0 0 0 0 0 0 0

[5] [5]

RR: relative risk; OR: odds ratio. a BARD1 not included since breast and ovarian cancer risk estimates are inconsistent [3,4,82]. b Risks higher in those with significant breast cancer family history; 95% confidence interval reported for RR in parenthesis when single RR reported. c Risk estimate based on one mutation: c.657del5. d Based on population with Cowden syndrome, which may overestimate risk. e May be an overestimate due to ascertainment from Peutz-Jeghers syndrome cohorts. f Sex-cord tumors (no increase in epithelial ovarian cancer).

Please cite this article as: M.L. Peters, et al., Managing hereditary breast cancer risk in women with and without ovarian cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.04.013

M.L. Peters et al. / Gynecologic Oncology xxx (2017) xxx–xxx

Genetic testing for cancer susceptibility can be conducted either for a single gene, a specific cancer, or comprehensively for mutations in multiple known cancer risk genes. As the cost of testing has decreased, testing is increasingly conducted using one of a variety of commercially available multi-gene panels. The genes included in most commercially available panels are those for which mutations confer at least a twofold increase risk for cancer. Guidelines for BRCA1/2 genetic analysis suggest testing for women with a personal history of epithelial ovarian cancer, a personal history of young breast cancer (≤45–50 years), or a personal history of breast cancer and family members with breast, ovarian, pancreatic or aggressive prostate cancer [2,6]. Breast cancer patients with Ashkenazi Jewish heritage should also consider genetic testing regardless of family history given the high prevalence of BRCA1/2 mutations in this population [7]. Guidelines emphasize testing both for women with a significant chance of having a mutation, as well as for those for whom a mutation would change medical management [8]. Certain models such as BOADICEA (ccge.medschl.cam.ac.uk/Boadicea/) [9], and BRCAPRO [10] are statistical tools that calculate the likelihood that a BRCA mutation exists. However, since no acceptable threshold for mutation identification has been established, criteria are often based on published guidelines (e.g., NCCN, ACOG). No guidelines exist for genetic testing for moderate-risk breast cancer susceptibility genes, since factors that predict for these mutations are lacking and the clinical validity (risk estimate) and clinical utility (improved outcomes) associated with identifying these mutations are not as well established. These mutations are often identified through multi-gene panel testing of individuals referred for BRCA1/2 testing. However, cancer risk associated with any inherited mutation varies among carriers based on several factors including age and family history. To determine the remaining lifetime risk of breast cancer for a woman with a BRCA1 mutation, for example, one must subtract the risk of breast cancer estimated to the age of that woman (i.e. the risk that has “expired”) from the lifetime risk associated with that mutation. This can either be done by using existing risk curves [11] and the formula: Remaining risk from age X ¼

risk to age 80−risk to age X 1−ðrisk to age XÞ

or by using statistical models such as BOADICEA [9]. The BOADICEA model now also incorporates age-associated risk estimates for mutations in BRCA1/2, CHEK2, ATM and PALB2. In addition, the breast cancer risk associated with any mutation is higher in women who also have a family history of breast cancer; this has been shown for carriers of PALB2 [12] and CHEK2 [13] mutations. 2. Breast cancer risk assessment in the absence of a mutation Despite the identification of an increasing number of breast cancer susceptibility genes, a mutation is identified in no more than 20% of women referred for genetic testing due to a potential hereditary risk [14]. For women without an identified predisposing mutation, breast cancer risk may be calculated by various models that estimate risk based on family history, reproductive and hormonal risk factors, and prior benign breast disease. Of these, the Gail model (i.e. Breast Cancer Risk Assessment Tool; www.cancer.gov/bcrisktool) [15] is most widely used, although it is limited in women with hereditary breast cancer since it incorporates very limited family history information. The Claus model incorporates more extensive family history but fails to utilize any other risk factors (http://young-ridge-2035.herokuapp.com) [16]. The IBIS/Tyrer-Cuzick model (www.cancertechnology.co.uk/ibissoftware-tyrer-cuzick-model) [17] allows incorporation of the most extensive family history information as well as other breast cancer risk factors. In women with a significant family history, the 10-year breast cancer risk estimates with this tool are quite accurate [18] though lifetime risk estimates tend to be higher than with many other models

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[19]. The Tyrer-Cuzick model is a bit more time consuming to use, though a user-friendly web-based application has recently been developed (http://ibis.ikonopedia.com/). Some risk models incorporate mammographic breast density, including the Breast Cancer Surveillance Consortium (BCSC) breast cancer risk assessment tool (https://tools.bcsc-scc.org) [20] and version 8 of the IBIS model (http://www.ems-trials.org/riskevaluator/). Women with heterogeneously and extremely dense breasts on mammography have a 1.2-fold and 2.1-fold increased breast cancer risk compared to the average woman, respectively [21]. While mammographic breast density is being included in some models, until measurement is standardized, routine integration is problematic. At least 94 common single nucleotide polymorphisms (SNPs) have been associated with breast cancer risk [22–24]. These hereditary gene variants are each associated with a b 2-fold increase in breast cancer risk. A combined risk from multiple SNPs can be calculated for an individual woman and is referred to as the Polygenic Risk Score. Including information about SNPs can improve the accuracy of risk assessment models [25]. However, breast cancer SNP assessment is not yet commercially available for routine clinical use. 3. Breast cancer screening For women with a significant familial risk of breast cancer, standard annual mammography is insufficient. In women at increased risk of breast cancer, MRI is approximately twice as sensitive and leads to detection of breast cancer at an earlier stage than with mammography alone [26]. Based on expert opinion, the American Cancer Society (ACS) recommends the use of breast MRI for any woman with a lifetime risk of breast cancer N20%, using models that emphasize family history [27]. There are drawbacks to using breast MRI for surveillance, including a higher false positive rate, the discomfort of the required positions, and the difficulty women with claustrophobia experience with the exam. In addition, intravenous contrast is required, and MRI is contraindicated in women with renal impairment. Additional costs of breast MRI must also be considered. However, given the high risk of breast cancer among BRCA1/2 and other high-risk mutation carriers, guidelines recommend the use of annual MRI in addition to annual mammography in this population [2]. This combination has been shown to provide sensitivity of 80–100% among women with high risk of breast cancer, although at the cost of lower specificity of 73–90% [26]. Norway instituted a national MRI screening program for BRCA1 carriers, which identified 68 breast cancers in 802 women over a period of 4 years, 85% of which were nodenegative at the time of diagnosis [28]. While downstaging has been demonstrated with breast MRI, no survival benefit has yet been demonstrated [28]. For BRCA1/2 carriers, NCCN recommends MRI surveillance beginning at age 25, with mammography added at age 30. Before that age, mammography is likely of little benefit given higher breast density in young women; in addition, the potential for radiation-induced breast cancer may outweigh any screening benefit in women younger than age 30 [29]. Several studies have shown that MRI is more likely to find the aggressive, triplenegative lesions more common among BRCA1 carriers [26,30]. Among women with moderate-risk gene mutations, the benefit of breast MRI is not as clear. The risk associated with mutations in several of these genes exceeds the lifetime risk threshold of 20% set by the ACS, as noted in Table 1. Management guidelines therefore recommend consideration of annual breast MRI in addition to mammograms for carriers such as those with ATM and truncating CHEK2 mutations [2,31]. Some have proposed that rather than using lifetime risk, MRI would be beneficial for women with 5-year breast cancer risk of N2.5% [31]. The age at which breast cancer surveillance should begin in these women is also less clear than for BRCA1/2 carriers. It has been suggested that mammogram screening should begin when a woman's 5-year risk of breast

Please cite this article as: M.L. Peters, et al., Managing hereditary breast cancer risk in women with and without ovarian cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.04.013

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M.L. Peters et al. / Gynecologic Oncology xxx (2017) xxx–xxx

cancer exceeds 1%, that of the average 50-year-old woman [31], and for convenience, MRI surveillance could be initiated at that time as well. The Women Informed to Screen Depending On Measures of risk (WISDOM) study is a randomized trial that is comparing the efficacy of a risk-based algorithm for screening vs. standard care (Clinical Trials identifier NCT02620852) [32]. In the risk-based screening arm, biennial mammograms are initiated when 5-year risk of breast cancer exceeds 1.3% (i.e. equivalent to an average 50-year old Caucasian woman by SEER data). Breast MRI is reserved for women with 5-year risk ≥ 6%, high-risk mutations (e.g., BRCA1/2) or moderate-risk mutations (e.g., ATM, CHEK2) and a family history of breast cancer. Moderaterisk mutation carriers without a family history receive annual mammography alone. The use of enhanced mammography is also being evaluated. Tomosynthesis (3D mammography in combination with 2D mammography) has been shown to be slightly more sensitive than standard 2D mammography alone and results in 10–15% fewer callbacks among average risk women [33]. Cohort studies demonstrate that one additional invasive breast cancer per 1000 women screened will be detected by using tomosynthesis [33], though the results of randomized trials comparing 2D mammography and tomosynthesis are pending. In addition, tomosynthesis has not been specifically studied in women with hereditary risk of breast cancer. This modality is associated with a higher radiation burden, although this is likely of minimal significance. Among women with dense breasts, ultrasound as an adjunct to mammography was comparable to tomosynthesis in one study, although BRCA1/2 carriers were not included [34]. However, other studies have demonstrated higher false positive rates with the use of adjunct ultrasound for screening among high-risk women in particular [35]. Contrast mammography is an investigational modality that is being studied as a potential substitute for MRI [36]. In one study of 216 women, contrast-enhanced mammography substantially improved the predictive power of digital mammography. The future application of this technology is being actively investigated. 4. Breast cancer risk-reducing medications The use of tamoxifen to reduce the risk of breast cancer has been well-established, though its benefit in women with hereditary risk of breast cancer is less clear. In the NSABP P1 tamoxifen prevention study, tamoxifen was shown to reduce the risk of primary invasive and non-invasive breast cancer by ~ 50% (hazard ratio [HR] 0.51 (95% confidence interval [CI], 0.39–0.66) and 0.50 (95% CI, 0.33–0.77), respectively) [37]. The risk reduction in this study was even greater for women with atypical hyperplasia or lobular carcinoma-in-situ (LCIS), with an 86% and 56% risk reduction, respectively. The magnitude of effect for women with atypical hyperplasia or LCIS must be considered in the context of a relatively small sample size. Five years of treatment can result in up to 15 years of risk reduction, as the benefit of tamoxifen persists after discontinuation [38]. Aromatase inhibitors were evaluated in the MAP.3 and IBIS-2 studies and were shown to further reduce the risk of primary breast cancer among post-menopausal women with a relative risk reduction of 53–65% [39,40]. In the STAR trial, raloxifene was shown to decrease breast cancer risk less than tamoxifen (relative risk (RR) of breast cancer was 1.2 for raloxifene compared with tamoxifen), though with fewer side effects [41]. Compared with tamoxifen, raloxifene does not increase the risk of endometrial cancer, and is associated with a lower risk of thromboembolic events (HR 0.75; 95% CI, 0.60–0.93). USPSTF and ASCO recommend consideration of these medications for women with a 5-year breast cancer risk of at least 1.7%, though for postmenopausal women a threshold of 3% is often recommended to ensure that benefits outweigh risks [42,43]. For premenopausal women, tamoxifen is the only proven-effective medication, whereas all of these agents may be considered in postmenopausal women. In postmenopausal women older than age 50, Freedman et al. have developed

extremely useful tables to determine whether the benefits of tamoxifen and raloxifene outweigh risks for women according to their breast cancer risk, age and whether their uterus is intact [44]. However, these medications only decrease the incidence of ER-positive, not ERnegative, breast cancers. In addition, there is no evidence of a survival benefit with these agents as the prevention trials were not powered to assess survival differences. Among BRCA1/2 carriers, there is extremely limited information regarding the use of primary prevention medications. A subgroup analysis of the NSABP P-1 tamoxifen prevention trial identified 8 BRCA1 and 11 BRCA2 carriers and showed a trend toward tamoxifen benefit for BRCA2 carriers only [45]. This may be explained by the different types of breast cancers that develop among BRCA1 and BRCA2 carriers. 70–80% of BRCA2-associated breast cancers are ER-positive [46]. In contrast, approximately 75% of BRCA1-associated breast cancers are ERnegative, which would not be prevented by the use of tamoxifen [46] An ongoing trial (NCT00673335) is evaluating the benefit of the aromatase inhibitor letrozole for primary breast cancer prevention among a planned 386 BRCA1 and BRCA2 postmenopausal carriers. Another role for medication is in the prevention of contralateral breast cancer among BRCA1/2 carriers who have previously been diagnosed with breast cancer. While many of these women choose to undergo contralateral prophylactic mastectomy, among those who do not, tamoxifen was shown to significantly reduce the risk of contralateral disease by 62–67% in both BRCA1 and BRCA2 mutation carriers [47]. One retrospective, observational study evaluated the risk of CBC in 2464 BRCA1/2 carriers, of whom 837 used tamoxifen. Tamoxifen was associated with a significant decrease in CBC for both BRCA1 (HR 0.38; p b 0.001) and BRCA2 (HR 0.33; p b 0.001) carriers, and for those with either an initial ER-positive or ER-negative breast cancer [47]. There are no data regarding the benefit of tamoxifen, raloxifene, or aromatase inhibitors for breast cancer prevention among carriers of mutations in other breast cancer susceptibility genes. In one study, 72% of the breast cancers that develop in women with inherited CHEK2 mutations are ER-positive [48] suggesting that these prevention agents may provide significant risk reduction. Additional information regarding the breast cancer phenotypes associated with mutations in each susceptibility gene is necessary to better understand the value of these medications in these subpopulations. 5. Risk-reducing surgery Prophylactic mastectomy (PM) is a common consideration among BRCA1/2 carriers and women with a strong familial risk of breast cancer. When used as primary prevention, this surgery has been shown to decrease breast cancer risk by 90%, though any survival benefit is likely small [49,50]. Compared with surveillance of BRCA1/2 carriers who undergo RRSO, one model estimates that survival is increased by at most 3% with prophylactic mastectomy performed at age 40 [51]. The major benefit of prophylactic mastectomies is avoidance of breast cancer diagnosis and the need for frequent breast surveillance. Given the significant risk reduction, NCCN [2], USPSTF [52], and NICE [53] (www.nice.org.uk/ guidance/cg164) all recommend discussion of PM in women with BRCA1, BRCA2, or other high-risk gene mutations. The risk of contralateral breast cancer (CBC) among BRCA1/2 carriers has been estimated to be 83% for BRCA1 carriers and 62% for BRCA2 carriers by age 70 [54]. However, the risk of CBC depends greatly on the age at which the initial breast cancer occurred. The 25-year risk of CBC is 62.5% for carriers initially diagnosed before age 40, but only 19.5% for those diagnosed after age 50 [55]. As in the primary prevention setting, it is not clear whether contralateral prophylactic mastectomy (CPM) provides a survival benefit. Three studies have demonstrated a 48%–63% relative reduction in mortality from CPM. However, in some cases these women had the CPM performed years after their primary diagnosis, potentially introducing selection bias toward a survival benefit [56–58].

Please cite this article as: M.L. Peters, et al., Managing hereditary breast cancer risk in women with and without ovarian cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.04.013

M.L. Peters et al. / Gynecologic Oncology xxx (2017) xxx–xxx

The use of prophylactic mastectomy, either for primary or secondary prevention, has not been studied for moderate-risk mutation carriers (e.g. CHEK2, ATM). By extrapolation from BRCA1/2, given the lower associated breast cancer risk with these mutations, prophylactic mastectomy is unlikely to provide a survival benefit in these carriers. Nevertheless, an increased risk of CBC has been reported with some mutations, such as truncating CHEK2 mutations [59]. Risk-reducing salpingo-oopherectomy (RRSO) has been considered a powerful tool for breast cancer risk reduction, especially for BRCA1/2 carriers. Several previous studies showed that in pre-menopausal carriers, RRSO reduces breast cancer incidence by approximately 50%, with greater risk reduction the earlier it is performed [49,54,60]. Domchek et al. found a 37% and 64% breast cancer risk reduction with RRSO for BRCA1 and BRCA2 carriers respectively who had not had prior breast cancer [49]. However, two recent studies failed to show a reduction in breast cancer with RRSO in BRCA1/2 carriers without a previous diagnosis of breast cancer. One retrospective Dutch study with a median of 3.2 years of follow-up showed no benefit of RRSO in 822 BRCA1/2 carriers [61]. This was attributed to potential bias in prior studies due to the effect of a breast cancer diagnosis to drive genetic testing, and the way in which lifespan prior to RRSO was analyzed. A second similar analysis also failed to show a breast cancer risk reduction for RRSO in BRCA1 carriers without prior cancer, but did show a benefit for BRCA2 carriers who underwent RRSO before the age of 50 (HR 0.18; 95% CI, 0.05–0.63; p = 0.007) [62]. However, even with a 50–60% breast cancer risk reduction, it is important to note that the post-RRSO incidence of breast cancer among BRCA1 and BRCA2 carriers remains higher than the general population risk. The magnitude of breast cancer risk reduction from RRSO for other mutation carriers is unknown, though the relative risk reduction may be similar to that seen in BRCA1/2 carriers for similar mechanistic reasons. RRSO also reduces the risk of ovarian cancer by at least 80% [63,64]. In several of these studies, RRSO was shown to provide a survival benefit at 3 to 5 years, due to both breast and ovarian cancer specific mortality [49,64]. NCCN recommends that RRSO be performed when childbearing is complete, between the ages of 35–40 years for BRCA1 mutation carriers [2]. Since BRCA2 carriers have a lower risk of ovarian cancer and tend to develop ovarian cancer at an older age than BRCA1 carriers, delaying RRSO for BRCA2 carriers until age 45 can be considered [2,11,63]. However, delaying RRSO will likely decrease the magnitude of the benefit of breast cancer risk reduction. 6. Breast cancer risk management in BRCA1/2 carriers after ovarian cancer diagnosis 6.1. Ovarian cancer prognosis in BRCA1/2 carriers When considering the potential benefit of breast cancer screening or prevention strategies for BRCA1/2 carriers following a diagnosis of ovarian cancer, one must first consider the recurrence and mortality risk associated with ovarian cancer. A number of studies have shown that BRCA1 and particularly BRCA2 carriers with epithelial ovarian cancer have a better prognosis than noncarriers independent of age, stage, or grade of disease [65–68]. A meta-analysis including N3000 women with ovarian cancer demonstrated improved mortality rates for BRCA1 and BRCA2 carriers with HR 0.73 (95% CI, 0.64–0.84) and 0.49, (95% CI, 0.39–0.61) respectively [65]. This is thought to be due at least in part to improved platinum sensitivity [1,69]. However, some studies have demonstrated that this benefit may only be short-term with carriers having improved survival at two years, but no survival advantage by ten years [70,71]. To evaluate the potential benefit of breast cancer screening or risk reduction in this population it would be most helpful to know the risk of ovarian cancer recurrence within the first 5 years. If high, the benefit of early breast cancer detection or prevention would be minimal. Unfortunately, many studies only report overall survival (OS) rather than

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progression- or disease-free survival. Table 2 summarizes the available studies of ovarian cancer prognosis among BRCA1/2 carriers. Ovarian cancer recurrence is unlikely after 5 years, even among those with late-stage disease [72]. While studies often report lower 10-year compared with 5-year OS, this is largely due to recurrences earlier in the disease course. In addition, most ovarian cancer recurrences occur within 2 years after diagnosis. Kurta et al. showed that among women who achieve remission, the likelihood of remaining disease-free is 80.5% after 2 years in remission, increasing to 97.7% after 5 years in remission [72]. Known risk factors for ovarian cancer recurrence such as degree of surgical debulking, stage, age and grade also influence outcomes in BRCA carriers. As with noncarriers, 70% of BRCA1/2 carriers present with advanced stage disease [73]. Among patients with early stage ovarian cancer, prognosis does not seem to differ between carriers and noncarriers with 5-year OS 75% [1,74]. Among carriers with advanced disease, recurrence rates among BRCA1/2 carriers with specific prognostic factors are not often reported. However, Alsop et al. found that only the extent of debulking at primary surgery persisted as an independent prognostic factor for survival in mutation carriers. Carriers with no residual disease had a 5-year progression-free survival (PFS) of 50% whereas carriers with any degree of residual disease had a 5-year PFS of 18%. Boyd et al. found that among carriers, residual disease of b2 cm was a favorable prognostic factor for survival (compared to N2 cm of residual disease: HR 1.48; 95% CI, 1.18–1.86.) [75]. 6.2. Risk of breast cancer after ovarian cancer in BRCA1/2 carriers There are limited data regarding the risk of breast cancer after an ovarian cancer diagnosis for BRCA1/2 carriers. Studies show approximately a 10% chance of developing breast cancer during the 10 years after ovarian cancer diagnosis. In these studies, the overall survival from ovarian cancer ranged from 17% to 68% at 10 years, substantially impacting the number of carriers alive to develop a potential breast cancer diagnosis [76–78]. The risk of breast cancer among BRCA1/2 carriers who survive a diagnosis of ovarian cancer is lower than that reported for carriers who have not developed ovarian cancer. This reduced incidence of breast cancer could be attributed to the use of oophorectomy to induce early menopause or to the use of platinumcontaining chemotherapy that could eliminate microscopic breast cancer. Table 3 summarizes this information, which is also described below. A Dutch case-control study found that with a median follow-up of 6.6 years, BRCA1/2 carriers with ovarian cancer have a lower risk of primary or contralateral breast cancer than carriers without a prior diagnosis of ovarian cancer. For carriers with ovarian cancer, the 2-, 5and 10-year risk of breast cancer was 3%, 6% and 11%, significantly lower than the risk in unaffected carriers (HR 0.43; 95% CI, 0.20–0.95). Likewise, for BRCA1/2 carriers with both breast and ovarian cancer, the 10-year risk of contralateral breast cancer was 7%, lower than for carriers with breast cancer but no prior ovarian cancer, a non-significant HR of 0.40 (95% CI, 0.14–1.09). Of note, the 10-year mortality rate among the ovarian cancer patients was 55% for carriers without prior breast cancer and 61% for those with both ovarian and breast cancer. Thus, the 10-year risk of breast cancer (i.e. 7–11%) must be interpreted in the context of this significant 10-year mortality rate (i.e. 55–61%). The women in this population underwent regular breast cancer screening, most with breast MRI (after the year 2000) [76]. A similar study at MSKCC and University of Pennsylvania followed 164 BRCA1 and BRCA1/2 carriers with a prior diagnosis of ovarian cancer for an average of 5.8 years. While 5-year and 10-year OS were 85% and 65%, respectively only 11% of carriers developed breast cancer, none of whom died from breast cancer. The breast cancer screening approach for these women is not reported [77]. A third study evaluated 135 BRCA1/2 carriers from Cedars-Sinai hospital with ovarian cancer. Of these, 8.9% developed breast cancer, with a

Please cite this article as: M.L. Peters, et al., Managing hereditary breast cancer risk in women with and without ovarian cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.04.013

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M.L. Peters et al. / Gynecologic Oncology xxx (2017) xxx–xxx

Table 2 Prognosis of ovarian cancer in BRCA carriers. Study

Design and population

5-Year PFS

5-Year OS

Chetrit et al., JCO 2008 [74]

Prospective observational study of 779 Jewish patients in Israel with epithelial ovarian cancer 159 BRCA1 54 BRCA2

N/A

N/A BRCA1/2: all stages: 46% Early stage: 74% Stage 3: 38% Stage 4: 36% BRCA1:44% N/A BRCA2: 61%

N/A

No survival advantage over non-carriers for those with early stage disease Advanced stage: both BRCA1 and BRCA2 had better OS compared with noncarriers

N/A

BRCA2, not BRCA1 mutations associated with increase in OS and PFS

Yang et al., JAMA 2011 [67]

Retrospective observational study of 316 patients with high-grade serous ovarian cancer 35 BRCA1 27 BRCA2 Hyman et al., Cancer Retrospective observational study of 190 2012 [66] patients with Stage III/IV serous ovarian cancer 30 BRCA1 17 BRCA2 Alsop et al. JCO 2012 Prospective observational study of 709 [1] patients with serous ovarian cancer 74 BRCA1 44 BRCA2

BRCA1: 13% BRCA2: 39%

Pooled analysis of 26 observational studies of epithelial ovarian cancer

BRCA1: 58% BRCA2: 76%

N/A

N/A

Optimal debulking was borderline significant Age and BRCA2 significant factors for improved OS

BRCA1: 28%

BRCA1: 55%

N/A

N/A

Suboptimal debulking was an independent risk factor for reduced survival among carriers.

BRCA2: 21%

BRCA2: 45%

Residual disease: 18% N/A

2666 non-carriers 909 BRCA1: 77% stage 3/4 304 BRCA2: 85% stage 3/4 McLaughlin et al., JNCI 2013 [70]

Retrospective observational study of 1626 patients in Ontario and Florida with epithelial ovarian cancer

N/A

Candido-dos-Reis et al., Clin Cancer Res 2015 [71]

245 BRCA1 99 BRCA2 Retrospective pooled analysis of 27 studies of epithelial ovarian cancer 404 BRCA1: 76% stage 3/4 162 BRCA2: 76% stage 3/4 1924 noncarriers

Improved response to 2nd line therapy among carriers.

No residual disease: 76% Residual disease: 32% BRCA1: 44%, HR 0.73 (adj) BRCA2 52%, HR 0.49 (adj) BRCA1: 52%, HR 0.83 (adj)

N/A

N/A

N/A

BRCA1: 28%, HR 0.96 (adj)

BRCA1: 32%

BRCA1: 22%

BRCA2: 32%, HR 0.88 (adj) BRCA1: 36%

BRCA2: 45%

BRCA2: 70%

BRCA2: 35%

BRCA2: 49%

N/A

BRCA1: 45%

N/A

BRCA1: 25%, HR 0.53

BRCA2: 54%

No survival advantage over non-carriers for those with low-grade disease

Overall BRCA1 and BRCA2, improved OS c/w noncarriers; BRCA2 better than BRCA1

BRCA2: 58%, HR 0.65 (adj) BRCA1: 62%

129 BRCA1: 74% stage 3/4 89 BRCA2: 84% stage 3/4 Retrospective observational study of Vencken et al., Annals Oncol 2013 patients in the Netherlands with epithelial ovarian cancer [68]

Comment

N/A

No residual disease: 50%

Bolton et al., JAMA 2012 [65]

10-Year 10-Year PFS OS

Short-term (3-year) survival benefit only for BRCA1/2 carriers; 10-year OS, no difference

Short-term survival benefit is eventually reversed; HR for BRCA became N1 at 4.8 years, HR for BRCA2 predicted to become N1 at 10 years.

BRCA2: 35%, HR 0.42

c/w: compared with; OS: overall survival; PFS: progression-free survival; adj: adjusted; carrier: BRCA1 or BRCA2 carrier; noncarrier: no BRCA1 or BRCA2 mutation; N/A: not available.

median time to diagnosis of 50.5 months. The 10-year overall survival rates were 17% for the overall population, 13.8% for those who did not develop breast cancer and 50% for those who did, although this may reflect the fact that women who had a rapid recurrence of their ovarian cancer never underwent surveillance or lived long enough to develop breast cancer. 59% of these women underwent annual mammography and 44% annual MRI in addition to mammography [78].

In summary, information regarding the incidence and prognosis of breast cancer in BRCA1/2 carriers after a diagnosis of ovarian cancer is limited. However, available studies demonstrate that approximately 10% of BRCA1/2 carriers will develop breast cancer within 10 years, with only approximately 2–3% in the first 2.5 years and 2–6% in the first 5 years [76–78]. In addition, while deaths from breast cancer have been reported in these carriers [76], breast cancer-related mortality

Please cite this article as: M.L. Peters, et al., Managing hereditary breast cancer risk in women with and without ovarian cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.04.013

Gangi et al., JAMA Surg 2014 [78]

12 patients (8.9%) developed breast cancer, median time to diagnosis 50.5 months 135 carriers with OC 103 BRCA1 32 BRCA2 Retrospective observational study 59% mammography 44% annual MRI and mammography

Domchek et al., Cancer 2013 [77]

6.3. Breast cancer risk management after ovarian cancer in BRCA1/2 carriers after ovarian cancer As discussed in the sections above, for the initial two to five years after ovarian cancer diagnosis, a carrier's risk of breast cancer is low and her overall prognosis is determined primarily by the prognosis of the ovarian cancer. Thus, while the 5-year risk of breast cancer for these carriers does exceed general thresholds for recommending mammography (N1% 5-year risk), breast MRI (N 2.5% 5-year risk or N20% lifetime risk) and prevention medications (N1.7% 5-year risk), ovarian cancer prognosis should dictate the appropriateness of breast cancer screening and prevention strategies. For carriers who remain diseasefree after 5 years, the risk of developing breast cancer exceeds the risk of ovarian cancer recurrence (i.e., 2.3% after 5 years [72]), and more intensive early detection and prevention strategies are appropriate. One suggested approach for breast cancer screening and prevention in BRCA1/2 carriers after a diagnosis of ovarian cancer is shown in Table 4. For patients who do not achieve remission from disease, screening and prevention strategies offer no advantage. For patients with early stage disease, or favorable stage 3 disease, breast cancer risk reduction and early detection are appropriate. Patients with less favorable advanced stage disease who achieve sustained remission (N 2–5 years) should also consider more aggressive strategies for breast cancer screening and prevention. OC: ovarian cancer; carrier: BRCA1 or BRCA2 mutation carrier; OS: overall survival; HR: hazard ratio; BCFS: breast-cancer-free survival.

BRCA1: 96% BCFS 85% OS BRCA2: 98% BCFS 85% OS No breast cancer: 39% DFS, 30% OS Breast cancer: 58% DFS, 58% OS

Contralateral breast cancer: 7% (vs. 16% control) 66% OS

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appears to be low, [77] and overall survival is determined almost solely by ovarian cancer outcomes [78].

Contralateral breast cancer: 7% (vs. 34% control) 45% OS HR 0.52 BRCA1: 88% BCFS 65% OS BRCA2: 98% BCFS 75% OS No breast cancer: 33% DFS, 14% OS Breast cancer: 50% DFS, 50% OS

18 patients (11%) developed breast cancer, none of whom died of breast cancer 164 carriers with OC 115 BRCA1 49 BRCA2 Retrospective observational study Screening for BC unknown

Vencken et al., Cancer 2013 [76]

4 patients (7%) developed contralateral breast cancer, none died of breast cancer

Comment

8 patients (11%) developed primary breast cancer, 3 died of breast cancer (1 unknown death)

10 year risk

Primary breast cancer: 11% (vs. 28% control) 39% OS HR 0.35

5 year risk

Primary breast cancer: 6% (vs. 16% control) 67% OS

Population

79 carriers with OC 37 carriers with OC and BC Controls (no OC) 351 carriers no cancer 294 carriers with BC

Design

Retrospective observational study Screening for BC varied; most received annual MRI, some mammography

Study

Table 3 Breast cancer risk after ovarian cancer in BRCA1/2 carriers.

M.L. Peters et al. / Gynecologic Oncology xxx (2017) xxx–xxx

6.3.1. Surveillance Surveillance with mammography and MRI is reasonable in carriers with early stage ovarian cancer or those with optimally debulked stage 3 disease since 5-year PFS is 73–80% and 50%, respectively. However, breast MRIs are associated with a higher frequency of false positive findings, necessitating call-back studies and unnecessary breast biopsies. Therefore, we recommend minimizing exposure to these risks for carriers with less favorable advanced ovarian cancer (i.e. stage 4 or stage 3 not optimally debulked). During the first two years when most cancers recur, mammography and breast MRI could be reserved for those with a more favorable prognosis. If a carrier with less favorable advanced disease remains disease free at 2 years, mammography and breast MRI can be initiated at that time. For some patients, including those who are already receiving breast cancer surveillance, it may be emotionally difficult not to undergo surveillance. Thus it may be reasonable to initiate or continue surveillance even for women with poor prognosis who have achieved an initial remission.

6.3.2. Risk-reducing medications Risk reduction via the use of medications such as tamoxifen, raloxifene, or aromatase inhibitors, could also be considered for women with early-stage ovarian cancer or with sustained remission at 5 years. Tamoxifen has been studied as potential therapy in recurrent ovarian cancer, with roughly 10% response rate as described in a Cochrane review [79]. Aromasin has also been tested in estrogen-receptor positive epithelial ovarian cancer with minimal responses [80]. However, it is important to consider that these medications have side effects, including an increased risk of venous thromboembolic events with tamoxifen and raloxifene. Further, the efficacy of these agents is not proven in BRCA1/2 carriers (especially BRCA1 carriers who develop ER-negative breast cancers), and there is no survival advantage yet demonstrated with any breast cancer prevention agent. Thus, consideration of these agents should be individualized and delaying initiation until a carrier is disease free for 5 years is reasonable.

Please cite this article as: M.L. Peters, et al., Managing hereditary breast cancer risk in women with and without ovarian cancer, Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.04.013

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M.L. Peters et al. / Gynecologic Oncology xxx (2017) xxx–xxx

Table 4 Suggested approach for breast cancer risk management for BRCA1/2 mutation carriers in remission after ovarian cancer. Ovarian cancer stage

2-Year and 5-year OC PFS: [11,85]

Screening with mammography and MRI

Preventive medication

Preventive surgery: BPM

Stage 4

N/A

Initiate screening if no relapse at 2 years

Consider if no relapse at 5 years

Stage 3 not optimally debulked

30–38% 2 years 18–20% 5 years

Stage 3 no residual disease (optimally debulked)

65% 2 years 50% 5 years

Initiate screening if no relapse at 2 years Consider immediately for patients with more favorable prognosis (e.g., less residual disease; young age) Alternate mammography and breast MRI each 6 months

Consider if no relapse at 5 years Consider if no relapse at 5 years

Stage 1 Stage 2

80–90% 2 years 73–80% 5 years

Alternate mammography and breast MRI each 6 months

Consider if no relapse at 5 years Consider

Consider if no relapse at 5 years May consider for patients with more favorable prognosis if no relapse at 2–3 years. especially if: unable to tolerate breast surveillance or future chemotherapy would be problematic Consider if no relapse at 5 years. May consider for patients with more favorable prognosis if no relapse at 2–3 years. especially if: unable to tolerate breast surveillance or future chemotherapy would be problematic Consider BPM

OC: ovarian cancer; PFS: progression-free survival; BPM: bilateral prophylactic mastectomy; N/A: not available.

6.3.3. Prophylactic mastectomy Prophylactic mastectomy is unlikely to offer a survival advantage for BRCA1/2 carriers after ovarian cancer even among early-stage patients. However, tolerance for surveillance and willingness to potentially undergo chemotherapy for a future breast cancer diagnosis should be considered. If a carrier remains disease free at 5 years, (or 2 years for those with more favorable prognosis), consideration of prophylactic mastectomies is reasonable. It is also worth considering that BRCA1 carriers are at risk for more aggressive, triple negative breast cancers that more often present as interval cancers and often require chemotherapy. Prior studies among BRCA1/2 carriers have shown that most who choose prophylactic mastectomy report significantly less anxiety regarding cancer risk after surgery. When asked to reflect on the decision, most women are satisfied with their choice to undertake this surgery. However, there can be negative effects on body image and sexuality among some women [11]. The specific psychological impact of prophylactic mastectomy after an ovarian cancer diagnosis has not been assessed.

6.4. Other breast cancer gene mutation carriers For ovarian cancer patients found to have mutations in other highrisk genes (PALB2, TP53, STK11, PTEN), similar recommendations for managing breast cancer risk would apply. For those with moderate breast cancer risk mutations (e.g., ATM, CHEK2), the 5-year risk of breast cancer would be even lower than that with associated with BRCA mutations, and we would therefore recommend a more conservative stance toward surveillance and prevention strategies.

7. Conclusions A significant percentage of women with a new diagnosis of ovarian cancer will have a germline mutation in one of a variety of cancer risk genes. In particular, 14–20% will have a BRCA1/2 mutation. Other highand moderate-risk genes are bring identified in the ovarian cancer population due to multi-gene panel testing, including PALB2, TP53, CHEK2, ATM, BRIP1, RAD51C and RAD51D, some of which are associated with increased breast cancer risk. Most women with ovarian cancer are undergoing genetic testing for the purpose of targeting their treatment. This information can also inform their risk of breast cancer, and for women with early-stage disease, can indicate a benefit for screening and prevention for a potential second malignancy. This consideration and discussion should be part of their regular cancer follow-up care. Of note, the risk of breast cancer among BRCA1/2 carriers who survive a diagnosis of ovarian cancer is

lower than that reported for carriers who have not developed ovarian cancer, possibly due to platinum exposure during treatment. For BRCA1/2 mutation carriers diagnosed with ovarian cancer, the impact of breast cancer detection and risk mitigation is largely dependent on their expected ovarian cancer prognosis. For women who do not achieve remission, breast cancer surveillance or prevention is not of value. For women with early-stage ovarian cancer, breast cancer surveillance and prevention is reasonable. For BRCA1/2 carriers with advanced disease, screening and prevention strategies should be tailored to ovarian cancer prognosis. Even for carriers with unfavorable advanced disease, it is reasonable to initiate surveillance if they are in remission after two years. Prophylactic mastectomy can be considered for BRCA1/2 carriers in remission after 5 years, or earlier for those with a favorable prognosis. Conflict of interest statement Dr. Mary Linton Peters: none. Dr. Judy Garber: Research Funding from Ambry Genetics (no salary support), consultant to Helix. Dr. Nadine Tung: Research Funding from Myriad Genetics, Inc., Ambry Genetics and AstraZeneca (no salary support).

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