BRCA mutation genetic testing implications in the United States

The Breast 31 (2017) 224e232

Contents lists available at ScienceDirect

The Breast journal homepage: www.elsevier.com/brst

Review

BRCA mutation genetic testing implications in the United States Soley Bayraktar a, Banu Arun b, * _ Department of Medical Oncology, Memorial Medical Center, Istanbul, Turkey Department of Breast Medical Oncology and Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

a

b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 31 October 2016 Received in revised form 22 November 2016 Accepted 28 November 2016

BRCA mutation carriers have a very high risk of breast and ovarian cancer by age 70, in the ranges 47% e66% and 40%e57%, respectively. Additionally, women with BRCA mutation-associated breast cancer also have an elevated risk of other or secondary malignancies. Fortunately, the breast and ovarian cancer outcome for BRCA1/2 mutation carriers is at least as good as for non-carriers with chemoprevention, prophylactic surgeries and appropriate use of therapies. Therefore, identification of those who might have a mutation is important so that genetic counseling, testing, screening and prevention strategies can be applied in a timely manner. This article reviews the impact of genetic testing in general, timing of genetic testing after diagnosis and prior knowledge of mutation status in BRCA carriers with newly diagnosed breast cancer. Additionally, risk-reducing surgeries including the prophylactic contralateral mastectomy, and bilateral salpingo-oophorectomy and the sensitivity of BRCA-defective breast cancer cell lines to differential chemotherapeutic agents will be discussed. © 2016 Elsevier Ltd. All rights reserved.

Keywords: BRCA1 BRCA2 Genetic testing Timing Hereditary breast cancer Prophylactic mastectomy Prophylactic oophorectomy PARP inhibitors Platinums

Contents 1. 2. 3.

4.

Genetic testing for hereditary breast and ovarian cancer syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 BRCA1-and BRCA2-associated breast cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Genetic testing implications for women with BRCA mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 3.1. Impact of BRCA mutation status on clinical stage of breast cancer diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 3.2. Impact of BRCA mutation status on local therapy for women with breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 3.3. Impact of BRCA mutation status on use of chemoprevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 3.4. Impact of BRCA mutation status on surveillance strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 3.5. Impact of BRCA mutation status for a woman with childbearing potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 3.6. Impact of BRCA mutation status on use of hormone replacement therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 3.7. Psychological consequences of genetic testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 3.8. Does genetic testing really benefit public health? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 3.9. Does timing of genetic testing matter? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 3.10. When is expedited genetic testing required? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

* Corresponding author. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1354, Houston, TX, 77030-4009, United States. E-mail addresses: [email protected] (S. Bayraktar), barun@ mdanderson.org (B. Arun). http://dx.doi.org/10.1016/j.breast.2016.11.021 0960-9776/© 2016 Elsevier Ltd. All rights reserved.

S. Bayraktar, B. Arun / The Breast 31 (2017) 224e232

225

Ethical approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

1. Genetic testing for hereditary breast and ovarian cancer syndrome

mutation carriers, thus will be the focus of this review. 2. BRCA1-and BRCA2-associated breast cancers

The most common hereditary cause of breast cancer is hereditary breast and ovarian cancer syndrome (HBOC), which is caused by a germline mutation in either the BRCA1 or BRCA2 gene. Depending on the technique used to test for BRCA1/BRCA2 mutations (e.g., sequencing with or without deletion/duplication testing), the prevalence of BRCA1/BRCA2 mutations in patients with breast cancer has been widely varied which may also be effected by patient age, gender, tumor histology, and strength of family history. Large genomic rearrangements account for 12e18% of all BRCA1/2 mutations, therefore quantitative PCR, multiplex ligation-dependent probe amplification (MLPA), or microarray-based techniques should be used in addition to sequencing [1e3] to detect these mutations. Table 1 summarizes the likelihood of detecting a BRCA1 or BRCA2 mutation in individuals unselected for family history [4e14]. Since 2013, because of changes in patent law, BRCA1/BRCA2 genetic testing is now offered at a variety of laboratories, and an increasing number of laboratories are utilizing next generation sequencing (NGS) to offer extensive hereditary cancer panel testing, which includes analysis of many genes simultaneously. NGS has some major advantages over traditional Sanger sequencing because of the ability to rapidly analyze multiple genes with relatively little increase in cost. In addition, NGS may help to overcome some of the issues faced by clinicians in cases with limited family structure, a long genetic differential diagnosis, or when the family history information is unreliable due to poor family communication. For clinicians offering genetic testing directly, counseling involves education about the benefits, risks, and limitations of genetic testing that is tailored to that patient's unique situation, including the possibility of results that may not be adequately interpretable or clinically actionable. Timing of genetic testing is also important as the results may impact immediate treatment of the patient's breast cancer (e.g.,consideration of bilateral mastectomy, oophorectomy, or radiation). In patients with a strong family history of breast cancer, care should be taken to avoid giving the patient a false sense of reassurance if they have negative genetic testing. Genetic testing is only one element of the complex process of assessment for breast cancer risk, and accurate interpretation and communication of genetic test results to patients is critical. The efficacy of screening and risk-reducing surgical or pharmacologic interventions has only been well-studied in BRCA1/BRCA2

Table 1 The likelihood of detecting a BRCA1 or BRCA2 mutation in individuals unselected for a family history. Frequency of a BRCA mutation If women is diagnosed with breast cancer <30e40 years old <45e50 years old Any age And with Ashkenazi Jewish ancestry And with triple-negative histology If men is diagnosed with breast cancer Any age

~6e18% [4e7] ~6% [5,7] 2% [8] ~10% [9] 9e28% [10e12] 4e14% [13,14]

BRCA mutation carriers have a very high risk of breast and ovarian cancer by age 70, in the ranges 47%e66% and 40%e57%, respectively. Additionally, women with BRCA mutation-associated breast cancer also have an elevated risk of other or secondary malignancies, such as male breast cancer, prostate cancer, pancreas cancer, gastrointestinal cancers (e.g., gall bladder, bile duct, colon and stomach), and melanoma [15,16]. BRCA1-associated breast cancers are more frequently high grade and triple-negative (TN) compared with sporadic tumors [17]. In contrast to BRCA1 tumors, BRCA2 tumors seem to be more similar to sporadic tumors. Most BRCA2 breast tumors exhibit a luminal phenotype featuring overexpression of estrogen receptor (ER), progesterone receptor (PR) and cytokeratins CK8 and CK18[17]. While most studies indicate a similar prognosis for women with hereditary breast cancers compared with age-matched women with sporadic breast cancers [18e22], other studies have reported worse survival outcomes [23e25]. Lee et al. [26] reported similar survival rates in BRCA1 mutation carriers with TN disease compared with non-carriers. Likewise, Bayraktar et al. [27] observed that overall prognosis of TN breast cancer in BRCA carriers and non-carriers was not significantly different within the first 5 years following initial diagnosis. In contrast, the aggressive nature of these breast cancers has been demonstrated through a higher median Oncotype DX recurrence score in ER-positive, node negative BRCA-associated breast cancers as compared with controls [28] and an inferior overall survival (OS) in BRCA1 mutation carriers with breast and ovarian cancer as compared with non-carrier patients. Notably, this OS difference was not seen in BRCA2 mutation carriers [29]. Importantly, we need to keep in mind that the prognostic studies are mostly retrospective that would need perfect adjustment on clinical stage and tumor biology, and may also suffer from retrospective biases and late access to genetic testing. 3. Genetic testing implications for women with BRCA mutations 3.1. Impact of BRCA mutation status on clinical stage of breast cancer diagnosis Knowledge of one's BRCA1/2 mutation status may aid earlier detection of breast cancers due to increased awareness and screening with breast MRIs. This has been shown in a retrospective analysis of 82 BRCA1/2 mutation carriers diagnosed with their first breast cancer [30]. 19.5% (16/82) were known BRCA1/2 mutation carriers prior to breast cancer diagnosis and the remaining 66 patients had genetic testing after cancer diagnosis. 62.5% (10/16) of known carriers were diagnosed with breast cancer following an abnormal MRI vs 0/66 of those identified as carriers only after breast cancer diagnosis. Patients who knew their BRCA1/2 mutation status were more likely to have smaller tumors (p ¼ 0.008) and node negative disease (p ¼ 0.004). There were no differences in the ER, PR or Her2 statuses between the 2 groups. Therefore, BRCA1/2 mutation carriers who have knowledge of their genetic status were more likely to have early stage disease at the time of breast cancer

226

S. Bayraktar, B. Arun / The Breast 31 (2017) 224e232

diagnosis, demonstrating the utility of identifying unaffected carriers who benefit from enhanced screening for early detection. 3.2. Impact of BRCA mutation status on local therapy for women with breast cancer Studies have shown that prophylactic mastectomy (PM) results in up to a 97% risk reduction of contralateral breast cancer (CBC) [31e33]. Recently, three studies have shown that PM appears not only decrease the risk of CBC but also to confer a OS advantage. In the first prospective study by Evans et al. [34], 105 female BRCA1/2 carriers with unilateral breast cancer who underwent PM were compared to controls (593 mutation carriers and 105 specifically matched) not undergoing PM. The 10-year OS was 89% in women electing for PM compared to 71% in the non-PM group; p < 0.001. The survival advantage remained after matching for oophorectomy, gene, grade and stage: [hazard ratio (HR): 0.37, 95% confidence interval (CI): 0.17e0.80, p ¼ 0.008] and PM appeared to act independently of risk-reducing salpingo-oophorectomy (RRSO). Another prospective study by Heemskerk [35]-Gerritsen et al. also examined the efficacy of PM on OS in mutation carriers with a history of unilateral breast cancer in a cohort of 583 patients. After a median follow-up of 11.4 years, four patients developed CBC (2%) in PM group, against 64 patients (19%) in the surveillance group (p < 0.001). The mortality was lower in the PM group vs surveillance group, 86% vs 74% (HR:0.49). Survival benefit was especially seen in young patients (<40 years), in patients having a breast cancer with a grade 1/2 and/or no TN phenotype, and in patients not treated with adjuvant chemotherapy. A third retrospective study by Metcalfe et al. [36] showed that after a median follow-up of 14.3 years (range 0.1e20.0 years), OS rate for women who had PM was 88% (95% CI: 83%e93%) and for those who did not was 66% (59%e73%). In a multivariable analysis, controlling for age at diagnosis, year of diagnosis, treatment, and other prognostic features, PM was associated with a 48% reduction in death from breast cancer (HR: 0.52, 95% CI: 0.29 to 0.93; P ¼ 0.03). Based on these results, they predicted that of 100 women treated with PM, 87 would be alive at 20 years compared with 66 of 100 women treated with unilateral mastectomy. It has been recommended that women with a BRCA1 mutation undergo RRSO by age 35e40 or once the completion of childbearing [US National Comprehensive Cancer Network (NCCN) version 2016]. Women who harbor only the BRCA2 mutation do not appear to be at an increased risk by age 50 and can delay surgery until their 50s. For example, in their prospective study, Finch et al. [37] found that if a woman with a BRCA1 mutation delays prophylactic surgery until age 40, her risk of ovarian cancer is raised to 4%. The risk developing ovarian cancer is up to 14.2% if a woman with a BRCA1 mutation waits until age 50. For patients with BRCA2 mutations, there was only one case of ovarian cancer diagnosed before age 50. RRSO clearly reduces the risk of tubal-ovarian cancer [38,39] and also reduces breast cancer [40]. Most studies have reported that RRSO reduces the risk of CBC in women with a history of BRCAassociated breast cancer by 50%e70%, with the greatest benefit observed if the surgery is performed before the age of 50 [31,41e43] A meta-analysis of 10 studies reported a significant reduction in the risk of CBC and ovarian cancer in BRCA mutation carriers who had undergone RRSO [44]. Overall, RRSO was associated with a 51% reduction in breast cancer risk (HR: 0.49; 95% CI: 0.37e0.65). Similar risk reductions were observed in BRCA1 (HR:0.47; 95% CI: 0.35e0.64) and BRCA2 (HR: 0.47; 95% CI: 0.26e0.84) mutation carriers. RRSO was also associated with a significant risk reduction of ovarian-fallopian tube cancer (HR:0.21; 95% CI: 0.12e0.39). PROSE study [45] demonstrated that RRSO is also associated with an overian and breast cancer risk reduction in

women with a BRCA1/2 mutation and who have no previous cancer history. After RRSO, the risk of ovarian cancer among BRCA1 carriers was 1.8% vs. 7.4% in women who did not have RRSO (HR:0.31; 95%CI:0.12e0.82). Among BRCA2 carriers, the risk of ovarian cancer after RRSO was none vs. 3.2% in women who did not have RRSO. When we compared the risk of breast cancer among BRCA carriers who have not had a previous history of breast cancer, the risk reduction was 37% (95%CI: 0.41e0.96), and 64% (95% CI: 0.16e0.81) among BRCA1 and BRCA2 carriers, respectively. Moreover, women with BRCA1 or BRCA2 mutations with no cancer at baseline who underwent RRSO experienced a 77% reduction [HR ¼ 0.23; 95% CI, 0.13e0.39; P < 0.001)] in their overall risk of death by age 70 [37]. The above findings justify the practice of offering the option of risk-reducing surgeries to the intact breasts (before or after any breast cancer diagnosis) and to the intact ovaries in BRCA carriers as the risk of breast cancer in women with BRCA mutations who undergo both procedures is less than 2% [32,33,46] The physician should also discuss that coordinated PM and reconstruction and RRSO is a feasible procedure with acceptable morbidity in selected high-risk patients who desire to undergo surgery at one operative setting [47]. A detailed discussion with the patient regarding the surgical risk-reducing intervention and its long-term side effects is central to the management of mutation carriers.

3.3. Impact of BRCA mutation status on use of chemoprevention As stated above, prophylactic surgeries to decrease the breast and ovarian cancer are the most preventive approach that could be offered to BRCA carriers. A study looked at the clinical factors associated with choosing RRSO over surveillance in women with a BRCA1 or BRCA2 mutations [48]. Age greater than 40 years, parity, and a personal history of breast cancer were associated with choosing RRSO. A short time interval (4.6 months) was noted from the time of receiving positive genetic test results to undergoing prophylactic surgery. Yet, preventive surgeries may not be the appropriate choice for some patients and they may be offered chemoprevention to decrease their cancer risk. While some studies have reported that adjuvant tamoxifen reduces the risk of CBC by 50%e70% in women with a history of BRCAassociated breast cancer [41,43,49], other studies have not reported a significant reduction [31,50e53]. For example, two studies have demonstrated that adjuvant use of tamoxifen was associated with a CBC risk reduction of 50% for BRCA1 carriers and 58% for BRCA2 carriers, regardless of ER status [49,54] This result differed from that of a small retrospective study comparing outcomes in earlystage BRCA mutation-associated and sporadic breast cancer treated with tamoxifen which observed a lower OS in BRCA carriers, suggesting relative resistance to tamoxifen [55]. Similarly, Metcalfe et al. did not observe a statistically significant reduction in CBC risk associated with the use of tamoxifen [56]. Importantly, in none of the studies [49,54] tamoxifen was associated with a risk reduction in women after oophorectomy. These results, however, require confirmation, and the use of adjuvant tamoxifen is recommended in patients with BRCA mutation-associated ER-positive breast cancer. There are no completed prospective studies evaluating the preventive role of AIs in women with BRCA mutations; however there is an ongoing French study evaluating letrozole versus placebo in women with BRCA mutations [ClinicalTrials.gov identifier: NCT00673335]. It is noteworthy to mention that a recent study evaluated the role of anastrazole in women with breast cancer who had BRCA mutations that showed a reduction in CBC with anastrozole use [57].

S. Bayraktar, B. Arun / The Breast 31 (2017) 224e232

3.4. Impact of BRCA mutation status on surveillance strategies Current screening recommendations for the asymptomatic BRCA mutation carrier encompass examination, imaging, and laboratory evaluation. Surveillance for female carriers emphasizes screening techniques for breast and ovarian cancers. There is general agreement that women with a higher lifetime risk of breast cancer, such as that conferred by a BRCA mutation, should undergo earlier and more frequent screening, with additional imaging modalities considered. Table 2 summarizes the breast and ovarian cancer screening recommendations published by the National Comprehensive Cancer Network (NCCN), American Cancer Society (ACS), and American College of Radiology (ACR) for BRCA mutation carriers [58e60] [61]. Of note European, Canadian or other guidelines may be different than the American guidelines. Mutations in the tumor suppressor genes BRCA1 and BRCA2 place male and female carriers at increased risk for a number of other cancers, notably pancreatic, melanoma, colorectal, and other gastrointestinal tumors. No expert consensus or evidence-based guidelines exist regarding screening for these cancers, and currently these are totally exploratory and outside of any recommendation; however there are some literature and investigational studies which support considering the additional surveillance modalities [62e64] (Table 3).

3.5. Impact of BRCA mutation status for a woman with childbearing potential Results of predictive genetic testing may affect women's decisions about family planning. In a caseecontrol study of men and women of reproductive age who were tested for a BRCA1 mutation, women with HBOC may be less likely to desire additional children than non carriers [65]. Women with unfulfilled childbearing plans are significantly more distressed about treatment-related

227

infertility, even 10 years after diagnosis [66,67]. This concern may be compounded when discussing BRCA genetic testing and the implications of a positive result for future and current children [68]. The few studies that have examined associations between reproductive history and the risk of breast cancer among BRCA1/2 mutation carriers have produced inconsistent results. In some studies [69e71], the authors observed a decreased risk of breast cancer among nulliparous BRCA1/2 mutation carriers and an increased risk of breast cancer with increasing number of full-term pregnancies; in other studies [72e74], breast cancer risk was not associated with either the number of full-term pregnancies or young age at first full-term pregnancy. Andrieu et al. [75] observed that an increasing number of full-term pregnancies was associated with a statistically significant decrease in the risk of breast cancer in a cohort of BRCA1/2 mutation carriers consistent with that observed in the general population. In BRCA2 mutation carriers, first childbirth at later ages was associated with an increased risk of breast cancer compared with first childbirth before age 20 years (20e24 years, HR ¼ 2.33 [95% CI ¼ 0.93 to 5.83], 25e29 years, HR ¼ 2.68 [95% CI ¼ 1.02 to 7.07], 30 or later, HR ¼ 1.97 [95% CI ¼ 0.67 to 5.81]), whereas in BRCA1 mutation carriers, first childbirth at age 30 or later was associated with a reduced risk compared with first childbirth before age 20 (HR ¼ 0.58 [95% CI ¼ 0.36 to 0.94]). A recent study [76] looking at survival in women with BRCA mutations who were diagnosed while pregnant or became pregnant after breast cancer found that pregnancy did not effect survival for either group of women. This study looked at a relatively small number of women and larger studies will be needed to confirm these findings. With assisted reproductive technologies (ART), alternative childbearing options are available. Beyond the choices of adoption and oocyte donation, women who desire to have their own biological children yet avoid transmission of a BRCA mutation may be offered prenatal diagnosis (PND), including chorionic villus

Table 2 Screening recommendations by NCCN and ACS for BRCA1/2 mutation carriers. Starting age Breast cancer screening recommendations for women Monthly breast self-exam 18 Semiannual clinical breast exam 25 Alternating annual mammograms with annual breast magnetic resonance 25e30 imaging Breast cancer screening recommendations for men Annual clinical breast exam 35 Annual mammograms 40 Ovarian cancer screening guidelines for women who are not undergoing RRSO Semiannual concurrent pelvic exam, transvaginal ultrasound, and CA-125 35, or 10 years earlier than the youngest age at which any family member was diagnosed with antigen levels ovarian cancer NCCN: National Comprehensive Cancer Network; ACS: American Cancer Society. RRSO: risk reducing salpingo-oophorectomy.

Table 3 Proposed screening methods for other cancers in BRCA1/2 mutation carriers (No expert consensus or evidence-based guidelines exist yet). Starting age Proposed pancreas cancer screening Annual endoscopic ultrasound Proposed melanoma screening Annual full body skin and ocular exam Proposed colorectal screening Annual fecal occult blood testing, or sigmoidoscopy every 5 years, or colonoscopy every 10 years Proposed prostate cancer screening for men Annual digital rectal examination and PSA levels

50, or 10 years prior to the earliest pancreatic cancer diagnosis in the family No age specified 50, and continue until 75 years of age

40

228

S. Bayraktar, B. Arun / The Breast 31 (2017) 224e232

sampling and amniocentesis. However, these methods are invasive and confer a slightly increased risk of miscarriage. In addition, they may present complicated and difficult choices regarding termination or continuation of an affected pregnancy [77]. A possible alternative to PND is preimplantation genetic diagnosis (PGD). PGD allows couples to avoid having a child with an inherited condition, potentially reducing cancer burden in families with a hereditary cancer predisposition. PGD involves in-vitro fertilization (IVF) and genetic testing to select embryos for uterine implantation that do not have the genetic disorder. Embryos with the mutation are discarded or stored long-term. It has been used for more than a dozen hereditary cancer syndromes including HBOC [78]. However, oocyte donation and pre-natal diagnosis in case of BRCA germline mutation are not at all a standard in many countries as ethical questions have been raised about the usage, and also there are other potential factors which include concern about exposure of cancer cells to high estrogen levels during IVF [79] [80]. Alternatively, parents may worry about the possible psychological impact on an existing at-risk child if they choose to have another child who will not be at risk because of PGD. Still, Rich et al. [79] suggest that most, but not all, BRCA carriers are interested in hearing about PGD. Therefore, healthcare providers should discuss the availability of reproductive technology with all BRCA carriers in a sensitive manner, acknowledging that some do not condone the procedure. In fact, consideration of PGD for hereditary cancer patients has been included in recent fertility preservation guidelines issued by the American Society for Reproductive Medicine and the American Society of Clinical Oncology [81]. In an ideal setting, a physician should provide oncofertility services and fertility preservation options to BRCA carriers to protect their reproductive health and preserve current or future fertility. 3.6. Impact of BRCA mutation status on use of hormone replacement therapy RRSO has become a standard of care in North America and Western Europe for preventing cancer in women with a BRCA1 or BRCA2 mutation. Yet, the decrease in cancer risk from ovary removal results in early menopause and menopausal symptoms including hot flashes, mood swings, sleep disturbances, cognitive functioning problems and vaginal dryness which are quality-of-life issues that may cause some women to delay or avoid the procedure [82,83]. Moreover, surgically-induced early menopause may also increase their risk of osteopenia/osteoporosis and cardiovascular problems [84e86]. BRCA carriers, and their physicians, may worry, based on other studies conducted in the general population showing a link between hormone replacement therapy (HRT) and elevated cancer risk, that taking HRT will increase their risk of breast cancer despite having RRSO. However, several studies [87,88] do support use of HRT in women with BRCA-associated breast cancer. Eisen et al. [87] examined safety of HRT use and the risk of breast cancer in BRCA1 mutation carriers. In that study, neither use of estrogen alone nor use of estrogen combined with progesterone was associated with an increase in breast cancer risk among BRCA1 mutation carriers. This observation is in contrast to the situation in the general (ie, noncarrier) population, in which formulations containing both estrogen and progesterone have been associated with a substantial increase in breast cancer risk. Of interest, there was no association between the duration of HRT use and the risk of breast cancer among BRCA1 mutation carriers, and the association with past use was similar to that of current use. This observation is consistent with the hypothesis that transient exposure to HRT is protective; ie, HRT might induce the differentiation of precursor cancer cells and thereby prevent cancer later in life. In another study, Rebbeck et al.

[88] examined the association between oophorectomy and breast cancer risk in a historical cohort study of 462 BRCA1 and BRCA2 mutation carriers. They found that the OR for breast cancer associated with oophorectomy was 0.40 (95% CI ¼ 0.18 to 0.92) in the entire study group and 0.37 (95% CI ¼ 0.14 to 0.96) in the subgroup of women with oophorectomy who used HRT. However, in that study, use of HRT was not evaluated independently of menopause because the sample size was small (there were only three women with breast cancer and HRT exposure in the study). In a prospective study of 1299 BRCA1/2 mutation carriers with limited follow-up [89], HRT following RRSO was not associated with an increased risk of breast cancer. While this is the largest study of its kind, it is important to recall that the data are not randomized. Also, the type of HRT (combination hormones vs. estrogen only) did not appear to matter, but the numbers are too small to evaluate this specific question. In conclusion, these data are reassuring in suggesting that HT is probably not contraindicated in women with a BRCA1 mutation. Women who receive HRT may derive important cardiovascular, bone-health, and quality-of-life benefits as a result. Women who undergo RRSO, particularly those who do not receive HRT, will require close monitoring of bone and cardiovascular health. While the findings are reassuring regarding use of HRT, the duration of HRT may be an issue. It is unclear if there would be increased risk of breast cancer with prolonged usage of HRT. Because HRT is associated with an increased risk of endometrial carcinoma, some experts advocate the removal of the uterus at the time of RRSO. Those who do use HRT long-term may benefit from counseling regarding this suggestion. 3.7. Psychological consequences of genetic testing Understanding the psychological consequences of genetic testing for BRCA1/2 mutations has been a key clinical question since testing became available; early findings demonstrated that adverse reactions to receiving positive test results are shortlived, if they are experienced at all, and receiving negative results may reduce anxiety and depression symptoms in some women [90,91]. More recent work has shown that receiving positive BRCA1/2 results may generate specific concerns related to the clinical and psychological integration of genetic risk information [92]. Mutation carriers reported significantly greater distress (eg, anxiety, sadness) and uncertainty (eg, understanding options for cancer prevention and early detection, difficulty making decisions about screening and prevention) compared with women who received negative or uncertain results. Because decisions about screening and uptake of prophylactic surgery may unfold over time [93], it is possible that these concerns persist for years after test results disclosure. However, Halbert et al. [94] conducted an observational study to evaluate the long-term impact of genetic testing for BRCA1/2 mutations, and showed that women were not likely to experience genetic testing concerns several years after receiving BRCA1/2 test results; distress and uncertainty are not likely to have adverse effects on screening among women at risk for hereditary disease. Overall, distress and uncertainty were low; 74% of women did not experience any distress, and 41% of women did not experience any uncertainty. A recent meta-analysis found that distress among carriers and noncarriers decreased over time during a 1-year period [95]. It could be that not only are women unlikely to experience adverse reactions such as distress several years after receiving BRCA1/2 test results, but also these concerns may dissipate over time after pretest counseling, test results disclosure, and post disclosure follow-up. However, mutation carriers may still experience distress, and identifying women who could benefit from further psychosocial support remains an important goal. Future research is needed to determine the level and types of support that

S. Bayraktar, B. Arun / The Breast 31 (2017) 224e232

may be most useful several years after genetic counseling and testing and to develop a model of care within which it can be provided. 3.8. Does genetic testing really benefit public health? For BRCA1/BRCA2 gene testing to benefit public health, mutation carriers must initiate appropriate risk management strategies. Schwartz et al. [96] evaluated long-term uptake and predictors of PM, RRSO, chemoprevention and cancer screening among women who have undergone BRCA1/2 testing. By a mean of 5.3 years posttesting, 37% of BRCA1/2 carriers opted for PM and 65% of opted for RRSO. Overall, 91.2% of affected carriers and 63.9% of unaffected carriers obtained PM and/or RRSO prior to or following testing. Scheuer et al. reported that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1/ 2 carriers [97]. Another report indicated that up to 75% of BRCA1/2 carriers with intact ovaries had received at least one transvaginal ultrasound in the three years following testing [98]. These data, coupled with emerging evidence of reduced mortality following risk reducing surgeries, suggest that BRCA1/2 testing may beneficially impact cancer mortality and thus public health.

229

inhibitors (PARPI) has been shown in several studies [113e116]. Ovarian, fallopian tube and primary peritoneal cancers differ from breast cancer as most are diagnosed in advanced stages when patients present with symptoms. While the diagnosis may be suspected prior to surgery, definitive diagnosis can only be made after pathological examination of the surgical specimen, limiting the feasibility of preoperative testing. BRCA mutation status may, in the future, help dictate the course of treatment for ovarian cancer. BRCA1-or BRCA2-deficient ovarian tumors are particularly responsive to PARPI [117e119]. In a recent randomized phase 3 trial among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of PFS was significantly longer among those receiving niraparib (PARPI) than among those receiving placebo, regardless of the presence or absence of BRCA mutations [120]. Genetic testing could get lost in the shuffle of complicated medical care and other immediate decisions that need to be made. Given the significant implications of the genetic test results, we believe that patients would be better served if genetic counseling is provided at the time of their initial diagnosis. However, the timing of genetic counseling and testing must balance the necessity for immediate testing with the stress patients feel as they cope with the diagnosis of cancer, treatment plans and prognosis. 3.10. When is expedited genetic testing required?

3.9. Does timing of genetic testing matter? Among health professionals, there is an ongoing debate about when to offer the genetic testing to high risk women. This timing not only provides additional dimensions to treatment decisions, but has psycho-social and familial implications as well. Some physicians support the idea that offering genetic testing around the time of breast cancer diagnosis would be more important since the results could alter treatment decisions. While some health care professionals do not support this idea as they believe that there is already an emotional overload in coping with the cancer diagnosis and decisions regarding existing cancer treatment options and that offering genetic testing would add too much additional stress. While we acknowledge the concerns of the latter group, herein, we want to highlight the reasons for offering the genetic testing at initial diagnosis. In breast cancer, this is of particular importance as knowledge of mutation status may influence immediate treatment recommendations including the performance of concomitant contralateral risk-reducing mastectomy and RRSO in a patient who would otherwise undergo only lumpectomy or unilateral mastectomy [99]. Knowledge of BRCA positive status at the time of treatment may enable cancer patients to avoid additional prophylactic breast surgeries at a later time. Schwartz et al. [100] demonstrated that BRCA1/2 test results significantly affect patients' surgical decisionmaking. If women knew that they carried BRCA mutations, they were more likely to view mastectomy as the best way to reduce future breast cancer recurrence while avoiding multiple surgeries and radiation. Furthermore, it is possible that timely genetic testing may actually decrease the rate of inappropriate bilateral mastectomy for young newly diagnosed breast cancer patients. Another reason for that genetic testing should take place prior to initiation/completion of chemotherapy as the approach to systemic treatment is changing based on data suggesting unique patterns of sensitivity and resistance to systemic therapies in BRCA mutation-associated breast cancers [101e106]. Several clinical studies have demonstrated that BRCA-defective cell lines are sensitive to DNA-damaging agents, such as platinums [107,108], and are relatively resistant to taxanes compared with BRCA-competent cell lines [109,110] [111,112]. Additionally, the sensitivity of BRCAdefective breast cancer cell lines to poly (ADP-ribose) polymerase

The standard genetic risk assessment (GCRA) and conventional (nonexpedited) BRCA testing allow women to consider prevention while making decisions about surgical management of breast cancer. Schwartz et al. reported that the mean elapsed time between breast cancer diagnosis and initiation of GCRA was 27 days (range, 3e72 days) [100]. The GCRA protocol consisted of pretest counseling, obtaining informed consent, commercial BRCA genotyping (standard 3-to-4 eweek turnaround), which often required insurance preauthorization, and a subsequent clinic session for individualized post-test counseling focused on the formation of a definitive combined treatment and risk reduction management plan. The optimum window of opportunity for GCRA to influence surgical decisions would be during neo-adjuvant chemotherapy if it is prescribed; then the definitive decision occurs after chemotherapy is completed, and before the surgery or initiation of radiotherapy. If the patient is not a candidate for neo-adjuvant chemotherapy, then expedited genetic testing may play a role in order to avoid a delay in surgical procedures. Future studies need to identify ways for fast and cheap testing of BRCA. 4. Conclusion Specific clinical interventions in BRCA mutation carriers reduces the risk of breast and ovarian cancers and may improve survival; thus, identification of mutation carriers is important.  Research has shown that women who carry the BRCA mutations benefit from risk-reduction procedures to reduce their risk of developing breast and ovarian cancers. ◦ The best risk-reduction strategy appears to be RRSO in the mid30s or early 40s (following childbearing) ◦ RRSO in this population results in an 80% reduction in ovarian/ fallopian tube cancer risk and a 50% reduction in breast cancer risk. ◦ RRSO for women in their 30se40s carrying a BRCA 1 or 2 mutation is currently recommended by the NCCN. ◦ Small prior studies have suggested that HRT following RRSO does not increase the risk of breast cancer, but further data are needed to establish the role of HRT, if any, in this specific population.

230

S. Bayraktar, B. Arun / The Breast 31 (2017) 224e232

◦ If patient is going to receive neo-adjuvant chemotherapy, with the standard turnaround times associated with nonexpedited BRCA-mutation testing (3e4 weeks), it is feasible to integrate GCRA into the management of women with newly diagnosed breast cancer.

Conflict of interest All authors do not have disclose any conflict of interest to declare.

[18]

[19]

[20]

[21]

Funding source There is not any involvement with funding to accomplish this work. Ethical approval Not applicable.

[22]

[23]

[24]

References [25] [1] Palma MD, Domchek SM, Stopfer J, Erlichman J, Siegfried JD, TiggesCardwell J, et al. The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res 2008;68(17):7006e14. [2] Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 2006;295(12):1379e88. [3] Weitzel JN, Clague J, Martir-Negron A, Ogaz R, Herzog J, Ricker C, et al. Prevalence and type of BRCA mutations in hispanics undergoing genetic cancer risk assessment in the southwestern United States: a report from the clinical cancer genetics community research network. J Clin Oncol Off J Am Soc Clin Oncol 2013;31(2):210e6. [4] Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 1999;91(11):943e9. [5] Malone KE, Daling JR, Neal C, Suter NM, O'Brien C, Cushing-Haugen K, et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer 2000;88(6):1393e402. [6] Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A. Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a populationbased series of early-onset breast cancer. J Natl Cancer Inst 2001;93(16): 1215e23. [7] Lalloo F, Varley J, Moran A, Ellis D, O'Dair L, Pharoah P, et al. BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer 2006;42(8):1143e50. [8] Prevalence and penetrance of BRCA1 and BRCA2 mutations in a populationbased series of breast cancer cases. Anglian breast cancer study group. Br J cancer 2000;83(10):1301e8. [9] King MC, Marks JH, Mandell JB. New York Breast Cancer Study G. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 2003;302(5645):643e6. [10] Rummel S, Varner E, Shriver CD, Ellsworth RE. Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer. Breast Cancer Res Treat 2013;137(1):119e25. [11] Evans DG, Howell A, Ward D, Lalloo F, Jones JL, Eccles DM. Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer. J Med Genet 2011;48(8):520e2. [12] Fostira F, Tsitlaidou M, Papadimitriou C, Pertesi M, Timotheadou E, Stavropoulou AV, et al. Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a hellenic cooperative oncology group study. Breast Cancer Res Treat 2012;134(1):353e62. [13] Basham VM, Lipscombe JM, Ward JM, Gayther SA, Ponder BA, Easton DF, et al. BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 2002;4(1):R2. [14] Couch FJ, Farid LM, DeShano ML, Tavtigian SV, Calzone K, Campeau L, et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet 1996;13(1):123e5. [15] Thompson D, Easton D. The genetic epidemiology of breast cancer genes. J mammary Gl Biol neoplasia 2004;9(3):221e36. [16] Mersch J, Jackson MA, Park M, Nebgen D, Peterson SK, Singletary C, et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 2015;121(2):269e75. [17] Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, et al. The pathology of familial breast cancer: predictive value of

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol Off J Am Soc Clin Oncol 2002;20(9):2310e8. Verhoog LC, Brekelmans CT, Seynaeve C, Dahmen G, van Geel AN, Bartels CC, et al. Survival in hereditary breast cancer associated with germline mutations of BRCA2. J Clin Oncol Off J Am Soc Clin Oncol 1999;17(11):3396e402. Rennert G, Bisland-Naggan S, Barnett-Griness O, Bar-Joseph N, Zhang S, Rennert HS, et al. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N. Engl J Med 2007;357(2):115e23. Brekelmans CT, Tilanus-Linthorst MM, Seynaeve C, vd Ouweland A, MenkePluymers MB, Bartels CC, et al. Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and nonBRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer 2007;43(5):867e76. Kriege M, Seynaeve C, Meijers-Heijboer H, Collee JM, Menke-Pluymers MB, Bartels CC, et al. Distant disease-free interval, site of first relapse and postrelapse survival in BRCA1- and BRCA2-associated compared to sporadic breast cancer patients. Breast Cancer Res Treat 2008;111(2):303e11. Bonadona V, Dussart-Moser S, Voirin N, Sinilnikova OM, Mignotte H, Mathevet P, et al. Prognosis of early-onset breast cancer based on BRCA1/2 mutation status in a French population-based cohort and review. Breast Cancer Res Treat 2007;101(2):233e45. Chappuis PO, Kapusta L, Begin LR, Wong N, Brunet JS, Narod SA, et al. Germline BRCA1/2 mutations and p27(Kip1) protein levels independently predict outcome after breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 2000;18(24):4045e52. Moller P, Evans DG, Reis MM, Gregory H, Anderson E, Maehle L, et al. Surveillance for familial breast cancer: differences in outcome according to BRCA mutation status. Int J Cancer 2007;121(5):1017e20. Lee EH, Park SK, Park B, Kim SW, Lee MH, Ahn SH, et al. Effect of BRCA1/2 mutation on short-term and long-term breast cancer survival: a systematic review and meta-analysis. Breast Cancer Res Treat 2010;122(1):11e25. Lee LJ, Alexander B, Schnitt SJ, Comander A, Gallagher B, Garber JE, et al. Clinical outcome of triple negative breast cancer in BRCA1 mutation carriers and noncarriers. Cancer 2011;117(14):3093e100. Bayraktar S, Gutierrez-Barrera AM, Liu D, Tasbas T, Akar U, Litton JK, et al. Outcome of triple-negative breast cancer in patients with or without deleterious BRCA mutations. Breast Cancer Res Treat 2011;130(1):145e53. Shah PD, Patil S, Dickler MN, Offit K, Hudis CA, Robson ME. Twenty-one-gene recurrence score assay in BRCA-associated versus sporadic breast cancers: differences based on germline mutation status. Cancer 2016;122(8): 1178e84. Zhong Q, Peng HL, Zhao X, Zhang L, Hwang WT. Effects of BRCA1/2 on ovarian and breast cancer survivaleresponse. Clin cancer Res Off J Am Assoc Cancer Res 2015;21(16):3807. Yam CSJ, Brandt A. Impact of prior knowledge of mutation status on tumor stage in BRCA1/2 mutation carriers with newly diagnosed breast cancer. J Clin Oncol Off. J Am Soc Clin Oncol 2015:33 (suppl; abstr 1562). Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol Off J Am Soc Clin Oncol 2004;22(12):2328e35. Metcalfe KA, Lubinski J, Ghadirian P, Lynch H, Kim-Sing C, Friedman E, et al. Predictors of contralateral prophylactic mastectomy in women with a BRCA1 or BRCA2 mutation: the hereditary breast cancer clinical study group. J Clin Oncol Off J Am Soc Clin Oncol 2008;26(7):1093e7. van Sprundel TC, Schmidt MK, Rookus MA, Brohet R, van Asperen CJ, Rutgers EJ, et al. Risk reduction of contralateral breast cancer and survival after contralateral prophylactic mastectomy in BRCA1 or BRCA2 mutation carriers. Br J cancer 2005;93(3):287e92. Evans DG, Ingham SL, Baildam A, Ross GL, Lalloo F, Buchan I, et al. Contralateral mastectomy improves survival in women with BRCA1/2-associated breast cancer. Breast Cancer Res Treat 2013;140(1):135e42. Heemskerk-Gerritsen BA, Rookus MA, Aalfs CM, Ausems MG, Collee JM, Jansen L, et al. Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Int J Cancer 2015;136(3):668e77. Metcalfe K, Gershman S, Ghadirian P, Lynch HT, Snyder C, Tung N, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. BMJ 2014;348:g226. Finch AP, Lubinski J, Moller P, Singer CF, Karlan B, Senter L, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol Off J Am Soc Clin Oncol 2014;32(15):1547e53. Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van't Veer L, Garber JE, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N. Engl J Med 2002;346(21):1616e22. Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, et al. Salpingooophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA 2006;296(2):185e92. Kotsopoulos J, Huzarski T, Gronwald J, Singer CF, Moller P, Lynch HT, et al. Bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2017;109(1). Pierce LJ, Levin AM, Rebbeck TR, Ben-David MA, Friedman E, Solin LJ, et al. Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 2006;24(16):2437e43.

S. Bayraktar, B. Arun / The Breast 31 (2017) 224e232 [42] Metcalfe K, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, Olopade OI, et al. Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat.127(1):287e296. [43] Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Neuhausen SL, et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet 2000;356(9245):1876e81. [44] Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst 2009;101(2):80e7. [45] Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA.304(9):967e975. [46] Heemskerk-Gerritsen BAMHM, Jager A, et al. Is risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer beneficial with respect to distant disease free survival and overall survival? Eur J Cancer Suppl 2010;8(206). [47] Batista LI, Lu KH, Beahm EK, Arun BK, Bodurka DC, Meric-Bernstam F. Coordinated prophylactic surgical management for women with hereditary breast-ovarian cancer syndrome. BMC Cancer 2008;8:101. [48] Schmeler KM, Sun CC, Bodurka DC, White KG, Soliman PT, Uyei AR, et al. Prophylactic bilateral salpingo-oophorectomy compared with surveillance in women with BRCA mutations. Obstet Gynecol 2006;108(3 Pt 1):515e20. [49] Gronwald J, Tung N, Foulkes WD, Offit K, Gershoni R, Daly M, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer 2006;118(9):2281e4. [50] Robson M, Svahn T, McCormick B, Borgen P, Hudis CA, Norton L, et al. Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic-based series. Cancer 2005;103(1):44e51. [51] Malone KE, Begg CB, Haile RW, Borg A, Concannon P, Tellhed L, et al. Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol Off J Am Soc Clin Oncol.28(14):2404e2410. [52] Reding KW, Bernstein JL, Langholz BM, Bernstein L, Haile RW, Begg CB, et al. Adjuvant systemic therapy for breast cancer in BRCA1/BRCA2 mutation carriers in a population-based study of risk of contralateral breast cancer. Breast Cancer Res Treat.123(2):491e498. [53] Robson ME, Chappuis PO, Satagopan J, Wong N, Boyd J, Goffin JR, et al. A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res 2004;6(1):R8e17. [54] Phillips KA. Tamoxifen may reduce contralateral cancers in BRCA mutation carriers. ASCO Chicago, IL J Clin Oncol 25, September 2013;31:3091e9. [55] Wesolowski R SA, Tao J, Moore HC, editors. Differential outcomes in patients treated with endocrine therapy for early or locally advanced breast cancer based on BRCA mutation status ASCO 2009; 2009 [Chicago, IL]. [56] Metcalfe K, Gershman S, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J cancer 2011;104(9):1384e92. [57] Shafaee MN G-BA, Lin HY, Arun B. Aromatase inhibitors and the risk of contralateral breast cancer in BRCA mutation carriers. ASCO breast cancer symposium, A3 oral presentation. [58] of ACSGftED, http://www.cancer.org/healthy/findcancerearly/ cancerscreeningguidelines/CAf, american-cancer-society-guidelines-fortheearly-, detection-of-cancer. Accessed December 6. [59] Lee CH, Dershaw DD, Kopans D, Evans P, Monsees B, Monticciolo D, et al. Breast cancer screening with imaging: recommendations from the Society of Breast Imaging and the ACR on the use of mammography, breast MRI, breast ultrasound, and other technologies for the detection of clinically occult breast cancer. J Am Coll Radiology JACR 2010;7(1):18e27. [60] Le-Petross HT, Whitman GJ, Atchley DP, Yuan Y, Gutierrez-Barrera A, Hortobagyi GN, et al. Effectiveness of alternating mammography and magnetic resonance imaging for screening women with deleterious BRCA mutations at high risk of breast cancer. Cancer 2011;117(17):3900e7. [61] NCCN GFH-RABaO, Available CPGiOv, http://www.nccn.org/professionals/ physician_gls/pdf/f, genetics_screening.pdf. Accessed December 9. [62] Brentnall TA. Cancer surveillance of patients from familial pancreatic cancer kindreds. Med Clin N. Am 2000;84(3):707e18. [63] Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, et al. Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clin gastroenterology hepatology Off Clin Pract J Am Gastroenterological Assoc 2004;2(7):606e21. [64] Cancer: UPSTFSC, http://www.ahrq.gov/Accessed November 2, 2016. [65] Smith KR, Ellington L, Chan AY, Croyle RT, Botkin JR. Fertility intentions following testing for a BRCA1 gene mutation. Cancer Epidemiol biomarkers Prev Publ Am Assoc Cancer Res cosponsored by Am Soc Prev Oncol 2004;13(5):733e40. [66] Canada AL, Schover LR. The psychosocial impact of interrupted childbearing in long-term female cancer survivors. Psychooncology 2012;21(2):134e43. [67] Camp-Sorrell D. Cancer and its treatment effect on young breast cancer survivors. Semin Oncol Nurs 2009;25(4):251e8. [68] Speice J, McDaniel SH, Rowley PT, Loader S. Family issues in a psychoeducation group for women with a BRCA mutation. Clin Genet 2002;62(2): 121e7.

231

[69] Jernstrom H, Lerman C, Ghadirian P, Lynch HT, Weber B, Garber J, et al. Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 1999;354(9193):1846e50. [70] Tryggvadottir L, Olafsdottir EJ, Gudlaugsdottir S, Thorlacius S, Jonasson JG, Tulinius H, et al. BRCA2 mutation carriers, reproductive factors and breast cancer risk. Breast Cancer Res 2003;5(5):R121e8. [71] Narod SA. Modifiers of risk of hereditary breast cancer. Oncogene 2006;25(43):5832e6. [72] Rebbeck TR, Wang Y, Kantoff PW, Krithivas K, Neuhausen SL, Godwin AK, et al. Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history. Cancer Res 2001;61(14):5420e4. [73] Hartge P, Chatterjee N, Wacholder S, Brody LC, Tucker MA, Struewing JP. Breast cancer risk in Ashkenazi BRCA1/2 mutation carriers: effects of reproductive history. Epidemiology 2002;13(3):255e61. [74] Chang-Claude J, Becher H, Eby N, Bastert G, Wahrendorf J, Hamann U. Modifying effect of reproductive risk factors on the age at onset of breast cancer for German BRCA1 mutation carriers. J Cancer Res Clin Oncol 1997;123(5):272e9. [75] Andrieu N, Goldgar DE, Easton DF, Rookus M, Brohet R, Antoniou AC, et al. Pregnancies, breast-feeding, and breast cancer risk in the international BRCA1/2 carrier cohort study (IBCCS). J Natl Cancer Inst 2006;98(8):535e44. [76] Valentini A, Lubinski J, Byrski T, Ghadirian P, Moller P, Lynch HT, et al. The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation. Breast Cancer Res Treat 2013;142(1):177e85. [77] MJGdaD Milunsky A. prevention,and treatment. sixth ed. Hoboken, NJ: Wiley-Blackwell; 2010. [78] Offit K, Kohut K, Clagett B, Wadsworth EA, Lafaro KJ, Cummings S, et al. Cancer genetic testing and assisted reproduction. J Clin Oncol official J Am Soc Clin Oncol 2006;24(29):4775e82. [79] Rich TA, Liu M, Etzel CJ, Bannon SA, Mork ME, Ready K, et al. Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes. Fam cancer 2014;13(2):291e9. [80] Ormondroyd E, Donnelly L, Moynihan C, Savona C, Bancroft E, Evans DG, et al. Attitudes to reproductive genetic testing in women who had a positive BRCA test before having children: a qualitative analysis. Eur J Hum Genet 2012;20(1):4e10. [81] Ethics Committee of the American Society for Reproductive M. Fertility preservation and reproduction in cancer patients. Fertil Steril 2005;83(6): 1622e8. [82] Fang CY, Cherry C, Devarajan K, Li T, Malick J, Daly MB. A prospective study of quality of life among women undergoing risk-reducing salpingo-oophorectomy versus gynecologic screening for ovarian cancer. Gynecol Oncol 2009;112(3):594e600. [83] Parker WH. Bilateral oophorectomy versus ovarian conservation: effects on long-term women's health. J Minim Invasive Gynecol 2010;17(2):161e6. [84] Faubion SS, Kuhle CL, Shuster LT, Rocca WA. Long-term health consequences of premature or early menopause and considerations for management. Climacteric 2015;18(4):483e91. [85] Rocca WA, Grossardt BR, Miller VM, Shuster LT, Brown Jr RD. Premature menopause or early menopause and risk of ischemic stroke. Menopause 2012;19(3):272e7. [86] Shuster LT, Rhodes DJ, Gostout BS, Grossardt BR, Rocca WA. Premature menopause or early menopause: long-term health consequences. Maturitas 2010;65(2):161e6. [87] Eisen A, Lubinski J, Gronwald J, Moller P, Lynch HT, Klijn J, et al. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 2008;100(19):1361e7. [88] Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol Off J Am Soc Clin Oncol 2005;23(31):7804e10. [89] DSe al. Is hormone replacement therapy (HRT) following risk-reducing salpingo-oophorectomy (RRSO) in BRCA1 (B1)- and BRCA2 (B2)-mutation carriers associated with an increased risk of breast cancer?. The Abramson Cancer Center of the University of Pennsylvania; 2011. [90] Croyle RT, Smith KR, Botkin JR, Baty B, Nash J. Psychological responses to BRCA1 mutation testing: preliminary findings. Health Psychol 1997;16(1): 63e72. [91] Schwartz MD, Peshkin BN, Hughes C, Main D, Isaacs C, Lerman C. Impact of BRCA1/BRCA2 mutation testing on psychologic distress in a clinic-based sample. J Clin Oncol Off J Am Soc Clin Oncol 2002;20(2):514e20. [92] Cella D, Hughes C, Peterman A, Chang CH, Peshkin BN, Schwartz MD, et al. A brief assessment of concerns associated with genetic testing for cancer: the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire. Health Psychol 2002;21(6):564e72. [93] Botkin JR, Smith KR, Croyle RT, Baty BJ, Wylie JE, Dutson D, et al. Genetic testing for a BRCA1 mutation: prophylactic surgery and screening behavior in women 2 years post testing. Am J Med Genet A 2003;118A(3):201e9. [94] Halbert CH, Stopfer JE, McDonald J, Weathers B, Collier A, Troxel AB, et al. Long-term reactions to genetic testing for BRCA1 and BRCA2 mutations: does time heal women's concerns? J Clin Oncol official J Am Soc Clin Oncol 2011;29(32):4302e6. [95] Hamilton JG, Lobel M, Moyer A. Emotional distress following genetic testing for hereditary breast and ovarian cancer: a meta-analytic review. Health

232

S. Bayraktar, B. Arun / The Breast 31 (2017) 224e232

Psychol 2009;28(4):510e8. [96] Schwartz MD, Isaacs C, Graves KD, Poggi E, Peshkin BN, Gell C, et al. Longterm outcomes of BRCA1/BRCA2 testing: risk reduction and surveillance. Cancer 2012;118(2):510e7. [97] Scheuer L, Kauff N, Robson M, Kelly B, Barakat R, Satagopan J, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol Off J Am Soc Clin Oncol 2002;20(5):1260e8. [98] Foster C, Watson M, Eeles R, Eccles D, Ashley S, Davidson R, et al. Predictive genetic testing for BRCA1/2 in a UK clinical cohort: three-year follow-up. Br J cancer 2007;96(5):718e24. [99] Armstrong J, Toscano M, Kotchko N, Friedman S, Schwartz MD, Virgo KS, et al. Utilization and outcomes of BRCA genetic testing and counseling in a national commercially insured population: the about study. JAMA Oncol 2015;1(9):1251e60. [100] Schwartz MD, Lerman C, Brogan B, Peshkin BN, Halbert CH, DeMarco T, et al. Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients. J Clin Oncol Off J Am Soc Clin Oncol 2004;22(10):1823e9. [101] Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C, et al. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 2009;115(2):359e63. [102] Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol Off J Am Soc Clin Oncol.28(3):375e379. [103] Arun B, Bayraktar S, Liu DD, Gutierrez Barrera AM, Atchley D, Pusztai L, et al. Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol Off J Am Soc Clin Oncol.29(28):3739e3746. [104] Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, et al. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol Off J Am Soc Clin Oncol.28(7):1145e1153. [105] Wen J, Li R, Lu Y, Shupnik MA. Decreased BRCA1 confers tamoxifen resistance in breast cancer cells by altering estrogen receptor-coregulator interactions. Oncogene 2009;28(4):575e86. [106] Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl J Med 2009;361(2):123e34. [107] Byrski T, Huzarski T, Dent R, Marczyk E, Jasiowka M, Gronwald J, et al. Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 2014;147(2):401e5. [108] Byrski T, Dent R, Blecharz P, Foszczynska-Kloda M, Gronwald J, Huzarski T, et al. Results of a phase II open-label, non-randomized trial of cisplatin

[109]

[110]

[111]

[112]

[113]

[114]

[115]

[116]

[117] [118]

[119]

[120]

chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res 2012;14(4):R110. Kriege M, Jager A, Hooning MJ, Huijskens E, Blom J, van Deurzen CH, et al. The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer.118(4):899e907. weekly RogBsathrHdirtn, paclitaxel followed by anthracycline-based chemotherapy. Boughey JC et al. San Antonio Breast Cancer Symposium 2015 aPe. Tassone P, Tagliaferri P, Perricelli A, Blotta S, Quaresima B, Martelli ML, et al. BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J cancer 2003;88(8):1285e91. Chabalier C, Lamare C, Racca C, Privat M, Valette A, Larminat F. BRCA1 downregulation leads to premature inactivation of spindle checkpoint and confers paclitaxel resistance. Cell Cycle 2006;5(9):1001e7. Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet.376(9737):235e244. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-ofconcept trial. Lancet.376(9737):245e251.. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol Off J Am Soc Clin Oncol 2015;33(3):244e50. De Bono JS, et al. First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. In: ASCO annual meeting JCO; 2013. suppl; abstr 2580. Lee JM, Ledermann JA, Kohn EC. PARP Inhibitors for BRCA1/2 mutationassociated and BRCA-like malignancies. Ann Oncol 2014;25(1):32e40. Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, et al. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol Off J Am Soc Clin Oncol 2012;30(4):372e9. Friedlander M, Hancock KC, Rischin D, Messing MJ, Stringer CA, Matthys GM, et al. A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol 2010;119(1):32e7. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl J Med 2016 Oct 7 [Epub ahead of print].