19 mayo, 2013

Management of hereditary breast and ovarian cancer syndrome and patients with BRCA mutations

Ovarian and breast cancer patients in a pedigr...
Ovarian and breast cancer patients in a pedigree chart of a family (Photo credit: Wikipedia)
Via: Alfonso Casi en grupo https://www.facebook.com/groups/informacionmedica/
Salud Juntos  RIESGO FAMILIAR DEL CANCER DE MAMA, el primer paso es conocer, en mujeres con intensa historia familiar de cáncer de mama, su situación de portadora o no de la mutación BRCA.

Sólo alrededor del 5% al 10% de los cánceres de mama que se diagnostican son causados por mutaciones BRCA 1 y 2; la mayoría son causados por otros factores.
Ciertas características señalan a las mujeres que tienen mayor riesgo de ser portadoras de la mutación, como una menor edad en el momento del diagnóstico, una intensa historia familiar y ciertos grupos étnicos. En estos casos se recomienda un asesoramiento genético para las mutaciones BRCA 1 y 2.
Las portadoras de la mutación BRCA tienen un 80% a 90% riesgo de cáncer de mama durante su vida (estudio retrospectivo), así como un 40% a 50% riesgo de cáncer de ovario. (Riesgo prospectivo de 1/200 aproximadamente).
Las principales opciones para el riesgo de cáncer de mama son la vigilancia, el tratamiento médico preventivo con tamoxifeno u otros agentes quimioterapéuticos, o la doble mastectomía profiláctica - la forma más eficaz de prevención pero con importantes implicaciones.
Para información exhaustiva ->http://ow.ly/lbr4s
http://ow.ly/lbrck
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Management of hereditary breast and ovarian cancer syndrome and patients with BRCA mutations
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2013. | This topic last updated: Apr 10, 2013.
INTRODUCTION — Although a family history of breast and/or ovarian cancer is common in women diagnosed with breast or ovarian cancer, less than 10 percent of all breast cancers and less than 15 percent of ovarian cancers are associated with germline (inherited) genetic mutations [1-4]. The majority of hereditary breast and ovarian cancers are associated with mutations in two genes, breast cancer type 1 and 2 susceptibility genes (BRCA1 and BRCA2). Less commonly, breast cancer is due to other hereditary cancer syndromes, such as Li-Fraumeni and Cowden syndromes, which are related to mutations in the TP53 and PTEN genes, respectively. (See "PTEN hamartoma tumor syndrome, including Cowden syndrome" and "Li-Fraumeni syndrome".)
Hereditary breast and ovarian cancer (HBOC) syndrome (ie, due to germline mutations in the BRCA1 and BRCA2 genes) is characterized by an autosomal dominant pattern of inheritance, markedly increased susceptibility to breast and ovarian cancer, with an especially early onset of breast cancer, and an increased incidence of tumors of other organs, such as the fallopian tubes, prostate, male breast, and pancreas.
The management of patients with hereditary breast and ovarian cancer syndrome is reviewed here. Selection of appropriate candidates for genetic testing, the characteristics of hereditary breast and ovarian cancer syndromes and their associated cancer risks, and the genetic counseling process are discussed separately.
CANCER RISKS — The cancer risks are variable in patients with hereditary breast and ovarian cancer (HBOC) syndrome:
Risks to relatives — Children of a parent with a BRCA1 or BRCA2 mutation have a 50 percent risk of having inherited the mutation. It is important that adult relatives are informed about this risk and the associated cancer risks, and should be made aware of the options for genetic counseling, testing, and management, as necessary.
CANCER SCREENING AND PREVENTION GUIDELINES
Recommendations of expert groups — Screening and prevention guidelines from expert groups are based upon nonrandomized trials and observational data. The recommendations included below are derived from a number of studies and are in keeping with the recommendations from National Comprehensive Cancer Network (NCCN). These guidelines based on expert consensus (lower level evidence), are regularly updated, and provide the most comprehensive guidelines currently available.  
CANCER SURVEILLANCE — Patients with hereditary breast and ovarian cancer (HBOC) syndrome are counseled to initiate screening considerably earlier than average-risk patients due to the early age of diagnosis of several cancers [2]. While breast and ovarian (including fallopian tube and peritoneal) cancers present the greatest risk, individuals with HBOC syndrome may have elevated risks for other cancers, including prostate cancer and pancreatic cancer, as described above.
Patients with HBOC syndrome should be educated regarding signs and symptoms of breast and ovarian cancer. (See "Breast masses and other common breast problems" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis".)
Women — The following screening strategy is recommended by expert groups for women with HBOC syndrome who have not undergone risk-reducing surgery [2,5-7]:
  • Monthly breast self-examination beginning at age 18
  • Clinical breast examination two to four times annually beginning at age 25
  • Annual mammography and breast magnetic resonance imaging (MRI) screening (commonly alternated every six months [8]) beginning at age 25 or individualized based on the earliest age of onset in the family  
  • Twice yearly ovarian cancer screening with transvaginal ultrasound and serum CA-125 levels (preferably drawn on day 1 to 10 of menstrual cycle for premenopausal women) beginning at age 35, or 5 to 10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family.

    However, the lack of efficacy of ovarian cancer screening has prompted many clinicians to recommend risk-reducing bilateral salpingo-oophorectomy at the completion of childbearing rather than intensified screening for ovarian cancer. Specific issues surrounding screening for ovarian cancer in high-risk populations are discussed in detail elsewhere; risk-reducing salpingo-oophorectomy is also discussed below. (See "Screening for ovarian cancer", section on 'Risk factors' and 'Salpingo-oophorectomy' below.)
Men — The following screening strategy is recommended for men (with BRCA1 and BRCA2 mutations) [2,6]:
  • Monthly breast self-examination
  • Clinical breast examination semiannually
  • Baseline mammogram with annual mammogram if baseline study shows gynecomastia or parenchymal/glandular breast density
  • Appropriate prostate cancer screening
Additional cancer screening may be indicated for other cancers associated with HBOC syndrome. (See "Characteristics of hereditary breast and ovarian cancer syndromes", section on 'Other cancers'.)
Breast cancer screening in women
Mammography — The sensitivity of mammography for detecting breast cancer in mutation carriers appears to be lower than in other high-risk women [5,9-11]. The lower sensitivity of mammography in women with BRCA mutations may be due to:
  • Higher breast density [11].
  • Differences in morphologic features (eg, less spiculation due to lack of tumor-surrounding fibrosis) [10].
  • Many of the histopathologic findings seen in the breasts of women undergoing prophylactic mastectomy because of a strong family history of breast cancer (eg, atypical lobular or ductal hyperplasia, lobular carcinoma in situ) are not detectable mammographically [12,13].
  • The frequent development of interval malignancies. In one analysis of women with deleterious BRCA mutations, among 165 women with breast tissue who opted for breast cancer screening, 12 were diagnosed with breast cancer over a two-year period [5]. One-half of these were interval cancers not detected by annual mammography; most were detected by breast self examination.

    Because of the frequent development of interval malignancies, more frequent mammography (eg, every six months) is sometimes considered [5,14,15]. However, there are no known studies that compare semiannual versus annual screening and thus no data to develop evidence-based recommendations [16].
As will be discussed below, breast cancer detection rates are clearly increased in high risk women undergoing breast MRI as a component of breast cancer surveillance; furthermore, the addition of breast MRI to the surveillance strategy increases the number of patients diagnosed at an earlier stage of disease. Despite this, most guidelines recommend conventional annual mammography in addition to breast MRI for women with an inherited predisposition to breast cancer [5-7,17]. While some studies suggest no difference in cancer detection rates from the addition of mammography to MRI as compared to breast MRI alone [18], others report greater sensitivity for mammography in this setting, particularly for ductal carcinoma in situ (DCIS) [19,20], and meta-analysis concluded that combined use of mammography and MRI is associated with higher sensitivity for detection of breast cancer than MRI alone [21]. (See 'Breast MRI' below and "Breast ductal carcinoma in situ: Epidemiology, clinical manifestations, and diagnosis", section on 'Mammography'.)
Findings from the GENE-RAD-RISK retrospective cohort study suggest that any radiation exposure before the age of 30 was associated with an increased risk of breast cancer among carriers of a BRCA mutation [22]. The authors concluded that the study supported use of non-ionizing radiation imaging (such as MRI) in young women with BRCA1/BRCA2 mutations. Further data are needed, however, to determine whether such an approach is optimal. We advise that mutation carriers begin annual mammography (as well as MRI, each alternating every six months, see below) at age 25, as in the NCCN guidelines [6]. This recommendation may be modified based upon individual factors (eg, breast density). It remains unclear whether the age at initiation of screening should be altered based on a pattern of late-onset cancers within the family, or patient concerns about the risks associated with radiation exposure, or whether one could safely omit mammography in younger age women and screen only with MRI. (See "Screening for breast cancer", section on 'Radiation' and "Factors that modify breast cancer risk in women".)
Breast MRI — The addition of breast MRI to the breast cancer surveillance strategy in high-risk women, such as those with HBOC, increases breast cancer detection rates, increases the number of patients diagnosed at an earlier stage of disease, and is cost-effective (image 1) [20,23-26]. Therefore, it is recommended in guidelines from expert groups [2,5-7]. However, the mortality impact of including breast MRI in the surveillance strategy is not clear. Breast cancer detection rates are clearly increased when high-risk women undergo breast MRI as a component of breast cancer surveillance; furthermore, the addition of breast MRI to the surveillance strategy increases the number of patients diagnosed at an earlier stage of disease .
MRI has been found to be more sensitive but less specific than mammography for the detection of invasive cancers in high-risk women in both retrospective [10,27-29] and prospective [20,30-33] studies. A systematic review of 11 studies compared test performance of screening MRI to mammography in high-risk women [21]. The mean or median age of women in the studies ranged from 40 to 47 years. The women were at very high risk of breast cancer, with a prevalence of 2 percent (about 13 times the overall breast cancer prevalence of approximately 0.15 percent in women of similar age). The following results were found:
  • Sensitivity of MRI was significantly better than that of mammography: 0.77 (95% CI 0.70-0.84) versus 0.39 (CI 0.37-0.41).
  • Specificity of MRI was worse than that of mammography: 0.86 (CI 0.81-0.92) versus 0.95 (CI 0.93-0.97).
  • Sensitivity of MRI and mammography together was 0.94 (CI 0.90-0.97) and specificity was 0.77 (CI 0.75-0.80).
The impact of any surveillance strategy (including MRI) on breast cancer mortality has not been established. The only prospective study that addressed long-term survival was the Dutch MRI Screening Study, in which women with high-risk for breast cancer (>15 percent cumulative lifetime risk) were screened with annual mammography and MRI (and biannual clinical breast examination); those who developed breast cancer were followed for a median of five years after diagnosis. The cumulative distant-metastasis free and overall survival at six years in the 42 BRCA1/2 mutation carriers with invasive cancer was 83.9 percent (95% CI, 64.1-93.3) and 92.7 percent (95% CI, 79.0-97.6), respectively [20]. This is in contrast to a median overall survival of 74.5 percent (range 50 to 95 percent) for an historical cohort of 1081 BRCA1/2 mutation carriers. While these data are promising, they do not prove a mortality benefit from breast MRI.
BRCA1-associated breast cancers present differently from BRCA2 and other familial cases of breast cancer. This was shown in a later report of the entire cohort from this study (n=2157 women, ages 25 to 75) that further analyzed the effects of MRI and mammography screening according to subgroups of breast cancer risk: lifetime risks of 50 to 80 percent (BRCA1 mutations, BRCA2 mutations, and PTEN/TP53 mutations); 30 to 50 percent (based on family history); and 15 to 30 percent (based upon family history) [19].
  • Overall sensitivity was 71 percent for MRI, 41 percent for mammography and 21 percent for CBE. MRI was more sensitive than mammography for invasive cancers (77 versus 36 percent); mammography showed a trend toward greater sensitivity than MRI for DCIS (69 versus 39 percent) although this difference was not statistically significant.
  • Overall specificity was 90 percent for MRI, 95 percent for mammography and 98 percent for CBE.
  • The positive predictive value of mammography was higher among BRCA2 mutation carriers than among BRCA1 mutation carriers. Positive predictive value for MRI varied, but not significantly, by subgroup.
  • As expected, breast cancer detection rates were much higher among mutation carriers than in women at increased risk because of family history (26.3 and 39.2 versus 5.6 and 6.9 per 1000 woman-years at risk). Breast cancer was diagnosed at younger ages in mutation carriers; 58 percent of BRCA1 and 50 percent of BRCA2 mutation carriers were diagnosed before age 40.
  • Breast cancers diagnosed among BRCA1 mutation carriers were significantly more likely to be larger, have higher histologic grade and have negative estrogen and progesterone receptor status. DCIS accounted for only 6.5 percent of breast cancers in BRCA1 carriers compared to 18.8 percent in BRCA2 carriers, 14.8 percent in women with 30 to 50 percent risk, and 31.3 percent in women with 15 to 30 percent risk, although the differences were not significant.
The results of the Dutch MRI study support MRI screening for women at highest risk for breast cancer, although numbers are small and conclusions are subject to multiple biases (patient selection, lead time bias, treatment differences) affecting observational studies in the absence of randomized trials. The study results also suggest that BRCA1 mutation carriers are at greater risk of developing cancers with poorer prognosis than BRCA2 mutation carriers and other women at increased risk.    
Ovarian cancer screening in women — Periodic screening of women with HBOC who have not undergone prophylactic oophorectomy, using a combination of the serum tumor marker CA 125 and transvaginal ultrasound, is recommended in guidelines from expert groups. While there are no high quality data on which to base recommendations regarding timing of screening, some have suggested initiation at age 35 years or five to ten years earlier than the earliest age of first diagnosis of ovarian cancer in the family. The evidence and recommendations for ovarian cancer screening in women with HBOC are discussed in detail separately. (See "Screening for ovarian cancer", section on 'High-risk family history'.)
RISK-REDUCING SURGERY — In patients with HBOC syndrome, prophylactic mastectomy reduces the risk of developing breast cancer, while risk-reducing salpingo-oophorectomy reduces the risk of both ovarian cancer and breast cancer (the latter when performed premenopausally).
While prophylactic surgery is effective in cancer risk-reduction, patients should be counselled preoperatively about the morbidity of such procedures, their impact on libido and sexual functioning, body image, and bone and cardiac health, and issues regarding surgical menopause and hormone therapy. They should also be aware that risk-reducing surgery is not 100 percent effective, given the remote possibility that not all at-risk tissue is removed.
Mastectomy — In both retrospective and prospective studies, risk-reducing or prophylactic bilateral mastectomy has been shown to decrease the incidence of breast cancer by as much as 90 percent or more in patients at risk of hereditary breast cancer and in BRCA 1 and BRCA 2 mutation carriers [14,34-39].
  • In one large prospective cohort study of women with BRCA1 or BRCA2 mutations, there were no breast cancer diagnoses during three years of follow-up among women who chose to undergo risk-reducing mastectomy (247 women) [39]. In contrast, 7 percent of 1372 women without risk-reducing mastectomy were diagnosed with breast cancer.
  • In a retrospective study with longer follow-up (median 13.4 years), the calculated risk reduction in BRCA1 and BRCA2 mutation carriers after bilateral prophylactic mastectomy (n = 26 women) was 89.5 to 100 percent (95% CI 41.4-100).
A bilateral total mastectomy is often recommended for prophylaxis because subcutaneous mastectomy leaves behind more glandular tissue that remains at risk for future cancers [34,40]. However, skin-sparing mastectomy with or without preservation of the nipple-areolar complex provides superior cosmetic results and while data are limited, appears to have no increased risk of local recurrence [40-42]. Most women are candidates for immediate breast reconstruction. (See "Mastectomy", section on 'Skin-sparing mastectomy'.)
For patients who develop BRCA-linked ovarian cancer, the predominant cause of mortality at five years is ovarian cancer. Therefore, we suggest that breast cancer screening and risk reduction surgical decisions be made in the context of the ovarian cancer. In a retrospective review of 164 patients with BRCA-linked ovarian cancer, metachronous breast cancer occurred in 18 women (median time to diagnosis 108 months, range 13 to 241), with no deaths reported from breast cancer with a median 5.8 year follow up [43]. The 5-year and 10-year breast-cancer-free survival rates for BRCA carriers was 97 and 91 percent, respectively, while the 5-year and 10-year overall survival rates were 85 percent and 68 percent, respectively. At 10 years of follow up for BRCA-ovarian cancer survivors, the risk of developing breast cancer is less than 10 percent.
Contralateral mastectomy in BRCA1 and BRCA2 mutation carriers who have been diagnosed with breast cancer are discussed separately. (See 'Treatment and prognosis of women who develop breast cancer' below.)
Salpingo-oophorectomy — Bilateral risk-reducing salpingo-oophorectomy is recommended for BRCA1 and BRCA2 mutation carriers by age 35 to 40 or when childbearing is completed, or individualized based on age of onset of ovarian cancer in the family [5,6,44-47]. Bilateral salpingo-oophorectomy decreases the risk of both breast cancer and ovarian cancer in BRCA1 and BRCA2 mutation carriers; however, estimates for risk and mortality reduction differ according to baseline cancer risks among BRCA1 and BRCA2 mutation carriers [39,44,45]. Risk-reducing salpingo-oophorectomy has also been associated with reduced all-cause, breast cancer-specific, and ovarian cancer-specific mortality. (See 'Treatment and prognosis of women who develop breast cancer' below and "Risk-reducing bilateral salpingo-oophorectomy in women at high risk of epithelial ovarian and fallopian tubal cancer".)
CHEMOPREVENTION — Chemopreventive strategies to reduce the risk of breast cancer have focused exclusively on prevention in high-risk women and involve the use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors for breast cancer prevention, while oral contraceptives have been used for chemoprevention of hereditary ovarian cancer.
Breast cancer chemoprevention — Chemoprevention using tamoxifen for five years reduces the incidence of breast cancer by approximately 50 percent in women with a moderately increased risk for breast cancer (defined as women over the age of 60 or over age 35 who have a history of lobular carcinoma in situ and those with a five-year estimated risk for breast cancer of at least 1.66 percent as determined by the Gail model, but who do not have HBOC syndrome), a benefit that continues for 5 to 10 years after drug discontinuation. Raloxifene is slightly less effective than tamoxifen in reducing breast cancer risk, but is associated with fewer serious side effects. Neither drug has shown a reduction in breast cancer mortality or all-cause mortality. In addition, these benefits only appear to pertain to a reduction in hormone-sensitive breast cancer. Most recently, benefit has also been shown for primary prevention with the aromatase inhibitor exemestane. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)
There are no data addressing the preventive benefit of raloxifene or an aromatase inhibitor in patients with BRCA mutations. Only limited data are available regarding the preventive benefit of tamoxifen in BRCA1 and BRCA2 mutation carriers. Evidence for the benefit of tamoxifen in women who have never had a diagnosis of breast cancer comes from a subset analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention trial (P-1 trial). Tamoxifen reduced breast cancer risk by 62 percent in BRCA2 carriers (RR 0.38, 95% CI 0.06 to 1.56), but not in BRCA1 carriers (RR 1.67, 95% CI 0.32 to 10.07) [48]. However this analysis is limited by the small number of mutation carriers (of the 288 women in the study who developed breast cancer, only 8 had BRCA1 mutations and 11 had BRCA2 mutations) [49].

A differential effect of tamoxifen in BRCA2 as compared to BRCA1 mutation carriers may be attributed to estrogen receptor (ER) status of BRCA1- and BRCA2-associated tumors. Tamoxifen might be expected to have an impact only against ER-positive tumors, and BRCA2-associated tumors have a greater likelihood than BRCA1-associated tumors of being ER-positive. However, in other settings, tamoxifen has shown benefit for both BRCA1- and BRCA2-associated tumors, irrespective of ER-status [50-52].
Women who do not opt for risk-reducing surgery may consider surveillance and prevention with tamoxifen, though this is a less effective alternative to prophylactic mastectomy. As discussed below, tamoxifen has been shown to decrease the risk of contralateral breast cancer in patients with BRCA-associated breast cancer. (See 'Treatment and prognosis of women who develop breast cancer' below.)
Oral contraceptives for prevention of ovarian cancer — Oral contraceptive use in BRCA1 and BRCA2 mutation carriers appears to decrease the risk of ovarian cancer.
A meta-analysis of 18 studies, which were either case-control or retrospective cohort studies, of oral contraceptive use in BRCA1 and BRCA2 mutation carriers included 2855 breast cancer cases and 1503 ovarian cancer cases [53]. Use of oral contraceptives in BRCA1 and BRCA2 mutation carriers was associated with a significantly reduced risk of ovarian cancer [summary relative risk (SRR), 0.50, 95% CI 0.33–0.75]. For each additional 10 years of oral contraceptive use, there was a significantly reduced ovarian cancer risk (SRR 0.64, 95% CI 0.53–0.78).
There is concern that oral contraceptives may increase the risk of breast cancer in mutation carriers. In the meta-analysis described above, there was no evidence of a significantly increased breast cancer risk in oral contraceptive users overall, for recent formulation of oral contraceptives, and in the first 10 years after cessation [53]. Specifically,
  • Overall, for BRCA1 and BRCA2 mutation carriers, breast cancer risk was not significantly increased by oral contraceptive use (SRR 1.13, 95% CI 0.88–1.45).
  • Compared to never users, BRCA1/2 carriers who stopped oral contraceptives at least 10 years before diagnosis had a significantly increased risk of breast cancer (SRR 1.46, 95% CI 1.07–2.07), but no significant association was observed for women who stopped oral contraceptive use within 10 years of breast cancer diagnosis.
  • Oral contraceptive formulations used before 1975 were associated with a significantly increased risk of breast cancer (SRR 1.47, 95% CI 1.06-2.04), but no evidence of a significant association was found with use of more recent formulations (SRR 1.17, 95% CI 0.74-1.86).
Use of oral contraceptives in BRCA1 and BRCA2 mutation carriers remains a controversial issue. Mutation carriers who have used oral contraceptives are still recommended to undergo risk-reducing salpingo-oophorectomy when childbearing is completed. Thus, each woman must carefully weigh the reasons for oral contraceptive use and their potential pros and cons with her physician.  
Options for men — Men who harbor a BRCA mutation are at an increased risk for multiple cancers, including breast and prostate cancers, compared to men who do not [54]. However, the overall incidence of breast cancer in men is low and it is not likely that men with a BRCA mutation would have a high enough risk to warrant anything other than cancer surveillance. The main risk for men who harbor a BRCA mutation appears to be for prostate cancer, but there is no evidence to support the use of chemoprevention to reduce this risk. Therefore, the primary recommendation for men with a BRCA mutation is for cancer surveillance, not chemoprevention. (See 'Men' above and "Chemoprevention strategies in prostate cancer".)
CLINICAL DECISION MAKING — Clinical decisions about which strategies to pursue for cancer risk-reduction (ie, surveillance, risk-reducing surgery, and/or chemoprevention) are difficult dilemmas that may involve a trade-off between life expectancy and quality of life. Several tools (decision aids or models) are available to help with decision making [25,26,55-57]. Most use decision analysis and the concept of time tradeoffs, ie, years of life saved by one strategy as compared to another. As an example;
  • Calculations from one model suggested that an average 30 year old woman with a BRCA1 or BRCA2 mutation would gain from 3 to 5 years of life expectancy from prophylactic mastectomy and from 0.3 to 2 years of life expectancy from risk-reducing oophorectomy, depending on her cumulative risk of cancer. In contrast, gains in life expectancy declined with age at the time of risk-reducing surgery and were minimal for 60-year-old women [55].
  • Calculations from a different model that compared risk-reducing surgery to surveillance suggested that prophylactic mastectomy at age 25 plus risk-reducing oophorectomy at age 40 years maximized survival probability. However, substituting mammography plus magnetic resonance imaging screening for prophylactic mastectomy seemed to offer comparable survival [26].
Weighing the pros and cons of alternative strategies with a clinical genetics counselor is often easier for patients to conceptualize than the concept of time tradeoffs, and takes individual patient preferences into account.
REPRODUCTIVE COUNSELING — Mutations in breast cancer genes (BRCA1 and BRCA2) are inherited in an autosomal dominant pattern, meaning that there is a 50 percent chance that children of BRCA1/2 carriers will have inherited the cancer-predisposition mutation. Reproductive counseling of BRCA1 and BRCA2 mutation carriers includes education about prenatal diagnosis and assisted reproduction. One option is preimplantation genetic diagnosis, which is used to analyze embryos (obtained by in vitro fertilization) genetically before their transfer into the uterus [2,58].
In addition, patients with a BRCA2 mutation who plan to have children with a partner who is also at increased risk of carrying a BRCA2 mutation (eg, owing to family cancer history or to the increased background frequency in individuals of Ashkenazi Jewish descent) are at risk for a rare, recessive syndrome which is characterized by the co-occurrence of brain tumors, Fanconi anemia, and breast cancer [59]. This syndrome occurs in individuals who have two copies of a BRCA2 mutation.
TREATMENT AND PROGNOSIS OF WOMEN WHO DEVELOP BREAST CANCER — Women from high-risk families who are diagnosed with breast cancer may wish to undergo BRCA1/2 testing prior to making treatment decisions, especially definitive surgical decisions [60]. As BRCA1 and BRCA2 mutation carriers have an increased risk of ipsilateral and contralateral breast cancer, women who test positive may choose to undergo bilateral mastectomy, even if they are candidates for breast conservation therapy (BCT) [61].
BCT appears to be as effective a local treatment option in mutation carriers as in women with sporadic breast cancer [61-64].  There is no evidence to suggest that patients with BRCA-related breast cancers are more radiosensitive or susceptible radiation-associated complications. (See "Breast conserving therapy", section on 'Inherited susceptibility' and "Role of radiation therapy in breast conservation therapy".)
However, over the long-term, mutation carriers appear to have higher risks of a new primary in their ipsilateral breast as well as an increased risk of contralateral breast cancer (five-year contralateral breast cancer rates of 10 to 20 percent versus 1 to 3 percent in those with sporadic breast cancer) [61]. The risk of contralateral breast cancer is dependent on age at diagnosis of the initial breast cancer, with higher absolute long-term risks noted in those initially diagnosed at a younger age [65,66].
Approaches for minimizing this risk include ipsilateral mastectomy and contralateral prophylactic mastectomy, prevention with a selective estrogen receptor modulator (SERM), and prophylactic bilateral oophorectomy in premenopausal patients.
  • Contralateral prophylactic mastectomy is an effective and popular option for reducing the risk of contralateral breast cancer recurrence, and evidence suggests that it may improve disease-free and overall survival [61,67-71].
  • Tamoxifen reduces the risk of contralateral breast cancers in patients with breast cancer and either BRCA1 or BRCA2 mutations [50,52,72,73]. As an example, the benefit of tamoxifen in BRCA mutation carriers was evaluated in a case control study of 1036 women BRCA mutation carriers with breast cancer, 285 of whom developed a second (bilateral) breast cancer and 751 who did not [52]. The history of tamoxifen use for treating the first breast cancer was compared between bilateral and unilateral cases. The odds ratio [OR] for contralateral breast cancer associated with tamoxifen use was 0.47 (95% CI 0.30-0.74) overall, and the effect was similar for carriers of BRCA1 mutations (OR 0.50, 95% CI 0.30-0.85) and BRCA2 mutations (OR 0.42, 0.17-1.02).

    The main benefit of tamoxifen is in reducing hormone receptor-positive breast cancer. Whether tamoxifen is effective in reducing recurrence in BRCA1/2 carriers with hormone receptor-negative breast cancers is unclear. Furthermore, its additive value in those carriers undergoing risk-reducing salpingo-oophorectomy is not well established [74]. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Tamoxifen'.)
  • Although bilateral salpingo-oophorectomy decreases the risk of breast cancer (as well as ovarian cancer) in BRCA1 and BRCA2 mutation carriers with and without a prior history of breast cancer, it is not clear that oophorectomy reduces the risk of breast cancer mortality in BRCA1 and BRCA2 mutation carriers with a diagnosis of breast cancer [39,72,73].
For BRCA1 and BRCA2 mutation carriers with breast cancer who do not opt for contralateral mastectomy, surveillance with clinical breast examination, mammography, and MRI are recommended, as outlined above. (See 'Cancer surveillance' above.)
BRCA-associated breast cancers occur in younger women than sporadic breast cancer [19,75]. Compared with BRCA2 and sporadic breast cancer, BRCA1-associated breast cancers are often associated with histopathologic features suggestive of a poor prognosis; they are often poorly differentiated, high grade with high proliferative rate, and with absent expression of estrogen and progesterone receptors, as well as human epidermal growth factor receptor 2 (HER2) [19,75-81]. However, it is not clear that the prognosis of BRCA-associated breast cancers is worse when adjusted for these adverse factors [78,80-87]. In addition, there is limited data regarding the effect of subsequent pregnancy or lactation on BRCA-associated breast cancer prognosis [88].
With regard to decisions about adjuvant chemotherapy, current data regarding the impact of BRCA1/2 status on breast cancer related prognosis are inconclusive, and thus mutation status generally does not factor into the decision making process regarding the type of systemic therapy. However, there is accumulating evidence of altered sensitivity of systemic agents in BRCA-related breast cancer, especially the increased sensitivity of platinums and poly ADP-ribose polymerase (PARP) inhibitors, and decreased sensitivity of taxanes [89]. For BRCA1 and BRCA2 carriers, there is some evidence that the use of chemotherapy, even for small tumors, may significantly improve outcome [80]. (See "Epidemiology, risk factors and the clinical approach to ER/PR negative, HER2-negative (Triple-negative) breast cancer", section on 'PARP inhibitors'.)
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SUMMARY AND RECOMMENDATIONS — Women with hereditary breast and ovarian cancers (HBOC) syndrome have inherited mutations in breast cancer type 1 and 2 susceptibility genes (BRCA1 and BRCA2) and markedly elevated risks of breast cancer and ovarian cancer. Men with HBOC syndrome have increased risk for breast and prostate cancer, while both men and women with HBOC syndrome have other cancer risks, such as increased risk of pancreatic cancer.
Effective strategies for breast and ovarian cancer risk-reduction include cancer surveillance, risk-reducing surgery, and/or chemoprevention.
  • For women who have not undergone risk-reducing surgery, breast and/or ovarian cancer surveillance entails (see 'Cancer surveillance' above):
  • Monthly breast self-examination beginning at age 18
  • Clinical breast examination two to four times annually beginning at age 25
  • Annual mammography and breast magnetic resonance imaging (MRI) screening (commonly alternated every six months) beginning at age 25 or individualized based on the earliest age of onset in the family
  • Twice yearly ovarian cancer screening with transvaginal ultrasound and serum CA-125 levels (preferably day 1 to 10 of menstrual cycle for premenopausal women) beginning age 35, or 5 to 10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family
  • Risk-reducing mastectomy is a highly effective strategy for breast cancer risk reduction, decreasing the incidence of breast cancer by as much as 90 percent or more in patients at risk of hereditary breast cancer. It should be considered by women with a BRCA1 or BRCA2 mutation. For women diagnosed with BRCA-ovarian cancer first, we prefer not performing risk-reducing mastectomies until at least five years after the ovarian cancer diagnosis, as survival is dominated by the mortality rate of ovarian cancer. (See 'Mastectomy' above.)
  • Risk-reducing salpingo-oophorectomy is highly effective in reducing ovarian and fallopian tube cancers in both BRCA1 and BRCA2 mutation carriers (by approximately 80 percent) and breast cancer in premenopausal women. This surgery is recommended to mutation carriers by age 35 to 40 or when childbearing is completed, or individualized based on age of onset of ovarian cancer in the family. (See 'Salpingo-oophorectomy' above.)
  • Women who do not opt for risk-reducing surgery may consider surveillance and chemoprevention with tamoxifen, though this is a less effective alternative to prophylactic mastectomy. (See 'Breast cancer chemoprevention' above.)
  • Oral contraceptive use in BRCA1 and BRCA2 mutation carriers appears to decrease the risk of ovarian cancer, but mutation carriers who have used oral contraceptives are still recommended to undergo risk-reducing salpingo-oophorectomy when childbearing is completed. (See 'Oral contraceptives for prevention of ovarian cancer' above.)
There is no single management strategy in reducing the risk of breast and ovarian cancer for all women with HBOC syndrome. The decision is individualized, and is highly dependent upon the patient's own set of values, and these values may change over the course of time (for example, pre- and post-childbearing). The clinician's job is to make the information about each option clear and to support the patient in the decision-making process.
  • For men with HBOC syndrome (with BRCA1 and BRCA2 mutations), cancer surveillance includes (see 'Cancer surveillance' above):
  • Monthly breast self-examination
  • Clinical breast examination semiannually
  • Baseline mammogram with annual mammography if gynecomastia or parenchymal/glandular breast density is seen at baseline
  • Appropriate prostate cancer screening
  • Individuals with BRCA1 or BRCA2 mutations should also have annual full body skin examinations.
  • Patients from high-risk families who are diagnosed with breast cancer may wish to undergo BRCA1/2 testing prior to making treatment decisions, in particular, consideration of an increased risk of ipsilateral and contralateral breast cancer with BRCA-related breast cancer may prompt patients to consider bilateral mastectomy. (See 'Treatment and prognosis of women who develop breast cancer' above.)
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