Cancer In BRCA1 Mutation Carriers Research Articles

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.

Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Oral contraceptives and risk of ovarian and breast cancers in BRCA mutation carriers: a meta-analysis

Prophylactic salpingo-oophorectomy is currently the only effective strategy available for decreasing ovarian cancer risk in BRCA1/2 mutation carriers. Significantly decreased risk of ovarian cancer associated with the use of combined oral contraceptives (COCs) was shown in the general population, which could be an alternative approach for those who do not accept risk-reducing surgery. Cohort, case–control and case–case studies published in English up to December 2009 reporting the association of ovarian or breast cancer risk with the use of COCs and presenting BRCA status were selected for meta-analysis. Meta-analysis of three case–control studies showed a significant risk reduction of ovarian cancer in BRCA1/2 mutation carriers who were associated with any past COC use (odds ratio [OR]: 0.57; 95% CI: 0.47–0.70; p < 0.001) and significant trend by duration of COC use (OR: 0.95; 95% CI: 0.93–0.97; p < 0.001). No significant increase in breast cancer risk associated with COC use has been found in case–control studies in BRCA1 (OR: 1.08; p = 0.250), in BRCA2 (OR: 1.03; p = 0.788) mutation carriers or in case–case studies in BRCA1/2 carriers (OR: 0.80; p = 0.147). Significantly increased risk of breast cancer was only shown on a subset of cohort studies in BRCA1 mutation carriers (OR: 1.48; 95% CI: 1.14–1.92). In conclusion, meta-analysis confirmed significantly decreased ovarian cancer risk in BRCA1/2 mutation carriers associated with the use of COCs comparable to the relative extent shown in the general population. Data on the risk of breast cancer associated with COC use in BRCA mutation carriers are heterogeneous and results are inconsistent. COCs can be considered as an alternative strategy in the chemoprevention of ovarian cancer in BRCA1 mutation carriers who do not accept prophylactic salpingo-oophorectomy above the age of 30 years.

Identification of abrogated pathways in fallopian tube epithelium from BRCA1 mutation carriers

The discovery of occult invasive and intra-epithelial tubal carcinomas in BRCA1 mutation carriers undergoing prophylactic surgery has implicated the fallopian tube epithelium as the source of serous cancer. However, little is known of the early molecular events of serous oncogenesis, or why cancers in BRCA1 mutation carriers are found preferentially in tissues which are responsive to reproductive hormones. We hypothesize that molecular alterations present in morphologically normal tubal epithelium from BRCA1 heterozygotes reflect the earliest events in serous carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. Genetic profiling of microdissected tubal epithelium from histologically normal BRCA1 mutation carriers and controls was performed. We sought to define a signature which differentiated BRCA1 mutant tubal epithelium from women with low risk of developing ovarian cancer. Molecular differences between the follicular and luteal phases were prominent and, by using filtering techniques and a two-way ANOVA without a False Discovery Rate correction, we identified 440 probe sets with a more than two-fold change in gene expression related to BRCA1 mutation status. Using gene ontology and known associations to cancer pathways, we selected five genes for further analysis by qPCR and immunohistochemistry, and were able to demonstrate statistically significant differentiation of BRCA1 and control cases in an independent set of cases. The altered expression profiles in histologically normal tubal epithelium from BRCA1 heterozygotes suggest that these cells may respond differently to microenvironmental stresses.

Risk of Ipsilateral and Contralateral Cancer in BRCA Mutation Carriers with Breast Cancer

BRCA1 and BRCA2 mutation carriers with breast cancer have a high risk of ipsilateral breast cancer tumor recurrence (IBTR) and a high lifetime risk of contralateral breast cancer (CBC). The IBTR risk is significantly higher in women who elect breast conservation. Oophorectomy has a protective effect for both ipsilateral breast tumor recurrence and CBC. Patients with younger age of breast cancer onset have a significantly greater risk of CBC. Given the higher risk of IBTR and CBC, when indicated, patients with breast cancer should undergo genetic counseling early in their treatment course to assist them in their surgical decision-making. Knowledge of expected outcomes for BRCA1/2 mutation carriers following breast cancer treatment can help appropriately council patients and personalize cancer therapy.

Decreased expression of BRCA1 in SK-BR-3 cells is the result of aberrant activation of the GABP Beta promoter by an NRF-1-containing complex

BackgroundBRCA1 has recently been identified as a potential regulator of mammary stem/progenitor cell differentiation, and this function may explain the high prevalence of breast cancer in BRCA1 mutation carriers, as well as the downregulation of BRCA1 in a large proportion of sporadic breast cancers. That is, loss of BRCA1 function results in blocked differentiation with expansion of the mammary stem/progenitor cells. Because BRCA1 also maintains genomic integrity, its loss could produce a pool of genetically unstable stem/progenitor cells that are prime targets for further transforming events. Thus, elucidating the regulatory mechanisms of BRCA1 expression is important to our understanding of normal and malignant breast differentiation.ResultsLoss of BRCA1 expression in the ErbB2-amplified SK-BR-3 cell line was found to be the result of loss of activity of the ets transcription factor GABP, a previously characterized regulator of BRCA1 transcription. The expression of the non-DNA binding GABPβ subunit was shown to be deficient, while the DNA binding subunit, GABPα was rendered unstable by the absence of GABPβ. Deletion analysis of the GABPβ proximal promoter identified a potential NRF-1 binding site as being critical for expression. Supershift analysis, the binding of recombinant protein and chromatin immunoprecipitation confirmed the role of NRF-1 in regulating the expression of GABPβ. The siRNA knockdown of NRF-1 resulted in decreased GABPβ and BRCA1 expression in MCF-7 cells indicating that they form a transcriptional network. NRF-1 levels and activity did not differ between SK-BR-3 and MCF-7 cells, however the NRF-1 containing complex on the GABPβ promoter differed between the two lines and appears to be the result of altered coactivator binding.ConclusionsBoth NRF-1 and GABP have been linked to the regulation of nuclear-encoded mitochondrial proteins, and the results of this study suggest their expression is coordinated by NRF-1's activation of the GABPβ promoter. Their linkage to BRCA1, a potential breast stem cell regulator, implies a connection between the induction of mitochondrial metabolism and breast differentiation.

Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.

IntroductionCurrent attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.MethodsWe successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers.ResultsSNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r2 = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, Ptrend = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, Ptrend = 0.018).ConclusionsThis study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.

Managing BRCA Mutation Carriers in China: Reply

The reply from Kalogerakos [1] to our article has highlighted the importance of the need to understand the risk conferred by BRCA mutation carriers in Chinese and other ethnic groups in order to achieve personalized medicine. Guidelines for prophylactic interventions and intensive surveillance are based on studies performed mainly in Caucasian cohorts. BRCA1 and BRCA2 mutation carriers have a 4.5-fold and 3.4-fold increased risk of getting contralateral breast cancer. The relative risk of contralateral breast cancer in BRCA1 mutation carriers increases as the age at first diagnosis decreases, and can be as high as 11-fold if the age at first diagnosis of breast cancer is under 35 [2]. Occult invasive cancers found in prophylactic mastectomy specimens ranges from 0.7 to 10.7%. Prophylactic mastectomy is found to be effective in preventing invasive breast cancer in BRCA mutation carriers as the remaining risk is less than 0.2% per woman-year [3]. Similarly, salpingo-oophorectomy significantly reduces the risk of breast cancer (hazard ratio [HR] = 0.36-0.63) and ovarian or fallopian tube cancer (HR = 0.14-0.28) in BRCA mutation carriers. There is also reduction in breast cancer (HR = 0.44) and ovarian cancer-specific mortality (HR = 0.21) [4]. However, there is limited information on BRCA2 mutation carriers since it is less common in Caucasian cohorts. Because of a lower incidence of breast cancer in Chinese (1 in 20) and also a higher BRCA2 detection rate found in our study, risk in this group is likely to be different. Therefore, it is important to have more precise ethnicity-specific estimates of specific risks so that more accurate guidelines based on the efficacy of risk-reducing interventions, surveillance, and use of novel drugs such PARP inhibitors can be made. Next-generation sequencing technology (also known as massive parallel sequencing) allows the development of studies unachievable a few years ago. Nowadays, next-generation sequencing technology provides an unprecedented ability to search for mutations, copy number aberrations, and somatic rearrangements in an entire cancer genome at base pair resolution which can be performed in a matter of weeks. By comparing BRCA mutations carriers who do not develop cancer with those who do, it may be possible to identify novel genetics changes associated with development of BRCA-related breast/ovarian and related cancers. As sequencing capacity improves, scientists will move forward from one genome per individual to multiple genomes per individual from sources including precancerous cells and cancer cells. Furthermore, recent genome-wide association studies using high-throughput human SNP arrays also identified new breast cancer susceptibility genes which can increase cancer risk prediction [5, 6]. As the complexity of assessing cancer risk genetically increases in technology and knowledge of ethnic differences, clinical recommendations will need to be standardized and personalized accordingly.

BRCA1 Basal-like Breast Cancers Originate from Luminal Epithelial Progenitors and Not from Basal Stem Cells

Breast cancers in BRCA1 mutation carriers frequently have a distinctive basal-like phenotype. It has been suggested that this results from an origin in basal breast epithelial stem cells. Here, we demonstrate that deleting Brca1 in mouse mammary epithelial luminal progenitors produces tumors that phenocopy human BRCA1 breast cancers. They also resemble the majority of sporadic basal-like breast tumors. However, directing Brca1 deficiency to basal cells generates tumors that express molecular markers of basal breast cancers but do not histologically resemble either human BRCA1 or the majority of sporadic basal-like breast tumors. These findings support a derivation of the majority of human BRCA1-associated and sporadic basal-like tumors from luminal progenitors rather than from basal stem cells. They also demonstrate that when target cells for transformation have the potential for phenotypic plasticity, tumor phenotypes may not directly reflect histogenesis. This has important implications for cancer prevention strategies.

The Effects of Parity, Breastfeeding, and Infertility Treatment on the Risk of Hereditary Breast and Ovarian Cancer: A Review

Knowledge of the potential association of parity, breastfeeding, and infertility treatment on breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers is important and should be a crucial part of genetic counseling. The discussion of parity and clinical management of infertility in these women is complex, and patient preferences should be considered. Ideally, these preferences should be informed by accurate information on the risks and benefits of the interventions considered. However, this important subject has been investigated in a relatively small number of studies, thus, the existing data remain somewhat limited, and the estimated risk of cancer in BRCA mutation carriers is imprecise.

Association between mitogen-activated protein kinase kinase kinase 1 rs889312 polymorphism and breast cancer risk: evidence from 59,977 subjects

Published data on the association between mitogen-activated protein kinase kinase kinase 1 (MAP3K1) gene rs889312 polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between them. A total of seven eligible articles including 26,015 cases and 33,962 controls based on the search criteria were involved in this meta-analysis. We observed that the MAP3K1 rs889312 polymorphism was significantly correlated with breast cancer risk from the fixed effects model when all studies were pooled into the meta-analysis (the allele contrast model: OR 1.09, 95% CI 1.07-1.12; the homozygote codominant: OR 1.22, 95% CI 1.15-1.29; the heterozygote codominant: OR 1.07, 95% CI 1.04-1.11; the dominant model: OR 1.10, 95% CI 1.06-1.13; the recessive model: OR 1.18, 95% CI 1.12-1.25). No significant association was found in the BRCA1 mutation carriers in all genetic models. When stratified by BRCA2 mutation carriers status, statistically significantly elevated risk was found in this meta-analysis (C vs. A: OR 1.12, 95% CI 1.01-1.23; CC vs. AA: OR 1.35, 95% CI 1.06-1.71; the recessive model: OR 1.31, 95% CI 1.05-1.65). There was no evidence for significant association between MAP3K1 rs889312 polymorphism and breast cancer risk in BRCA1 and BRCA2 positive cohort for all comparison models. In conclusion, this meta-analysis suggests that the MAP3K1 rs889312 C allele is a low-penetrant risk factor for developing breast cancer, and there is limited evidence to indicate that MAP3K1 rs889312 polymorphism is associated with increased risk of breast cancer in BRCA1 mutation carriers.

Are estrogen receptor-positive breast cancers in BRCA1 mutation carriers sporadic?

There is a strong association between BRCA1 mutation carrier status and estrogen receptor-negative breast cancer. This has led to the idea that estrogen receptor-positive breast cancers in BRCA1 mutation carriers may be incidental or sporadic in nature and not as a direct result of BRCA1 dysfunction. A recent paper in Breast Cancer Research challenges this view.

Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age

Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the general population in this region. We identified 1188 female mutation carriers and first-degree female relatives in 185 families with a pathogenic BRCA1 or BRCA2 mutation. The occurrence of breast cancer, contralateral breast cancer and ovarian cancer was recorded. The cumulative incidence of breast cancer by age 70 was 71.4% (95% CI 67.2-82.4%) in BRCA1 and 87.5% (82.4-92.6%) in BRCA2 mutation carriers. For ovarian cancer at age 70, it was 58.9% (53.5-64.3%) in BRCA1 and 34.5% (25.0-44.0%) in BRCA2 mutation carriers. For breast cancer we saw a rise of 24.2% in the cumulative incidence in the seventh decade for BRCA2 mutation carriers versus 6.3% for BRCA1. For ovarian cancer the rise in the seventh decade was 17.3% for BRCA1 mutation carriers and 15.1% for BRCA2. The 10-year risk for contralateral breast cancer was 34.2% (29.4-39.0%) in BRCA1 families and 29.2% (22.9-35.5%) in BRCA2. We show that the incidence of breast and ovarian cancer in BRCA2 mutation carriers and of ovarian cancer in BRCA1 mutation carriers is still high after 60 years. This may justify intensive breast screening as well as oophorectomy even after age 60. The risk of contralateral breast cancer rises approximately 3% per year, which may affect preventive choices.

Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features.

IntroductionMost breast cancers that occur in women with germline BRCA1 mutations are estrogen receptor-negative (ER-) and also typically lack expression of progesterone receptor (PR) and HER2 overexpression. We undertook a study to assess the clinical factors that predict for an estrogen receptor positive (ER+) breast cancer in BRCA1 mutation carriers and to characterize the pathologic features of these tumors.MethodsClinical characteristics of BRCA1 carriers with 58 ER+ and 114 ER- first invasive breast cancers were compared. Pathologic features of BRCA1 ER+ cancers were compared to those of BRCA1 ER- cancers and to age-matched ER+ sporadic cancers.ResultsBRCA1 carriers aged ≥ 50 at diagnosis of first invasive breast cancer were more likely to have an ER+ cancer compared to those aged < 50 (57% vs 29%, P = 0.005). ER+ BRCA1 cancers were less likely than ER- BRCA1 cancers to have "BRCA-associated" features such as high mitotic activity, geographic necrosis/fibrotic focus, and pushing margins (RR 0.06, 0.22, 0.24; P < 0.001, 0.02, 0.03 respectively). When compared to sporadic ER+ cancers, ER+ BRCA1 cancers were more often of invasive ductal type (RR 2.4, P = 0.03), with a high mitotic rate (RR 5.0, P = 0.006) and absent or mild lymphocytic infiltrate (RR 10.2, P = 0.04).ConclusionsBRCA1 carriers who are older at first breast cancer diagnosis are more likely to have ER+ tumors than younger BRCA1 carriers. These ER+ cancers appear pathologically "intermediate" between ER- BRCA1 cancers and ER+ sporadic breast cancers raising the possibility that either some ER+ BRCA1 cancers are incidental or that there is a unique mechanism by which these cancers develop.

A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population

A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population

Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer

Breast cancers related to BRCA mutations are associated with particular biological features. Here we report the clinical and pathological characteristics of breast cancer in Chinese women with and without BRCA mutations and of carriers of BRCA1 mutations compared to BRCA2 mutations. Two hundred and 26 high-risk Hong Kong Chinese women were tested for BRCA mutations, medical information was obtained from medical records, and risk and demographic information was obtained from personal interviews. In this cohort, 28 (12.4%) women were BRCA mutation carriers and among these carriers, 39.3% were BRCA1 and 60.7% were BRCA2 mutations. Mutation carriers were more likely to have a familial history of breast and ovarian cancer, high-grade cancers, and triple negative (TN) cancers. Prevalence of TN was 48.3% in BRCA carriers and 25.6% in non-carriers and was 67.7% in BRCA1 and 35.3% in BRCA2 carriers. Estrogen receptor (ER) negative cancer was significantly associated with BRCA1 mutations, especially in those under 40 years of age. BRCA-related breast cancer in this Chinese population is associated with family history and adverse pathological/prognostic features, with BRCA2 mutations being more prevalent but BRCA1 carriers having more aggressive and TN cancers. Compared to Caucasian populations, prevalence of BRCA2 mutations and TN cancer in BRCA2 mutation carriers in Chinese population are elevated.

Selenium Supplementation Reduced Oxidative DNA Damage in Adnexectomized BRCA1 Mutations Carriers

Some experimental evidence suggests that BRCA1 plays a role in repair of oxidative DNA damage. Selenium has anticancer properties that are linked with protection against oxidative stress. To assess whether supplementation of BRCA1 mutation carriers with selenium have a beneficial effect concerning oxidative stress/DNA damage in the present double-blinded placebo control study, we determined 8-oxodG level in cellular DNA and urinary excretion of 8-oxodG and 8-oxoGua in the mutation carriers. We found that 8-oxodG level in leukocytes DNA is significantly higher in BRCA1 mutation carriers. In the distinct subpopulation of BRCA1 mutation carriers without symptoms of cancer who underwent adnexectomy and were supplemented with selenium, the level of 8-oxodG in DNA decreased significantly in comparison with the subgroup without supplementation. Simultaneously in the same group, an increase of urinary 8-oxoGua, the product of base excision repair (hOGG1 glycosylase), was observed. Therefore, it is likely that the selenium supplementation of the patients is responsible for the increase of BER enzymes activities, which in turn may result in reduction of oxidative DNA damage. Importantly, in a double-blinded placebo control prospective study, it was shown that in the same patient groups, reduction in cancer incidents was observed. Altogether, these results suggest that BRCA1 deficiency contributes to 8-oxodG accumulation in cellular DNA, which in turn may be a factor responsible for cancer development in women with mutations, and that the risk to developed breast cancer in BRCA1 mutation carriers may be reduced in selenium-supplemented patients who underwent adnexectomy.

Tamoxifen and the risk of ovarian cancer in BRCA1 mutation carriers

ObjectiveBRCA1 mutation carriers have a high rate of both breast and ovarian cancer. Tamoxifen is a selective estrogen receptor modulator (SERM), which is used for the treatment of primary breast cancer and for the prevention of contralateral breast cancer. Our objective is to assess if tamoxifen treatment is associated with an increase in the subsequent risk of ovarian cancer among women with a BRCA1 mutation. MethodsA matched case-control study was performed. Cases were 154 women with ovarian cancer and a previous history of breast cancer. Controls were 560 women with no ovarian cancer and a history of breast cancer. All cases and controls carry a deleterious BRCA1 mutation. Cases and controls were matched for year of birth, age at diagnosis of breast cancer and country of residence. The effect of tamoxifen treatment on the risk of subsequent ovarian cancer was estimated using conditional logistic regression. ResultsThe unadjusted odds ratio for ovarian cancer, given previous tamoxifen treatment was 0.89 (95% CI 0.54–1.49, p = 0.66). After adjusting for other treatments, the odds ratio was 0.78 (95% CI 0.46–1.33, p = 0.36). ConclusionTamoxifen treatment for breast cancer does not appear to increase the risk of ovarian cancer in BRCA1 mutation carriers.

Framingham risk score after risk-reducing salpingo-oophorectomy in women at risk for hereditary breast ovarian cancer: A controlled observational study

11048 Background: Risk-reducing salpingo-oophorectomy (RRSO) effectively prevents ovarian cancer in BRCA mutation carriers and in women at risk for hereditary breast-ovarian cancer. RRSO induces immediate menopause, which may increase the risk of coronary heart disease (CHD). Our aim was to determine CHD risk using Framingham risk score and examine factors associated with this risk in women who had undergone RRSO compared to population-based controls. Methods: A sample of 326 (65% of invited) women who underwent RRSO after genetic counseling from 1980–2005 provided completed questionnaires, physical measures, and blood samples. Controls were 1,630 age-matched controls from the Norwegian Nord-Trøndelag Health Study (HUNT-2) (1995- 97). Results: Mean age in both the RRSO and control groups at survey was 54.4 years. Mean follow-up after surgery was 6.5 years (SD 4.4). The RRSO group had a more favorable CHD risk profile (higher education, more physical activity, less smoking, lower total cholesterol, higher HDL cholesterol, lower systolic blood pressure and lower BMI) and lower Framingham total score compared to controls (p&lt;0.05). In multiple logistic regression analyses RRSO was inversely associated with Framingham 10-year risk ≥5% (Odds Ratio 0.49, 95% CI [0.34, 0.71] p&lt;0.001). Conclusions: In contrast to expectation, women at increased risk of hereditary breast ovarian cancer had a favorable CHD risk profile after RRSO compared to age-matched controls from the general population, and RRSO was associated with lower Framingham risk score. Follow-up time, self-selection of women seeking genetic counseling, changes in lifestyle after surgery and survival bias are possible explanations of this finding. No significant financial relationships to disclose.

BRCA in breast cancer: ESMO Clinical Recommendations

Familial susceptibility to breast cancer accounts for ∼25% of all breast cancer cases. In familial breast cancer, mutations in the BRCA1, BRCA2, CHEK2, TP53 and PTEN genes account for ∼5–10% of breast and ovarian cancer cases overall. The prevalence of BRCA1 or BRCA2 mutations varies considerably between ethnic groups and geographical areas. Population-specific mutations have been described in Iceland, the Netherlands, Sweden, Norway, Germany, France, Spain, countries of central and eastern Europe and among Ashkenazi Jews. The prevalence of BRCA mutation carriers in the general population is estimated at between 1/800 and 1/1000. BRCA1 and BRCA2 mutation frequencies in breast and ovarian cancer patients unselected for family history or age at onset are generally low (<1–7% for BRCA1 and 1–3% for BRCA2). Higher prevalence is associated with a family history of breast or ovarian cancer, young age at onset, male breast cancer or multiple tumors (bilateral breast cancer or breast and ovarian cancer in the same patient). Women with an inherited BRCA1 mutation have a lifetime risk of 65–80% of developing breast cancer and 37–62% of developing ovarian cancer, while BRCA2 mutation carriers have a lifetime risk of 45–85% for breast cancer and 11–23% for ovarian cancer. There is an increased risk of prostate cancer among BRCA carriers (5–25%) and breast cancer among males with BRCA2 mutations (6%). Other cancers at increased risk are pancreatic (up to 2%), stomach, and head and neck. Genetic testing criteria may differ between countries based on mutation prevalence. Widely accepted criteria for referral include: three or more breast and/or ovarian cancer cases, at least one aged <50 years; two breast cancer cases aged <40 years; male breast cancer and early onset female breast cancer; and breast and ovarian cancer in the same patient [IV, C]. In some countries, the criterion for testing is that there should be at least a 10–20% probability of finding a mutation. In all cases, genetic testing should be performed after genetic counseling and informed consent. Most clinically deleterious mutations are protein-truncating mutations and a small number are missense mutations. Genetic testing should include complete sequencing of coding regions, either directly or after a screening method. Since 2–12% of high-risk families may harbor a large genomic alteration, specific techniques to detect duplications or deletions of one or more exons may be indicated [III, B]. Surveillance of breast cancer in BRCA carriers includes monthly self-examinations, clinical breast examinations once or twice a year and yearly mammograms and magnetic resonance imaging (MRI) of breasts starting at age 25–30 [IIa, B]. There are yet no data available to determine whether alternating mammogram and MRI every 6 months or having both once yearly is more effective at young ages, considering the high rate of interval cancers. Adjuvant tamoxifen reduces the risk of contralateral breast cancer in affected BRCA mutation carriers [III, B], while the benefit of tamoxifen for primary prevention of breast cancer has not been demonstrated [III,B]. It is the most effective strategy available for risk reduction of breast cancer in mutation carriers [III, B], although no benefit in survival has been demonstrated and many women do not find this strategy acceptable for cosmetic reasons. Contralateral prophylactic mastectomy is an option to consider in those BRCA mutation carriers with early breast cancer and unilateral mastectomy [IV, C]. It is associated with a risk reduction of breast cancer in premenopausal BRCA mutation carriers, risk reduction of ovarian cancer and there is evidence of reduction in overall mortality. Bilateral salpingo-oophorectomy is recommended after age 35 and when childbearing decisions are complete [IIa, B]. Short-term hormonal replacement therapy after bilateral salpingo-oophorectomy seems not to decrease the overall benefit of this strategy for breast cancer risk reduction [III, B]. Decisions about surgical treatment of breast cancer in BRCA mutation carriers should be based on the same parameters as sporadic cancer, while considering the higher risk of contralateral breast cancer [III, B]. Standard prognostic features should be used to decide adjuvant treatment in BRCA mutation carriers with breast cancer. Ongoing clinical trials in the metastatic setting are testing the sensitivity to platinum-based chemotherapy of BRCA tumors and the specific DNA-repair deficiency with the use of PARP inhibitors. Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO Faculty.

Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers

Environmental or lifestyle factors are likely to explain part of the heterogeneity in breast and ovarian cancer risk among BRCA1 and BRCA2 mutation carriers. We assessed parity as a risk modifier in 515 and 503 Spanish female carriers of mutations in BRCA1 and BRCA2, respectively. Hazard ratios (HR) and their corresponding 95% confidence intervals (CI) were estimated using weighted Cox proportional hazards regression, adjusted for year of birth and study centre. The results for ever being parous and number of live-births were very similar for carriers of mutations in both genes. For all mutation carriers combined, the estimated HR associated with ever having had a live-birth was 0.74 (95% confidence interval [CI] = 0.55-1.01, P = 0.06), and that associated with each live-birth was 0.87 (95%CI = 0.77-0.98, P = 0.02). The latter association was observed only in women aged 40 and above (HR = 0.81, 95%CI = 0.70-0.94, P = 0.004 vs. HR = 0.99, 95%CI = 0.83-1.18, P = 0.9 for women under age 40), and this trend was highly consistently observed for carriers of mutations in each gene. There was no evidence of an association between breast cancer risk and age at first birth for parous BRCA1 or BRCA2 mutation carriers (P-trend >or= 0.3). The power to detect associations with ovarian cancer risk was much lower, especially for BRCA2 mutation carriers. Nevertheless, having a live-birth was associated with protection for BRCA1 mutation carriers (HR = 0.41, 95%CI = 0.18-0.94, P = 0.03), and a strong and consistent protective effect of age at first birth was observed for parous carriers of mutations in both genes (HR = 0.65, 95%CI = 0.52-0.83, P < 0.001). This is the third independent study to find that, as in the general population, parity appears to be associated with protection from breast cancer in women with mutations in BRCA1 and BRCA2. Parity appears to be protective for ovarian cancer in BRCA1 mutation carriers, but its role in BRCA2 mutation carriers remains unclear. Whether later age at first birth is also protective for ovarian cancer in mutation carriers requires further confirmation.