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BackgroundPolygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.MethodsWe generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.ResultsIn the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).ConclusionsExtant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values

Abstract Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

Intracellular Ca2+ signaling and Na+ homeostasis are inextricably linked via ion channels and co‐transporters, with alterations in the concentration of one ion having profound effects on the other. Evidence indicates that intracellular Na+ concentration ([Na+]i) is elevated in breast tumors, and that aberrant Ca2+ signaling regulates numerous key cancer hallmark processes. The present study therefore aimed to determine the effects of Na+ depletion on intracellular Ca2+ handling in metastatic breast cancer cell lines. The relationship between Na+ and Ca2+ was probed using fura‐2 and SBFI fluorescence imaging and replacement of extracellular Na+ with equimolar N‐methyl‐D‐glucamine (0Na+/NMDG) or choline chloride (0Na+/ChoCl). In triple‐negative MDA‐MB‐231 and MDA‐MB‐468 cells and Her2+ SKBR3 cells, but not ER+ MCF‐7 cells, 0Na+/NMDG and 0Na+/ChoCl resulted in a slow, sustained depletion in [Na+]i that was accompanied by a rapid and sustained increase in intracellular Ca2+ concentration ([Ca2+]i). Application of La3+ in nominal Ca2+‐free conditions had no effect on this response, ruling out reverse‐mode NCX activity and Ca2+ entry channels. Moreover, the Na+‐linked [Ca2+]i increase was independent of membrane potential hyperpolarization (NS‐1619), but was inhibited by pharmacological blockade of IP3 receptors (2‐APB), phospholipase C (PLC, U73122) or following depletion of endoplasmic reticulum Ca2+ stores (cyclopiazonic acid). Thus, Na+ is linked to PLC/IP3‐mediated activation of endoplasmic reticulum Ca2+ release in metastatic breast cancer cells and this may have an important role in breast tumors where [Na+]i is perturbed. [ABSTRACT FROM AUTHOR]

Abstract: Background: Breast cancer prevention with tamoxifen in high-risk women is limited due to concerns of endometrial cancer and thromboembolism. We report the risk of endometrial cancer, deep vein thrombosis and pulmonary embolism in women <50years given tamoxifen for breast cancer prevention. Methods: We searched the Cochrane Central Register of Controlled Trials and National Library of Medicine for published data from January 1970 to December 2010. We contacted principal investigators of clinical trials, and searched Grey literature and conference proceedings for unpublished data. We reviewed three breast cancer prevention trials comparing tamoxifen (20mg per day) with placebo for five years in high-risk women <50years. The absolute risk and relative risk (RR) for each outcome were estimated. Results: The RR for endometrial cancer in women <50years given tamoxifen is 1.19 (95% CI, 0.53–2.65; p =0.6) as compared to the placebo. The RR for deep vein thrombosis with tamoxifen is 2.30 (95% CI, 1.23–4.31; p =0.009) in the active phase of treatment. The risk decreases to 1.00 (95% CI, 0.38–2.67; p =0.9) in the follow-up phase. The RR for pulmonary embolism with tamoxifen is 1.16 (95% CI, 0.55–2.43; p =0.6). Interpretation: The risk of endometrial cancer, deep vein thrombosis and pulmonary embolism is low in women <50years who take tamoxifen for breast cancer prevention. The risk decreases from the active to follow-up phase of treatment. Education and counseling are the cornerstones of breast cancer chemoprevention. [Copyright &y& Elsevier]

Background: Multiparity, young age at first childbirth, and breast-feeding are associated with a reduced risk of breast cancer in the general population. The breast cancer predisposition gene, BRCA1, regulates normal cell differentiation. Because mammary gland cells divide and differentiate during pregnancy, reproductive factors may influence breast cancer risk in BRCA1/2 mutation carriers differently than they do in non-carriers. Methods: We performed a retrospective cohort study of 1601 women in the International BRCA1/2 Carrier Cohort Study cohort, all of whom carried a mutation in BRCA1 or BRCA2. Information on reproductive factors was obtained from a questionnaire. At the time of interview 853 subjects were classified with breast cancer. Data were analyzed by using a weighted cohort approach. All statistical tests were two-sided. Results: There was no statistically significant difference in the risk of breast cancer between parous and nulliparous women. Among parous women, an increasing number of full-term pregnancies was associated with a statistically significant decrease in the risk of breast cancer (Ptrend = .008); risk was reduced by 14% (95% confidence interval [CI] = 6% to 22%) for each additional birth. This association was the same for carriers of mutations in either BRCA1 or BRCA2 and was restricted to women older than 40 years. 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 (20–24 years, hazard ratio [HR] = 2.33 [95% CI = 0.93 to 5.83]; 25–29 years, HR = 2.68 [95% CI = 1.02 to 7.07]; ≥30 years, HR = 1.97 [95% CI = 0.67 to 5.81]), whereas in BRCA1 mutation carriers, first childbirth at age 30 years or later was associated with a reduced risk of breast cancer compared with first childbirth before age 20 years (HR = 0.58 [95% CI = 0.36 to 0.94]). Neither history of interrupted pregnancies (induced abortions or miscarriage) nor history of breast-feeding was statistically significantly associated with the risk of breast cancer. Conclusions: BRCA1 and BRCA2 mutation carriers older than 40 years show a similar reduction in breast cancer risk with increasing parity as non-carriers. [ABSTRACT FROM AUTHOR]

Objectives: To describe and compare women's risk perceptions and recall of breast cancer risk information in a cohort of first-time attendees at a family history clinic. Methods: We conducted a 1-year prospective study of 158 women aged 18-45 years with a confirmed lifetime risk of breast cancer of 1 in 6 or greater. Risk perception and recall were assessed using a self-report questionnaire, completed pre-counselling and 3, 6, 9 and 12 months post-counselling, and through interviews conducted at 3 and 12 months. Results: The proportion of women with accurate personal risk perceptions based on 'gambling' odds ('1 chance in x') significantly improved after risk counselling from 12% pre-counselling to 67% 3 months post-counselling (p < 0.001), which was maintained for 1 year. This was the method of reporting perceived risk associated with the best level of risk accuracy and the women's preferred format for describing risk, but the concept of lifetime risk was understood by only 44% of women. Qualitative risk categories ('high', moderate' or 'low') correlated significantly with women's self-reported odds values, but each category comprised a wide range of women's perceived numeric risks. Describing risk as the 'likelihood of breast cancer' resulted in a broad and somewhat inaccurate reporting of risk, compared with numeric ratings made at the same time. There was an increase of up to 4-fold in the proportion of women who failed to recall their risk value over time, and women were unable to accurately put the breast cancer risk in context compared with other health threats. Conclusions: All methods of describing risk have limitations, but the results of the present study provide good support for women's accurate recall of numeric risk values and their preference for use of these 'gambling' odds. This may have been influenced by consistency of the use of this method both in risk communication and in personal summary letters. Descriptive risk formats reflected higher levels of perceived vulnerability to breast cancer, and genetic counsellors need to be aware of these different perceptions. [ABSTRACT FROM AUTHOR]

Background: In Manchester, approximately 120 women at ≥1: 4 lifetime risk of breast cancer have considered preventative surgery since 1992. Women treated within the Manchester protocol receive two genetic counselling sessions, a psychological assessment and a surgical consultation pre-operatively and annual follow-up post-operatively. The vast majority of women have breast reconstruction. Methods: Since 1996, mental health and body image have been assessed in women attending annual follow-up using self-report questionnaires: the 28-item General Health Questionnaire (GHQ) and 10-item Body Image Scale (BIS). Women with high scores are assessed by clinical interview together with a proportion who have no significant problems. Results: Between 1995 and 1999, 76 women completed surgery. Ten were awaiting post-operative review and 60 (91%) attended for follow-up of whom 45 (75%) were interviewed. Questionnaire data were available for 52 (79%) women, mean age 40.8 years (range 27–58). Six women were gene mutation carriers and of these three had had breast cancer. One additional patient was affected but had not been genetically tested. Eight (17%) of 47 women with assessments in the first post-operative year scored in the ‘caseness’ range on the GHQ: the mean GHQ score was 3.8 (S.D. 6.7), range 0–25. Results were comparable with those for women attending the Family History Clinic for risk assessment. The mean score on the BIS was 5.1 (S.D. 5.5), range 0–25, comparable with scores for women undergoing conservative surgery for breast cancer. Twenty-one percent of women reported no negative change in body image following surgery (i.e. zero questionnaire summary scores) and the majority of changes reported were of minor degree (item scores 0 or 1). The most frequently reported changes were in sexual attractiveness (55%), feeling less physically attractive (53%) and self-consciousness about appearance (53%): a third of women felt less feminine to a minimal degree. These results appeared stable over time. A minority of women had more serious psychological or body image concerns, usually in relation to surgical complications: they received further psychiatric intervention. Conclusions: For the majority of women there is no evidence of significant mental health or body image problems in the first 3 years following Bilateral Prophylactic Mastectomy (BPM), but women who have complications warrant additional psychological help. Careful pre-operative preparation and long-term monitoring are advocated in this new field of cancer prevention. Copyright © 2000 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

For genetic counselling of a woman on familial breast cancer, an accurate evaluation of the probability that she carries a germ-line mutation is needed to assist in making decisions about genetic-testing. We used data from eight collaborating centres comprising 618 families (346 breast cancer only, 239 breast or ovarian cancer) recruited as research families or counselled for familial breast cancer, representing a broad range of family structures.  Screening was performed in affected women from 618 families for germ-line mutations in BRCA1 and in 176 families for BRCA2 mutations, using different methods including SSCP, CSGE, DGGE, FAMA and PTT analysis followed by direct sequencing.  Germ-line BRCA1 mutations were detected in 132 families and BRCA2 mutations in 16 families.  The probability of being a carrier of a dominant breast cancer gene was calculated for the screened individual under the established genetic model for breast cancer susceptibility, first, with parameters for age-specific penetrances for breast cancer only [7] and, second, with age-specific penetrances for ovarian cancer in addition [20].  Our results indicate that the estimated probability of carrying a dominant breast cancer gene gives a direct measure of the likelihood of detecting mutations in BRCA1 and BRCA2.  For breast/ovarian cancer families, the genetic model according to Narod et al. [20] is preferable for calculating the proband's genetic risk, and gives detection rates that indicate a 50% sensitivity of the gene test.  Due to the incomplete BRCA2 screening of the families, we cannot yet draw any conclusions with respect to the breast cancer only families. [ABSTRACT FROM AUTHOR]

Demand for clinical services for familial breast cancer is continuing to rise across Europe.  Service provision is far from uniform and, in most centres, its evolution has been determined by local conditions, specifically by local research interests, rather than by central planning.  However, in a number of countries there is evidence of progress towards co-ordinated development and audit of clinics providing risk assessment, counselling, screening and, in some cases, prophylactic intervention.  Much important information should emerge from continued observation and comparative assessment of these developments. In most countries for which relevant data are available, there is a distinct bias towards higher social class among those who avail themselves of clinic facilities (in line with findings from many other health-promotion initiatives).  This should be addressed when considering future organisation of clinical services. Molecular genetic studies designed to identify the underlying mutations responsible for familial breast cancer are not generally regarded as part of the clinical service and are funded through research grants (if at all).  Economic considerations suggest that there is a case for keeping this policy under review. Familial cancers throw into sharp relief certain ethical and legal issues that have received much recent attention from government advisory bodies, patients' representatives, professional commentators and the popular media.  Two are of particular importance; first, the right to gain access to medical records of relatives, in order to provide accurate risk assessment for a given family member, versus the right to privacy in respect of personal medical information and, second, the obligation (or otherwise) to inform family members of their risk status if they have not actively sought that knowledge.  The legal position seems to vary from country to country and, in... [ABSTRACT FROM AUTHOR]

BACKGROUND: Surveillance programmes for women at increased genetic risk of breast cancer are being established worldwide but little is known of their efficacy in early detection of cancers and hence reduction in mortality. METHODS: Data were contributed from seven centres participating in the EU Demonstration Programme on Clinical Services for Familial Breast Cancer.  All breast tumours (n = 161) detected prospectively, from the time of enrolment of women in a screening programme, were recorded.  Analysis took account of age at diagnosis, whether tumours were screen-detected or not, their pathological stage and outcome by Kaplan—Meier survival plots. RESULTS: Mean age at diagnosis was 48.6 years. Overall, 75% of tumours were detected in the course of planned examinations.  For women under age 50 at diagnosis, this figure was 68%.  Eighteen percent were mammographically negative, (23% in patients under age 50).  At first ("prevalence") round and at follow-up screening, 16% and 22% of tumours respectively were carcinoma in situ (CIS) while 27% and 22% respectively had evidence of nodal or distant spread (CaN+).  Comparison of screen-detected and other tumours showed that the latter were more frequently mammogram-negative and CaN+.  Overall five-year survival was 89% and five-year event-free survival 86%.  Five-year event-free survival was 100% for CIS, 88% for invasive cancer without nodal or distant spread and 67% for CaN+. CONCLUSIONS: The majority of cancers arising in women at increased genetic risk of breast cancer can be detected by planned screening, even in those under age 50.  Surveillance should include regular expert clinical examination and teaching of "breast awareness" as well as mammography.  Attention to the logistics of screening programmes may improve still further the proportion of tumours that are screen-detected.  The... [ABSTRACT FROM AUTHOR]

The number of women in the UK seeking genetic counselling, testing and preventative treatment is rapidly increasing. In Manchester 600–800 women are now referred annually to the Family History Clinic. As yet there is no formal provision for this service within the NHS, but research is underway to evaluate such clinics and to identify the psychosocial sequelae of genetic risk counselling. To date, findings have been based on questionnaire data from which it is difficult to ascertain support needs accurately. We interviewed 158 women 3 months after genetic risk counselling because of a family history of breast cancer. Using standard assessment and diagnostic criteria, 21 (13%) women were diagnosed with an affective disorder. This compared with a prevalence of 26% using the 28 item General Health Questionnaire (GHQ). We did not find a relationship between GHQ distress levels and women's understanding of their risk before genetic counselling, but women with accurate risk knowledge post-counsel had significantly lower GHQ scores than those who continued to over or under-estimate and this finding warrants further investigation. Of women referred for psychological help, few reported risk of breast cancer as their main concern, but themes of loss, unresolved grief and relationship problems were common. The value of the GHQ as a screening instrument is discussed and we suggest a new threshold value based on our analysis. We conclude that risk counselling does not adversely affect the general mental health of attenders but a minority of women may need help with the impact of breast cancer in the family. © 1998 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Summary: Background: Bilateral prophylactic salpingo-oophorectomy (BPSO) is used widely used to reduce the risk of breast and ovarian cancer in women with BRCA1 and BRCA2 mutations. However, the reduction in mortality after this surgery is unclear. We aimed to assess whether BPSO improves overall mortality or cancer-specific mortality in BRCA1 and BRCA2 mutation carriers. Methods: We identified a prospective cohort of 666 women with disease-associated germline mutations in BRCA1 or BRCA2 and no previous cancer diagnosis. In our primary analysis, we compared 155 women who had had BPSO and 271 women matched for age at BPSO who had not had BPSO. In our secondary analysis, we compared 188 women who had had BPSO with 478 women who had not. In both analyses, we compared overall mortality and cancer-specific mortality. All analyses were adjusted for centre, mutation (BRCA1 vs BRCA2), and birth year. Findings: In the primary analysis, mean follow-up from BPSO to censoring was 3·1 years [SD 2·4] in the BPSO group and 2·1 years [2·0] in the non-BPSO group. The hazard ratio (HR) for overall mortality was 0·24 (95% CI 0·08–0·71), for breast-cancer-specific mortality was 0·10 (0·02–0·71), and for ovarian-cancer-specific mortality was 0·05 (0·01–0·46) for women who had BPSO compared with those who had not. In secondary analysis, BPSO was associated with reduced overall mortality (HR 0·28 [95% CI 0·10–0·74]), but not with breast-cancer-specific mortality (0·15 [0·02–1·18] or ovarian-cancer-specific mortality (0·23 [0·02–1·87]. When regarded as a time-dependent covariate, BPSO was not associated significantly with mortality. Interpretation: If confirmed, the finding that BPSO improves overall survival and cancer-specific survival in women with BRCA mutations will complement our existing knowledge of cancer-risk reduction associated with BPSO. Together, these data could give information to women who are considering genetic testing. [Copyright &y& Elsevier]

Background: Data concerning the efficacy of bilateral prophylactic oophorectomy for reducing the risk of gynecologic cancer in women with BRCA1 or BRCA2 mutations are limited. We investigated whether this procedure reduces the risk of cancers of the coelomic epithelium and breast in women who carry such mutations. Methods: A total of 551 women with disease-associated germ-line BRCA1 or BRCA2 mutations were identified from registries and studied for the occurrence of ovarian and breast cancer. We determined the incidence of ovarian cancer in 259 women who had undergone bilateral prophylactic oophorectomy and in 292 matched controls who had not undergone the procedure. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer was determined in 99 women who had undergone bilateral prophylactic oophorectomy and in 142 matched controls. The length of postoperative follow-up for both groups was at least eight years. Results: Six women who underwent prophylactic oophorectomy (2.3 percent) received a diagnosis of stage I ovarian cancer at the time of the procedure; two women (0.8 percent) received a diagnosis of papillary serous peritoneal carcinoma 3.8 and 8.6 years after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9 percent) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. With the exclusion of the six women whose cancer was diagnosed at surgery, prophylactic oophorectomy significantly reduced the risk of coelomic epithelial cancer (hazard ratio, 0.04; 95 percent confidence interval, 0.01 to 0.16). Of 99 women who underwent bilateral prophylactic oophorectomy and who were studied to determine the risk of breast cancer, breast cancer developed in 21 (21.2 percent), as compared with 60 (42.3 percent) in the control group (hazard ratio, 0.47; 95 percent confidence interval, 0.29 to 0.77). Conclusions: Bilateral prophylactic oophorectomy reduces the risk of coelomic epithelial cancer and breast cancer in women with BRCA1 or BRCA2 mutations. (N Engl J Med 2002;346:1616-22.) [ABSTRACT FROM AUTHOR]