Ashkenazi Jewish Women Research Articles

Improving a polygenic risk score (PRS) for breast cancer (BC) risk assessment in diverse ancestries.

10533 Background: Accurate BC risk assessment is essential to identify women for whom screening and preventive interventions may be lifesaving. Incorporation of PRS into clinical models can improve risk prediction, but most PRS have shown suboptimal performance among non-Europeans. We previously described a multiple-ancestry PRS (MA-149) based on 56 ancestry-informative and 93 BC-associated single-nucleotide polymorphisms (SNPs). MA-149 achieved accuracy for diverse populations by characterizing genetic ancestry at each SNP in terms of fractions attributable to reference ancestries (African, East Asian, European) and applying ancestry-specific risks and frequencies. MA-149 significantly outperformed the Tyrer-Cuzick (TC) model, and integration of MA-149 with TC improved predictive accuracy by roughly two-fold over TC alone. Here, we aimed to improve MA-149 by expanding the set of BC SNPs and refining ancestry-specific risks. Methods: We developed a novel stepwise regression methodology accounting for linkage disequilibrium to select an optimal set of BC SNPs. Women referred for hereditary cancer testing and negative for pathogenic variants in BC genes were divided into consecutive cohorts to (1) refine ancestry-specific SNP risks ( N=58,191 Black/African; N=27,160 East Asian), (2) develop the PRS ( N=184,322), and (3) conduct independent validation ( N=146,110). Predictive accuracy and calibration of the new PRS were evaluated in the full cohort and subpopulations of different ancestries. Odds ratios (OR) from multivariable regression are reported per standard deviation. Results: A set of 385 SNPs (56 ancestry, 329 BC) was selected for the new PRS (MA-385). MA-385 improved upon clinical factors and outperformed MA-149 within each ancestry (Table). Among non-Europeans, MA-385 was a better BC risk predictor (OR=1.47, 95% CI: 1.42-1.52) than MA-149 (OR=1.40, 95% CI: 1.35-1.45). The strongest associations were observed in Ashkenazi Jewish and Hispanic women (Table). MA-385 identified more women at >2-fold increased risk than MA-149 (6.5 % vs 2%). Goodness-of-fit tests showed that MA-385 was well-calibrated while a 385-SNP PRS with European weights was miscalibrated for non-Europeans. Conclusions: MA-385 was well-calibrated, improved upon clinical factors, and outperformed existing PRS in all tested ancestries. Incorporation of MA-385 into risk assessment could improve the early detection and prevention of BC. [Table: see text]

Abstract PO5-08-11: Genetic Landscape of Early Breast Cancer in an Ashkenazi Jewish Cohort

Abstract Background: The Ashkenazi Jewish (AJ) population exhibits a distinctive mutation profile in BRCA1 and BRCA2 (BRCA1/2), characterized by 3 common founder mutations: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. These 3 mutations are associated with 10% of invasive breast cancer (BC) cases among AJ women. However, the frequency of non-founder pathogenic variants in BRCA1/2 and other BC-related genes in AJ women with BC remains unclear. Methods: This retrospective study included AJ patients diagnosed with stage I-II human epidermal receptor growth factor 2 negative BC between 2004-2022 at the Weill Cornell Breast Center. We collected clinicopathological characteristics and genetic information to determine the frequency of predisposing mutations in BC and non-BC related genes in AJ patients with early BC. We also analyzed the clinicopathological characteristics and outcomes of patients with and without germline mutations in these genes. Results: The study included 232 self-identified AJ patients, with 98% being females. The median age at BC diagnosis was 62 years (IQR: 50-70). Stage I and II cancers accounted for 68% and 32% of cases, respectively. Hormone receptor positivity (HR+) was observed in 71% of patients, while 29% had triple-negative tumors. Genetic testing was performed on 88% (n=203) of the patients, while 5% of patients declined to undergo genetic testing. Among the tested patients, 12% (n=25/203) had pathogenic variants in BRCA1 or BRCA2, with 44% and 16% of these corresponding to the BRCA1 and BRCA2 founder mutations, respectively. Testing beyond BRCA1/2 genes was conducted on 154 patients, and only 6% (n=9/154) were found to have pathogenic variants in CHEK2, while no mutations were detected in other prevalent BC-related genes, including PALB2 and ATM. Fourteen-percent of patients had pathogenic mutations in other genes including APC, CFTR, FH, DIS3L2, FANCC, MUTYH, NF1 and VHL. The frequency of pathogenic BRCA1/2 variants was inversely proportional to the age at BC diagnosis: 50% (n=8/16), 21% (n=8/39), 15% (n=6/40), and 3% (n=3/108) of patients diagnosed at age < 40, 40-49, 50-59, and >60 years, respectively, had a pathogenic variant in either BRCA1 or BRCA2. The frequency of founder mutations varied according to age at diagnosis: 63%, 75%, 17%, and 100% for patients aged < 40, 40-49, 50-59, and >60 years, respectively. Patients with BRCA1/2 mutations exhibited higher-risk clinicopathological features compared to those without mutations, including a higher proportion of high histological grade (88%), and triple-negative tumors (76%). Mastectomy was the primary surgical treatment for 56% and 23% of patients with and without BRCA1/2 mutations, respectively. No difference in disease-free survival was found between patients with and without BRCA1/2 mutations with a median follow up of 3 years (IQR: 1-4). Conclusions: In our cohort, 17% of AJ patients with early BC carried a pathogenic variant in a BC-related gene, with BRCA1/2 being the most commonly affected genes. The proportion of pathogenic variants in BRCA1/2 showed an inverse correlation with the age at BC diagnosis, reaching up to 50% in patients diagnosed under the age of 40. These findings contrast with the lower prevalence of pathogenic variants in BRCA1/2 (38%) reported in the existing literature for this age group. Additionally, 8% of patients had pathogenic variants in other tested cancer genes carrying a genetic predisposition to colorectal cancer (CRC). These findings contribute to our understanding of the genetic landscape of early BC in the AJ population and emphasize the importance of comprehensive genetic testing, particularly among young patients. These results also suggest the need for earlier and more frequent CRC screening in a population of BC patients that may not be adhering to recommended guidelines. Furthermore, our study provides insight into how this genetic landscape may vary when analyzing late-stage BC in women of AJ heritage. Citation Format: Laura Munoz Arcos, Eleonora Nicolò, Maira Pires, Letizia Pontolillo, Leticia Varella, Tessa Cigler, Eleni Andreopolu, Anne Moore, Ashley Schreier, Carlos Munoz-Zuluaga, Lisa Newman, Georgia Syrnioti, Massimo Cristofanilli. Genetic Landscape of Early Breast Cancer in an Ashkenazi Jewish Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-11.

Risk-management decision-making data from a community-based sample of racially diverse women at high risk of breast cancer: rationale, methods, and sample characteristics of the Daughter Sister Mother Project survey

BackgroundTo understand the dynamics that limit use of risk-management options by women at high risk of breast cancer, there is a critical need for research that focuses on patient perspectives. Prior research has left important gaps: exclusion of high-risk women not in risk-related clinical care, exclusion of non-white populations, and lack of attention to the decision-making processes that underlie risk-management choices. Our objective was to create a more inclusive dataset to facilitate research to address disparities related to decision making for breast cancer risk management.MethodsThe Daughter Sister Mother Project survey collects comprehensive information about the experiences of women at high risk of breast cancer. We collected novel measures of feelings about and reactions to cancer screenings; knowledge, barriers, and facilitators of risk-management options; beliefs related to cancer risk and risk management; and involvement with loved ones who had cancer. Eligible individuals were non-Hispanic white and non-Hispanic Black adult women who self-identified as having high risk of breast cancer and had no personal history of cancer. Between October 2018 and August 2019, 1053 respondents completed the online survey. Of these, 717 were confirmed through risk prediction modeling to have a lifetime breast cancer risk of ≥ 20%. Sociodemographic characteristics of this sample were compared to those of nationally representative samples of the US population: the 2019 Health Information National Trends Survey and the Pew Research Center report: Jewish Americans in 2020.ResultsThe sample of 717 women at objectively high risk of breast cancer was largely (95%) recruited from non-clinical sources. Of these respondents, only 31% had seen a genetic counselor, 34% had had genetic testing specific to breast cancer risk, and 35% had seen at least one breast or cancer care specialist. The sample includes 35% Black respondents and 8% with Ashkenazi Jewish ancestry. Although encompassing a substantial range of ages, incomes, and education levels, respondents are overall somewhat younger, higher-income, and more educated than the US population as a whole.ConclusionsThe DSM dataset offers comprehensive data from a community-based, diverse sample of women at high risk of breast cancer. The dataset includes substantial proportions of Black and Ashkenazi Jewish women and women who are not already in clinical care related to their breast cancer risk. This sample will facilitate future studies of risk-management behaviors among women who are and are not receiving high-risk care, and of variations in risk-management experiences across race and ethnicity.

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

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...

A new population screening program for BRCA mutations in Israel – Attitudes and barriers among Ashkenazi Jewish women

Israeli Jewish women of Ashkenazi ancestry have a high BRCA mutation carrier rate. Therefore, recently, Israel included free genetic testing among all Jewish women with Ashkenazi ancestry, 25 yrs. and older in its public health system. The aim of this study was to assess the intention of eligible women to be tested for BRCA mutations, and to find factors that may affect their decision. We distributed an online survey to a panel of participants in a commercial research institute. The survey included socio-demographic characteristics, attitudes towards preventive actions, views related to benefits and limitations of performing the BRCA test, worry regarding cancer morbidity, knowledge about breast cancer morbidity and hereditary breast cancer genetics. The survey concluded with a question regarding the woman’s interest in undergoing the BRCA test. The results showed that among the 506 respondents, 250 (49%) were interested in BRCA testing, 42 (8%) objected and 214 (43%) were undecided. In comparing the undecided to the other groups, we found that most presented a positive attitude towards screening tests and preventive medicine, they showed acceptable knowledge about the proposed test, and yet were interested in learning and further expanding the knowledge and the consequences of doing the test. Most respondents of all groups expressed concern of breast cancer morbidity and were reluctant to perform the test for reasons of reducing uncertainty, implications for children and implications for their own health. Within all groups, many women expressed their desire to consult with a medical professional about the test. We conclude that aiming to improve the performance of BRCA genetic testing, women need a thorough explanation about its implications. The main way to inform them would be by medical professionals, especially in primary care. This implies that front line nurses and physicians need to become more knowledgeable and committed to this subject.

Breast cancer polygenic risk scores derived in White European populations are not calibrated for women of Ashkenazi Jewish descent

PurposePolygenic risk scores (PRSs) are a major component of accurate breast cancer (BC) risk prediction but require ethnicity-specific calibration. Ashkenazi Jewish (AJ) population is assumed to be of White European (WE) origin in some commercially available PRSs despite differing effect allele frequencies (EAFs). We conducted a case-control study of WE and AJ women from the Predicting Risk of Cancer at Screening Study. The Breast Cancer in Northern Israel Study provided a separate AJ population–based case-control validation series. MethodsAll women underwent Illumina OncoArray single-nucleotide variation (SNV; formerly single-nucleotide polymorphism [SNP]) analysis. Two PRSs were assessed, SNV142 and SNV78. A total of 221 of 2243 WE women (discovery: cases = 111; controls = 110; validation: cases = 651; controls = 1772) and 221 AJ women (cases = 121; controls = 110) were included from the UK study; the Israeli series consisted of 2045 AJ women (cases = 1331; controls = 714). EAFs were obtained from the Genome Aggregation Database. ResultsIn the UK study, the mean SNV142 PRS demonstrated good calibration and discrimination in WE population, with mean PRS of 1.33 (95% CI 1.18-1.48) in cases and 1.01 (95% CI 0.89-1.13) in controls. In AJ women from Manchester, the mean PRS of 1.54 (1.38-1.70) in cases and 1.20 (1.08-1.32) in controls demonstrated good discrimination but overestimation of BC relative risk. After adjusting for EAFs for the AJ population, mean risk was corrected (mean SNV142 PRS cases = 1.30 [95% CI 1.16-1.44] and controls = 1.02 [95% CI 0.92-1.12]). This was recapitulated in the larger Israeli data set with good discrimination (area under the curve = 0.632 [95% CI 0.607-0.657] for SNV142). ConclusionAJ women should not be given BC relative risk predictions based on PRSs calibrated to EAFs from the WE population. PRSs need to be recalibrated using AJ-derived EAFs. A simple recalibration using the mean PRS adjustment ratio likely performs well.

Evaluation of genetic alterations in hereditary cancer susceptibility genes in the Ashkenazi Jewish women community of Mexico.

Background: Individuals of Ashkenazi Jewish ancestry have been identified as having higher prevalence of specific pathogenic variants associated with susceptibility to specific rare and chronic diseases. In Mexico, the prevalence and composition of rare cancer predisposing germline variants in Ashkenazi Jewish individuals has not been evaluated. Aim and methods: We aimed to evaluate the prevalence of pathogenic variants by massive parallel sequencing in a panel of 143 cancer-predisposing genes in 341 women from the Ashkenazi Jewish community of Mexico, who were contacted and invited to participate in the study through the ALMA Foundation for Cancer Reconstruction. Pre- and posttest genetic counseling was given and a questionnaire on personal, gyneco-obstetric, demographic and lifestyle variables was conducted. From peripheral blood DNA, the complete coding region, and splicing sites of a panel of 143 cancer susceptibility genes, including 21 clinically relevant genes, were sequenced. The Mexican founder mutation BRCA1 ex9-12del [NC_000017.10(NM_007294):c. (825+1-826-1)_(4,589+1-4,590-1)del] was also evaluated. Results: Among study participants (mean age ±standard deviation: 47 ± 14) 15% reported a personal history of cancer (50/341). Fourteen percent of participants (48/341) were carriers of pathogenic and likely pathogenic variants distributed among seven high-risk genes (APC, CHEK2, MSH2, BMPR1A, MEN1, MLH1, and MSH6), whereas 18.2% (62/341) had variants of uncertain clinical significance in genes associated with breast and ovarian cancer susceptibility (list of genes with VUS). Pathogenic and likely pathogenic variants in 16 susceptibility genes with ambiguous or non-well-established risk association for cancer were detected in 17.6% (60/341) of participants. Sixty four percent of participants reported current alcohol consumption compared with the 39 percent prevalence of alcohol consumption in Mexican women. None of the participants carried the recurrent Ashkenazi and Mexican founder mutations in BRCA1 or BRCA2, but 2% (7/341) had pathogenic Ashkenazi Jewish founder variants in BLM. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of Ashkenazi Jewish ancestry in Mexico consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary breast cancer in this group and implement appropriate preventative programs.

Carrier screening program for BRCA1/BRCA2 pathogenic variants among Ashkenazi Jewish women in Israel: An observational study

PurposeThe aim of the study was to evaluate the results of a large-scale BRCA1/2 carrier screening program among Ashkenazi Jewish (AJ) women. MethodsWe performed a cross-sectional study of women who were eligible for BRCA1/2 screening program. Women who self-reported as complete or partial AJ were screened for 14 pathogenic variants in BRCA1/2 genes, following the Israeli Ministry of Health’s national screening program. ResultsThe study included 13,502 women who underwent screening between June 2020 and June 2022. The prevalence of the pathogenic variants in BRCA1/2 was 0.89% (120 of 13,502) among the tested women. Of the 14 variants tested, only 6 variants were detected. Three variants, known as the founder variants among AJ, accounted for 96.6% of identified variants (NM_000059.4(BRCA2):c.5946del, p.(Ser1982fs); NM_007294.4(BRCA1):c.68_69del, p.(Glu23fs); NM_007294.4(BRCA1):c.5266dup, p.(Gln1756fs)). The tested women were younger and of a higher socioeconomic status compared with the eligible non-tested women. ConclusionThe study provides a new insight into a large carrier screening program for BRCA1/2 pathogenic variants in AJ women in Israel. These findings present real-world prevalence of women who are heterozygous for BRCA1/2 pathogenic variants in AJ population and the importance of such programs.

Attitudes and interest in incorporating BRCA1/2 cancer susceptibility testing into reproductive carrier screening for Ashkenazi Jewish men and women.

Pathogenic variants in the BRCA1 and BRCA2 (BRCA1/2) genes are associated with elevated cancer risks in men and women. Due to a founder effect, Ashkenazi Jewish individuals are at higher risk for carrying three specific BRCA1/2 pathogenic variants. There have been recent calls for population screening in this population because many carriers do not have family histories suggestive of hereditary cancer. One approach could be to integrate optional BRCA1/2 testing into routinely offered reproductive carrier screening for recessive and X-linked disorders. However, the differing goals of these types of testing (i.e., personal health risks versus family planning) raise questions about the implications for patient education and informed consent. To this end, we aimed to determine interest, attitudes, and preferences regarding integrating such testing by electronically surveying 331 Ashkenazi Jewish participants in JScreen — a national, not-for-profit, at-home carrier screening program focused on genetic risks in Jewish communities. We found that while 41% of participants had plans to pursue BRCA1/2 testing, 93% would have opted for such testing if offered as an add-on to reproductive carrier screening. This was particularly true of those with higher perceived cancer risk and more positive attitudes toward genetic testing. With respect to preferences about delivery of this service, more than 85% of participants preferred remote (telephone, print, or web-based) genetic education rather than traditional genetic counseling. These results suggest that offering optional BRCA1/2 testing within the context of reproductive carrier screening might provide opportunities for cancer prevention without overburdening scarce genetic counseling resources.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12687-022-00590-3.

Abstract P3-13-07: A comprehensive germline genetic landscape in young Jewish & Arab women with breast cancer

Abstract Background: After decades of research on Ashkenazi Jewish (AJ) founder mutations in BRCA1 and BRCA2 (BRCA), there is still little known about genetics in non-AJ and Arab breast cancer populations in Israel and non-BRCA pathogenic variants (PV) in the total population. We used multigene panel testing (MGPT) to characterize the spectrum and prevalence of PV in cancer susceptibility genes in various Jewish and Arab demographic subgroups. Methods: A population-based cohort of women diagnosed with breast cancer before the age of 46 in a defined geographical area in Northern Israel was recruited as part of the BCINIS study and underwent MGPT. Probability matrices of proportion of PV by gene, and by ethnic sub-group (AJs, Sephardi Jews of North African origin, Sephardi Jews of other Eastern origins, Arabs), age-sub-group (35 and under, 36-45) and first-degree family history of breast, ovary or pancreatic cancer were calculated. Results: Overall, 1650 women were tested, including 1012 Jewish, 530 Arab and 108 non-Jewish/non-Arab women. We detected 375 PV among 363 women (22.7%): 212 in AJ (33.4% of AJs), 61 in Sephardi Jews (14.2% of Sephardi), and 69 in Arabs (13.0% of Arab). Only 162 of the PV (43.2%) were the BRCA AJ founders, another 39 BRCA PV (10.4%) were reported previously, while 15 BRCA PV (4.0%) are likely private. The remaining non-BRCA PV (42.4%) were distributed across 18 genes, with findings predominantly in CHEK2, MUTYH, ATM, BLM, ERCC3, PALB2, and FANCA. The prevalence of PV varied significantly across the ancestral subsets, from 95.5% probability in AJ women diagnosed before age 36 and with first degree family history to only 9.3% in Arab women diagnosed at age 36-45 and without family history. Conclusions: In this comprehensive, population-based, cohort of women with young onset breast cancer, the presence of PV in more than 15 genes is compelling and informs a necessarily broader approach to genetic testing and counseling. Citation Format: Gad Rennert, Bita Nehoray, Flavio Lejbkowicz, Sara Dishon, Shiri Kalet, Joseph Herzog, Thomas Slavin, Danielle Castillo, Kevin Tsang, Sharon Sand, Hedy S Rennert, Jeffrey Weitzel. A comprehensive germline genetic landscape in young Jewish & Arab women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-07.

Can Social Media Be Used as a Community-Building and Support Tool among Jewish Women Impacted by Breast and Ovarian Cancer? An Evidence-Based Observational Report.

About 1 in 40 Ashkenazi Jewish women carry a deleterious mutation in BRCA1/2 genes, predisposing them to hereditary breast/ovarian cancer (HBOC). Thus, efforts to prevent and control HBOC in the US must include sufficient outreach and education campaigns within and across the Jewish community. Social media (SM) is utilized in public health campaigns focused on cancer, but very little is known about the efficacy of those efforts when directed toward Jewish women at risk for (“previvors”) and affected by (“survivors”) HBOC. Here, we report on outcomes of a targeted SM campaign for this population, as led by a national not-for-profit HBOC advocacy organization. Mixed-methods data were obtained from n = 393 members of the community, including n = 20 key informants, and analyzed for engagement and satisfaction with its SM campaign and HBOC resources. Message recipients identified the SM campaign as helpful/meaningful (82%), of ‘newsworthy’ value (78%), and actionable/navigable (71%): interviews revealed that women were more likely to engage with SM if/when it featured stories relevant to their personal cancer experiences. SM is a valuable public health education tool to address the comprehensive cancer control and prevention needs of those previving and surviving with HBOC, including high-risk Jewish women.

Jewish cultural and religious factors and uptake of population-based BRCA testing across denominations: a cohort study.

To evaluate the association of Jewish cultural and religious identity and denominational affiliation with interest in, intention to undertake and uptake of population-based BRCA (Breast Cancer Gene)-testing. Cohort-study set within recruitment to GCaPPS-trial (ISRCTN73338115). London Ashkenazi-Jewish (AJ) population. AJ men and women, >18 years. Participants were self-referred, and attended recruitment clinics (clusters) for pre-test counselling. Subsequently consenting individuals underwent BRCA testing. Participants self-identified to one Jewish denomination: Conservative/Liberal/Reform/Traditional/Orthodox/Unaffiliated. Validated scales measured Jewish Cultural-Identity (JI) and Jewish Religious-identity (JR). Four-item Likert-scales analysed initial 'interest' and 'intention to test' pre-counselling. Item-Response-Theory and graded-response models, modelled responses to JI and JR scales. Ordered/multinomial logistic regression modelling evaluated association of JI-scale, JR-scale and Jewish Denominational affiliation on interest, intention and uptake of BRCA testing. Interest, intention, uptake of BRCA testing. In all, 935 AJ women/men of mean age = 53.8 (S.D = 15.02) years, received pre-test education and counselling through 256 recruitment clinic clusters (median cluster size = 3). Denominational affiliations included Conservative/Masorti = 91 (10.2%); Liberal = 82 (9.2%), Reform = 135 (15.1%), Traditional = 212 (23.7%), Orthodox = 239 (26.7%); and Unaffiliated/Non-practising = 135 (15.1%). Overall BRCA testing uptake was 88%. Pre-counselling, 96% expressed interest and 60% intention to test. JI and JR scores were highest for Orthodox, followed by Conservative/Masorti, Traditional, Reform, Liberal and Unaffiliated Jewish denominations. Regression modelling showed no significant association between overall Jewish Cultural or Religious Identity with either interest, intention or uptake of BRCA testing. Interest, intention and uptake of BRCA testing was not significantly associated with denominational affiliation. Jewish religious/cultural identity and denominational affiliation do not appear to influence interest, intention or uptake of population-based BRCA testing. BRCA testing was robust across all Jewish denominations. Jewish cultural/religious factors do not affect BRCA testing, with robust uptake seen across all denominational affiliations.

Knowledge and perceptions of BRCA1/2 genetic testing and needs of diverse women with a personal or family history of breast cancer in South Florida.

The vast majority of (BRCA1/2) genetic testing has been conducted in White women, in particular Ashkenazi Jewish women, with limited information available for Black and Hispanic women. Understanding perspectives of those who are underserved is critical to developing interventions to support inclusive approaches to genetic testing. This qualitative study explored knowledge and perceptions of BRCA1/2 genetic testing among diverse women in South Florida. We also explored participants' information needs. Convenience sampling was used to recruit a diverse group of 15 women with a personal or family history of breast cancer. We conducted semi-structured interviews and used grounded theory method to analyze the data. Five themes were identified: (1) lacking awareness and knowledge of BRCA1/2 genetic testing and results among Black women, (2) perceiving BRCA1/2 genetic testing as beneficial to themselves and a way to be proactive about cancer risk, (3) perceiving BRCA1/2 genetic testing as beneficial to family members, (4) interactions with healthcare providers and the healthcare system that shape genetic testing experiences, and (5) information needs for reducing cancer risk and promoting health. Our findings suggest that diverse underserved women perceived genetic testing as beneficial to themselves and family members. Women needed more information about the BRCA genes and genetic testing, prevention strategies, and the latest breast cancer research. Healthcare providers, particularly nurse practitioners, need to engage diverse high-risk women in discussions about their cancer risk, address unmet information needs, and, in particular, educate Black women about the benefits of pursuing genetic testing.

Prevalence of Germline Pathogenic and Likely Pathogenic Variants in Patients With Second Breast Cancers.

BackgroundFew studies have examined gene-specific associations with contralateral and/or second breast cancer (SBC).MethodsThe frequency of pathogenic and likely pathogenic (P/LP) variants in clinically actionable genes (BRCA1, BRCA2, PTEN, TP53, CHEK2, CDH1, ATM, PALB2, NBN, and NF1) was compared between women with a primary breast cancer (PBC) and SBC who underwent multigene panel testing at a single diagnostic testing laboratory. Race- and ethnicity-specific logistic regression burden tests adjusted for age at diagnosis of first breast cancer, histology, presence of first- or second-degree relatives with breast cancer, and prior testing for BRCA1/2 genes were used to test for associations with SBC. All statistical tests were 2-sided.ResultsThe study was comprised of 75 550 women with PBC and 7728 with SBC. Median time between breast cancers for SBC was 11 (interquartile range = 6–17) years. Restricting to women tested for all actionable genes (n = 60 310), there were 4231 (7.8%) carriers of P/LP variants in actionable genes among the controls (PBC) compared with 652 (11.1%) women with SBC (P< .001). Among Caucasians, exclusive of Ashkenazi Jewish women, those carrying a P/LP variant in a clinically actionable gene were 1.44 (95% confidence interval [CI] = 1.30 to 1.60) times as likely to have SBC than noncarriers, after accounting for potential confounders. Among African American and Hispanic women, a P/LP variant in a clinically actionable gene was 1.88 (95% CI = 1.36 to 2.56) and 1.66 (9% CI = 1.02 to 2.58) times as likely to be associated with SBC, respectively (P < .001 and P = .03).ConclusionWomen with P/LP variants in breast cancer predisposition genes are more likely to have SBC than noncarriers. Prospective studies are needed confirm these findings.

Epidural/spinal anesthesia during delivery in women with factor XI deficiency, a single center experience.

The safety of neuro-axial anaesthesia (epidural/spinal) at labour of women with partial factor XI (FXI) deficiency is uncertain. Although FXI deficiency is frequent in Ashkenazi Jews, it is not routinely measured before labour. Our institute serves a large Ashkenazi population. We assumed that 10% of them have undiagnosed FXI deficiency. Assess the incidence, bleeding tendency and coagulation status among Jewish Ashkenazi women with FXI deficiency that underwent neuro-axial anaesthesia at delivery. Jewish Ashkenazi women who underwent neuro-axial anaesthesia at labour completed the SSC ISTH bleeding assessment tool (BAT) and had blood drawn for coagulation tests, FXI and thrombin generation after labour. Estimation for 10years was calculated from the 1-year sample. We recruited 261 women during 12months. Among them, 39 (15%) had FXI deficiency (<70%) with median FXI levels of 63% (range: 33%-70%). Around 50% of them underwent amniocentesis in the current pregnancy and prior neuro-axial anaesthesia with no bleeding complications. BAT score and thrombin generation did not differ between women regardless of FXI status. aPTT was longer in women with partial FXI deficiency (median - 28.6 sec vs 26.3 sec, P < .001, Table 2), although within the normal range in all women. No bleeding complications after neuro-axial anaesthesia at delivery were reported in our centre in the last decade though, and according to our estimation, at least 2150 women had partial FXI deficiency. A significant number of Jewish Ashkenazi women with undiagnosed partial FXI deficiency undergo neuro-axial anaesthesia at labour without bleeding complications.

PF334 EPIDURAL/SPINAL ANESTHESIA IN PREGNANT JEWISH ASHKENAZI WOMEN HETEROZYGOTES FOR FACTOR XI DEFICIENCY, A SINGLE CENTER PROSPECTIVE STUDY

Background:Factor XI deficiency is a rare bleeding disorder worldwide. The prevalence of heterozygous and homozygotes among Ashkenazi Jews is 8–9% and 0.22–0.53%, respectively. The severity of bleeding does not always correlate with plasma factor XI levels and many heterozygotes patients, with factor XI levels of 20–70 IU dl−1 are undiagnosed. Data regarding bleeding phenotype is scarce. Likewise, there is no consensus regarding safety of neuro‐axial anesthesia (epidural/spinal) in these women. During pregnancy, aPTT is shortened due to physiological changes of pregnancy such as elevation in factor VIII, while the level of factor XI remains stable. Thus, in Ashkenazi Jews there is no indication to test aPTT or factor XI levels before neuro‐axial anesthesia. We assume that up to 10% of the Ashkenazi Jewish women who had neuro‐axial anesthesia in our center each year undergo neuro axial anesthesia without knowing factor XI deficiency status.Aims:1. Assess the incidence of Jewish Ashkenazi women heterozygotes for factor XI deficiency who underwent neuro‐axial anesthesia in our center. 2. Asses the bleeding tendency, aPTT and thrombin generation in Jewish women of Ashkenazi descent with/without factor XI deficiency.Methods:Jewish women from Ashkenazi origin who underwent neuro‐axial anesthesia during labor in our center were recruited. After labor and signing an informed consent form, women were asked to complete the SSC ISTH bleeding assessment tool (BAT) and had blood drawn for PT, aPTT, fibrinogen, factor XI and thrombin generation. Thrombin generation was tested on a fully automated coagulation analyzer using low concentration of tissue factor 0.3pM. Reduced factor XI was defined as below 70 IU dl−1. Patients were divided according to factor XI levels; group A &lt;70 IU dl−1 and group B ≥ 70 IU dl−1.Results:Between August 2017 and October 2018, 248 women were recruited. Of them 81% were of full Ashkenazi ethnicity. Group A included 39 (16%) women with median factor levels of 63 IU dl−1 (range: 32–69.6 IU dl−1) and group B included 209 women with a median of 96 IU dl−1 (range: 70.1–270 IU dl−1). Among group A, 20 women (51%) underwent neuro‐axial anesthesia in previous labors and 17 women (44%) underwent amniocentesis in the current pregnancy. No bleeding complications were noted in these procedures as well as in the present neuro‐axial anesthesia. Only 1 patient (group B) reported a family history of FXI deficiency. 240 women (97%) completed the BAT. There was no difference in bleeding history as reported in BAT between the 2 groups. 9 women (23%) from group A reported any bleeding complications (2 epistaxis, 1 menorrhagia, 6 postpartum hemorrhages (PPH);1 in the present labor) compared to 48 (23%) women from group B (including 13 women with PPH). Thrombin generation did not differ between the groups (Table 1). Although aPTT was within the normal range in all women, aPTT levels were significantly lower in group A compared to group B.Summary/Conclusion:A significant number of Jewish Ashkenazi women with undiagnosed partial FXI deficiency undergo neuro‐axial anesthesia. Bleeding phenotype does not differ between women with or without partial factor XI deficiency. Thrombin generation at delivery does not differ between women with or without factor XI deficiency, suggesting that hypercoagulability of pregnancy may compensate for factor XI deficiency and neuro‐axial anesthesia may be safe in these women.image

The uptake of pan-ethnic expanded carrier screening is higher when offered during preconception or early prenatal genetic counseling.

To examine factors that influence uptake of expanded carrier screening (ECS) among women undergoing preconception and prenatal genetic counseling. We retrospectively reviewed 500 medical records from women with prenatal or preconception genetic counseling at a prenatal genetic counseling service. We tabulated acceptance of ECS by indication for genetic counseling along with demographic and pregnancy-related factors. ECS was offered to 483 of 500 women, and 192 (39.8%) accepted. Of the 67 women counseled preconceptionally, 46 (68.7%) accepted ECS. This was significantly more than for 416 women counseled during pregnancy, of whom 146 (35.1%) accepted (P≤0.001). For pregnant patients, the mean gestational age of those accepting ECS (12weeks 3days; n=146) was significantly lower than those declining (13weeks 4days; n=270; P≤0.001). The acceptance rates were 7 of 12 (58.3%, P=0.195) for Ashkenazi Jewish women, 12 of 41 (29.3%; P=0.186) for Asian women, and 7 of 25 (28.0%; P=0.241) for women of mixed ethnicity. These results suggest that receiving genetic counseling prior to or earlier in the first trimester is associated with acceptance of ECS and support the importance of early genetic counseling about carrier screening options.

A Pragmatic Testing-Eligibility Framework for Population Mutation Screening: The Example of BRCA1/2.

Eligibility guidelines for genetic testing may be revisited, given technological advances, plummeting costs, and proposals for population mutation screening. A key property of eligibility criteria is the tradeoff between the number of mutation carriers identified versus population members tested. We assess the fractions of mutation carriers identified, versus women undergoing mutation testing, for BRCA1/2 founder mutation screening in U.S. Ashkenazi-Jewish women. BRCA1/2 carrier probabilities, based on personal/family history, were calculated using the risk-prediction tool BRCAPRO for 4,589 volunteers (102 mutation carriers) in the population-based Washington Ashkenazi Study. For each carrier-probability threshold between 0% and 10%, we compared the percentage of founder mutations detected versus the percentage of women requiring mutation testing. PCR mutation testing was conducted at the NIH for the 3 Ashkenazi-Jewish founder mutations (5382insC and 185delAG in BRCA1, and 6174delT in BRCA2). Identifying 90% of BRCA1/2 founder mutations required testing the 60% of Ashkenazi-Jewish women with carrier probabilities exceeding 0.56%, potentially avoiding mutation testing for approximately 0.7 to 1.1 million U.S. Ashkenazi-Jewish women. Alternatively, testing the 44% whose carrier probability exceeded 0.78% identified 80% of mutation carriers, increasing to 89% of mutation carriers when accounting for cascade testing triggered after mutation-positive daughters were identified by screening. We present data on all carrier-probability thresholds, e.g., a 5% threshold identified 46% of mutation carriers while testing 10% of women. Different carrier-probability thresholds offered diverse tradeoffs between numbers of identified mutation carriers versus women tested. Low carrier-probability thresholds identified 90% of BRCA1/2 founder mutation carriers, without testing approximately 1 million U.S. Ashkenazi-Jewish women with lowest carrier probabilities. In general, this risk-based framework could provide useful new options to consider during eligibility-criteria development for population mutation screening.

Highlights of This Issue

In a Seattle-based cohort of patients diagnosed with clinically localized prostate cancer, patients who reported vigorous physical activity at least once per week during the year before diagnosis were less likely to progress to metastatic–lethal prostate cancer compared to those who had less frequent physical activity (adjusted hazard ratio = 0.63, p-value = 0.029). Dai and colleagues identified a differentially methylated region (associated with both physical activity and metastatic–lethal progression) in the promoter region of CRACR2A, a gene encoding a calcium binding protein involved in innate immune response and neutrophil degranulation.Previous studies investigating associations of breast cancer with dietary intakes of lignans, phytoestrogens prevalent in whole grains, vegetables, fruits, and seeds, have been inconsistent. Some inconsistency may be related to genetic variation in lignan metabolism. Chang and colleagues investigated the impact of polymorphisms in 29 genes involved in steroid hormone and xenobiotic metabolism on lignan excretion after a flaxseed intervention in African American and European American healthy postmenopausal women. They identified several SNPs associated with lignan excretion, particularly among African American women. Future dietary interventions to reduce breast cancer burden may benefit from incorporating information on genetic variation in metabolism.Folic acid and vitamin-B12 play key roles in one-carbon metabolism, which has been implicated in the development of cancer. Given current considerations on folic acid fortification globally, it is essential to evaluate potential adverse effects. The aim of this study was to conduct secondary analyses on cancer incidence within the B-PROOF study, a randomized controlled trial on vitamin-B12 and folic acid supplementation on fracture risk. Oliai Araghi and colleagues found that B-vitamin supplementation increased the risk of cancer, and colorectal cancer in particular. This suggests that folic acid and vitamin-B12 supplementation should be limited to patients with proven deficiencies.Decreasing sequencing costs make population genetic screening increasingly feasible. However, the substantial infrastructure needs require thoughtful consideration of screening eligibility guidelines, which range from full-population testing to testing only those with strong personal or family histories. This study utilized a clinical risk prediction tool (BRCAPRO) to calculate BRCA1/2 carrier-probabilities for a population of Ashkenazi-Jewish women whose mutation status was known. Best and colleagues found that identifying 90% of known BRCA1/2 founder-mutations required testing only 60% of Ashkenazi-Jewish women (carrier-probability&gt;0.56%). An estimated 0.7-1.1 million U.S. Ashkenazi-Jewish women might avoid unnecessary mutation-testing. Low carrier-probability thresholds (&lt;1%) could maximize the public-health benefit of BRCA1/2 screening.

Localized Provoked Vulvodynia: Association With Nerve Growth Factor and Transient Receptor Potential Vanilloid Type 1 Genes Polymorphisms.

The aim of the study was to study the associations between localized provoked vulvodynia (LPV) and several single-nucleotide polymorphisms (SNPs) in the transient receptor potential vanilloid type 1 (TRPV1), nerve growth factor (NGF), and the heparanase (HPSE) genes. Prevalence of SNPs among 65 women with moderate or severe primary LPV (initial symptoms occur with first provoking physical contact) and 126 healthy, ethnically matched controls was analyzed in an observational case-control study. Each participant answered a questionnaire addressing familial LPV occurrence and comorbid pain conditions. Familial occurrences of LPV, temporomandibular joint (TMJ) symptoms, recurrent vaginitis, and irritable bowel syndrome were significantly higher among LPV women than healthy controls. Genotyping analyses revealed a novel, statistically significant high prevalence of polymorphism c.945G>C (rs222747) of TRPV1 and a SNP in the promoter region of NGF (rs11102930) in LPV women compared with controls. A logistic regression model for rs222747 and rs11102930 frequent alleles indicates significant LPV association within the entire study group and Ashkenazi Jewish women, respectively. Comparison of pain conditions with frequent alleles showed the rs222747 "CC" genotype of TRPV1 associated with women with TMJ, recurrent vaginitis, and LPV. Our results suggest novel genetic susceptibility to primary LPV associated with specific alleles in genes TRPV1 and NGF and propose the rs222747 "C" allele of TRPV1 as a common genetic predisposition for other pain syndromes.