Hereditary Breast And Ovarian Cancer Testing Research Articles

Screening Familial Risk for Hereditary Breast and Ovarian Cancer.

Most patients with pathogenic or likely pathogenic (P/LP) variants for breast cancer have not undergone genetic testing. To identify patients meeting family history criteria for genetic testing in the electronic health record (EHR). This study included both cross-sectional (observation date, February 1, 2024) and retrospective cohort (observation period, January 1, 2018, to February 1, 2024) analyses. Participants included patients aged 18 to 79 years enrolled in Renown Health, a large health system in Northern Nevada. Genotype was known for 38 003 patients enrolled in Healthy Nevada Project (HNP), a population genomics study. An EHR indicating that a patient is positive for criteria according to the Seven-Question Family History Questionnaire (hereafter, FHS7 positive) assessing familial risk for hereditary breast and ovarian cancer (HBOC). The primary outcomes were the presence of P/LP variants in the ATM, BRCA1, BRCA2, CHEK2, or PALB2 genes (cross-sectional analysis) or a diagnosis of cancer (cohort analysis). Age-adjusted cancer incidence rates per 100 000 patients per year were calculated using the 2020 US population as the standard. Hazard ratios (HRs) for cancer attributable to FHS7-positive status were estimated using cause-specific hazard models. Among 835 727 patients, 423 393 (50.7%) were female and 29 913 (3.6%) were FHS7 positive. Among those who were FHS7 positive, 24 535 (82.0%) had no evidence of prior genetic testing for HBOC in their EHR. Being FHS7 positive was associated with increased prevalence of P/LP variants in BRCA1/BRCA2 (odds ratio [OR], 3.34; 95% CI, 2.48-4.47), CHEK2 (OR, 1.62; 95% CI, 1.05-2.43), and PALB2 (OR, 2.84; 95% CI, 1.23-6.16) among HNP female individuals, and in BRCA1/BRCA2 (OR, 3.35; 95% CI, 1.93-5.56) among HNP male individuals. Being FHS7 positive was also associated with significantly increased risk of cancer among 131 622 non-HNP female individuals (HR, 1.44; 95% CI, 1.22-1.70) but not among 114 982 non-HNP male individuals (HR, 1.11; 95% CI, 0.87-1.42). Among 1527 HNP survey respondents, 352 of 383 EHR-FHS7 positive patients (91.9%) were survey-FHS7 positive, but only 352 of 883 survey-FHS7 positive patients (39.9%) were EHR-FHS7 positive. Of the 29 913 FHS7-positive patients, 19 764 (66.1%) were identified only after parsing free-text family history comments. Socioeconomic differences were also observed between EHR-FHS7-negative and EHR-FHS7-positive patients, suggesting disparities in recording family history. In this cross-sectional study, EHR-derived FHS7 identified thousands of patients with familial risk for breast cancer, indicating a substantial gap in genetic testing. However, limitations in EHR family history data suggested that other identification methods, such as direct-to-patient questionnaires, are required to fully address this gap.

Abstract PO4-09-08: Perceptions and Experiences of Black Women on Family History Sharing and Genetic Testing for Hereditary Breast and Ovarian Cancer

Abstract Black women experience significant disparities in morbidity and mortality related to hereditary breast and ovarian cancer (HBOC). Early identification of women with HBOC is essential for proactive screening and timely diagnosis. However, evidence suggests that Black women receive genetic testing for HBOC at lower rates than their White counterparts. We conducted in-depth qualitative interviews with 107 Black women with a personal or family history of breast or ovarian cancer, to understand their perceptions of their familial risk of HBOC and interest in genetic testing. In phase 1 of this study, participants were recruited from the networks of patient support organizations and historically Black sororities representing mostly highly educated and well insured patients. In phase 2, participants were recruited from a family medicine safety net clinic in Jacksonville, FL for socioeconomic diversity. Participants in both cohorts frequently expressed a lack of awareness about their family cancer history and identified many barriers to family disclosure of a cancer diagnosis. These include a culture of silence around medical issues and a belief that personal difficulties should be kept to oneself. Practical and cultural barriers to family history sharing were magnified among those with lower socioeconomic status. Many participants in both cohorts indicated a strong desire to understand their own risk of HBOC. They also expressed interested in genetic testing to proactively mitigate risk to themselves and future generations. Understanding of the potential relevance of HBOC testing to one’s personal health and post-test actionability was variable across both groups, although perceptions of genetic testing were generally favorable. These findings suggest that culturally tailored educational materials and alternative clinical modalities to collect family health history may be beneficial to improve timely identification of Black women who meet NCCN Guidelines for HBOC testing. Specifically, greater attention should be given to addressing barriers that led to underestimation of HBOC risk among patients experiencing disparities driven by adverse social determinants of health. Citation Format: Kirsten Riggan, Jane Yap, Ewan Cobran, Michele Halyard, Sarah James, Marion Kelly, Daphne Phillips, Megan Allyse. Perceptions and Experiences of Black Women on Family History Sharing and Genetic Testing for Hereditary Breast and Ovarian Cancer [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 PO4-09-08.

Abstract A067: Perceptions and experiences of Black women on hereditary breast and ovarian cancer genetic testing

Abstract Black women experience significant disparities in morbidity and mortality related to hereditary breast and ovarian cancer (HBOC). Early identification of women with HBOC is essential for proactive screening and timely diagnosis but evidence suggests that Black women receive genetic testing for HBOC at lower rates than their White counterparts. To understand Black women’s perspectives on HBOC genetic testing and potential factors influencing this decision, we conducted in-depth qualitative interviews with 107 Black women with a personal or family history of breast or ovarian cancer. Participants were recruited via the networks of patient support organizations and sororities as well as at a family medicine safety net clinic in Jacksonville, FL. Participants frequently expressed a lack of awareness about their family cancer history; many cancer patients stated that they only became aware of extensive family history upon their own diagnosis. Lack of family history sharing was attributed to a culture of silence around medical issues and a desire to protect family members from difficult information. However, most participants indicated a strong desire to understand their own risk of HBOC and were interested in genetic testing. Participants with a personal diagnosis were motivated to undergo HBOC genetic testing to reduce the risk for future generations. Clinical experiences with the offer of HBOC genetic testing were variable, with a few expressing that they had to make repeated inquiries from a provider to understand the relevance of the test to their own health. These findings suggest that investigation into alternative clinical modalities to collect family health history may be beneficial to identify Black women who meet NCCN Guidelines for HBOC testing. In contrast to the literature suggesting hesitancy for HBOC genetic testing, many participants perceived genetic results as having a positive impact for their medical decision-making and family's health. The development of patient materials and provider education on cultural and social factors that influence the uptake of HBOC genetic testing is also needed. Citation Format: Kirsten A. Riggan, Michele Halyard, Sarah E. James, Marion Kelly, Daphne Phillips, Megan A. Allyse. Perceptions and experiences of Black women on hereditary breast and ovarian cancer genetic testing [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A067.

Abstract P6-02-06: Implementation and outcomes of population-based hereditary cancer testing across a diverse multi-location breast imaging center

Abstract Introduction: Up to 10% of all breast cancers (BC) are attributed to inherited pathogenic variants (PV) in BC susceptibility genes, and genetic testing at the time of breast imaging may identify more patients who could benefit from enhanced surveillance and/or risk reduction interventions. Data are limited on the yield of PVs in the setting of a breast imaging center. Hypothesis: Hereditary cancer gene screening at the time of breast imaging may identify patients and families who could benefit from cancer risk management. Methods: This retrospective cohort study included de-identified clinical data and commercial multi-cancer panel (40 genes) test results from sequential patients undergoing breast imaging at 3 centers in Texas over a 17 month period. Patients of providers who elected not to participate were excluded from this cohort. PV prevalence was quantified and stratified based on level of risk for BC and other cancers: high-risk (relative risk >4) for BC, moderate-risk (relative risk 2-4) for BC, high-risk for other cancers, moderate-risk or undefined risk for other cancers. Results: A total of 1,943 patients undergoing breast imaging chose to have genetic testing during the study period. Median age was 66 yrs (range 18-89 yrs). Self-reported race/ethnicity: White (34.5%), Hispanic (27.7%), African American (17.9%), Asian (4.5%), Ashkenazi Jewish (0.6%), Other (3.5%) and unreported (13.0%). A personal history of breast or ovarian-related cancers was reported in 4% (n=78) and a family history of these cancers was reported in 38.9% (n=835) of patients. Among those tested, 44/1,943 (2.3%) had one or more PV in an autosomal dominant clinically actionable gene, further categorized as: high-risk BC gene (36.3%) moderate-risk BC gene (34.1%), high-risk gene for other cancers (13.6%), moderate-risk gene for other cancers (6.8%), or uncertain level of increased risk for other cancers (9.1%). A heterozygous PV in an autosomal recessive gene was present in 31/1943 (1.6%) patients. Overall, 354/1943 (18.2%) patients met current NCCN guidelines for hereditary breast and ovarian cancer (HBOC) gene testing. Only 15/44 (34.1%) patients with an autosomal dominant clinically actionable PV met current NCCN guidelines for HBOC testing. Genetic education was provided to 20/44 (45.5%) patients by lab-based genetic counselors and/or the patient’s healthcare provider. Conclusions: Offering genetic testing in a diverse breast imaging center population was associated with a significant yield (4%) of both dominant and recessive clinically actionable PVs. Of note, almost 2/3 of PVs in hereditary cancer genes were among women who did not meet NCCN testing guidelines. Identification of a PV enables risk stratification, cascade testing of family members and an opportunity to access enhanced surveillance and risk reduction interventions. Citation Format: Darlene Miltenburg, Laura Westbrook, Vivienne Souter, Melissa K. Maisenbacher, Katherine L. Howard, Youbao Sha, Maygol Yavari, Nicholas Kypraios, Sofia Hurtado, Mayra Rodas, Jeffrey N. Weitzel. Implementation and outcomes of population-based hereditary cancer testing across a diverse multi-location breast imaging center [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-06.

Mother and Daughter Perspectives on Genetic Counseling and Testing of Adolescents for Hereditary Breast Cancer Risk

To evaluate the risks, benefits, and utility of testing for adult-onset hereditary breast and ovarian cancer (HBOC) in adolescents and young adults. We evaluated interest in genetic testing of adolescents for adult-onset HBOC genes through semistructured interviews with mothers and adolescents who had previously participated in breast cancer research or had pursued (mothers) clinical testing for HBOC. The majority of mothers (73%) and daughters (75%) were interested in the daughter having genetic testing and were motivated by the future medical utility and current social utility of relieving anxiety and allowing them to prepare. Mothers and daughters both reported that approximately 3years in the future was the best time to test the daughter regardless of the current age of the daughter. Overall, both mothers and daughters expressed the importance of the involvement of the mother to provide educational and emotional support but ultimately it was the daughter's decision to test. Balancing the independence and maturity of the daughter while reinforcing communication and support within the dyad was a prominent theme throughout the interviews. There is interest among some high-risk adolescents and young adults to engage in genetic counseling and undergo testing. Providing pretest and posttest genetic counseling, assessing preferences for parent involvement, and offering psychosocial support may be important if genetic testing for HBOC is offered to adolescents and young adults before age 25years.

Statewide trends and factors associated with genetic testing for hereditary cancer risk in Arkansas 2013–2018

BackgroundEarly identification of hereditary cancer risk would save lives, but genetic testing (GT) has been inadequate. We assessed i) trends for hereditary breast and ovarian cancer (HBOC), Lynch syndrome, and other GT and ii) factors associated with receipt of GT.MethodsWe used data from the Arkansas All-Payer Claims Database from January 2013 through June 2018 (commercial, Medicaid), December 2017 (state employee), or December 2016 (Medicare) and identified enrollees with ≥1 month of enrollment. Using Current Procedural Terminology (CPT-4) codes, rates for GT were calculated per 100,000 person-quarters and time series regressions estimated. Second, GT and covariate information for enrollees with 24 months of continuous enrollment were used to estimate separate logistic regression models for each GT category.ResultsAmong 2,520,575 unique enrollees, HBOC testing rates were 2.2 (Medicaid), 22.0 (commercial), 40.4 (state employee), and 13.1(Medicare) per 100,000 person-quarters and increased linearly across all plans. Older age (OR=1.24; 95%CI 1.20 – 1.28), female sex (OR=18.91; 95%CI 13.01 – 28.86), higher comorbidity burden (OR=1.08; 95%CI 1.05 – 1.12), mental disorders (OR=1.53; 95%CI 1.15 – 2.00), and state employee coverage (OR=1.65; 95%CI 1.37 – 1.97) were positively associated with HBOC testing. Less than 1 of 10,000 enrollees received Lynch syndrome testing, while < 5 of 10,000 received HBOC testing.ConclusionGT rates for hereditary cancer syndromes have increased in Arkansas but remain low. Receipt of GT was explained with high discrimination by sex and plan type.ImpactExpansion of GT for hereditary cancer risk in Arkansas is needed to identify high-risk individuals who could benefit from risk-reduction strategies.

OP012: Perceptions of breast and ovarian cancer risk and genetic testing among Non-Hispanic Black women

Non-Hispanic Black (NHB) women experience health disparities from familial and hereditary breast and ovarian cancer (HBOC) compared to other racial and ethnic groups, including 40% higher mortality from breast cancer compared to non-Hispanic White women. One potential factor in these disparities includes lower uptake of HBOC genetic testing. This study explores potential factors for the lower use of HBOC genetic testing in NHB women and their families. Understanding these factors is critical to improving uptake of HBOC testing in the NHB community and improving HBOC racial and ethnic health disparities. A national sample of NHB women with personal or family history of HBOC were recruited through patient support organizations, historically Black colleges and university sororities, professional organizations for women of African descent, and snowball sampling. Participants were interviewed using an interview guide developed by content experts and a community advisory board. Interviews were audio recorded and transcribed verbatim. Interview transcripts were qualitatively analyzed using NVivo12 according to the principles of grounded theory. Sixty-one NHB women with personal (n=37, breast; n=6, ovarian) or family history (n=14, breast; n=2, ovarian; n=2 breast/ovarian) of HBOC participated in a qualitative interview. Participants reported on their own awareness of their family history of HBOC prior to their own diagnosis and how this informed their assessment of their pre-diagnostic risk of HBOC. The impact of family culture and cohesion, including perceptions of a familial ‘culture of silence’ around the sharing of personal or family medical history were also identified as potential barriers to awareness of HBOC risk. Thirty participants with a personal history and seven participants with family history received HBOC genetic testing upon recommendation of their provider or following their own request. Those that declined HBOC genetic testing described misperceptions of HBOC inheritance or expressed a belief that such testing would not be personally beneficial. Participants were also asked to describe family members’ interest in cascade testing and their reasons for accepting or declining HBOC genetic testing. Many participants felt that their daughters would be interested in HBOC genetic testing, but that siblings and other extended family members would decline out of belief that the results would have limited personal utility to themselves and/or their offspring or that a potential positive result would result in distress and life-long worry. Family members’ education status and views on healthcare were also thought to be important factors in their decision. This study is the largest qualitative study of its kind in NHB women with a personal or family history of breast and/or ovarian cancer. These findings suggests that there are significant barriers to HBOC genetic testing in the NHB community, including cultural factors influencing risk perception and the uptake of cascade testing. Culturally sensitive community outreach on the disparate impact of breast and ovarian cancer and how genetic testing may improve NHB cancer outcomes may improve uptake of HBOC genetic testing among at-risk NHB families.

A Collaborative Model to Implement Flexible, Accessible and Efficient Oncogenetic Services for Hereditary Breast and Ovarian Cancer: The C-MOnGene Study.

Simple SummaryWe recently developed an oncogenetic model to overcome the unprecedented demand for genetic counseling and testing for hereditary breast and ovarian cancer. Quality and performance indicators showed that the implementation of this model improved access to genetic counseling and minimized delays for genetic tests for patients, who reported to be overwhelmingly satisfied with the process. However, it remains unknown whether this model is robust and sustainable or requires adjustments. In addition, whether the model could be deployed elsewhere remains also to be elucidated. The C-MOnGene study was therefore designed to gain an in-depth understanding of the context in which the model was developed and implemented, and document the lessons that can be learned to optimize oncogenetic services delivery in other settings.Medical genetic services are facing an unprecedented demand for counseling and testing for hereditary breast and ovarian cancer (HBOC) in a context of limited resources. To help resolve this issue, a collaborative oncogenetic model was recently developed and implemented at the CHU de Québec-Université Laval; Quebec; Canada. Here, we present the protocol of the C-MOnGene (Collaborative Model in OncoGenetics) study, funded to examine the context in which the model was implemented and document the lessons that can be learned to optimize the delivery of oncogenetic services. Within three years of implementation, the model allowed researchers to double the annual number of patients seen in genetic counseling. The average number of days between genetic counseling and disclosure of test results significantly decreased. Group counseling sessions improved participants’ understanding of breast cancer risk and increased knowledge of breast cancer and genetics and a large majority of them reported to be overwhelmingly satisfied with the process. These quality and performance indicators suggest this oncogenetic model offers a flexible, patient-centered and efficient genetic counseling and testing for HBOC. By identifying the critical facilitating factors and barriers, our study will provide an evidence base for organizations interested in transitioning to an oncogenetic model integrated into oncology care; including teams that are not specialized but are trained in genetics.

Interventions Facilitating Family Communication of Genetic Testing Results and Cascade Screening in Hereditary Breast/Ovarian Cancer or Lynch Syndrome: A Systematic Review and Meta-Analysis.

Simple SummaryIn general, 5–20% of all cancers are due to pathogenic variants in cancer genes that are passed down in the family. It is recommended that blood relatives of individuals with such a pathogenic variant have genetic testing, to identify if they also carry the same variant. This information will help their healthcare providers to make individualized cancer screening and prevention plans. However, only around 30% of at-risk relatives have genetic testing, presumably due to a lack of communication about inherited cancer genes among family members. In this paper, we identified interventions that were designed to improve family communication about hereditary cancer and/or genetic testing among at-risk relatives for two common hereditary cancer syndromes. We analyzed the components of these interventions and synthesized outcomes with statistical methods. Although we identified 14 eligible studies, there are still many unanswered questions about clinical and research implications with diverse samples to be addressed in future studies.Evidence-based guidelines recommend cascade genetic testing of blood relatives of known Hereditary Breast and Ovarian Cancer (HBOC) or Lynch Syndrome (LS) cases, to inform individualized cancer screening and prevention plans. The study identified interventions designed to facilitate family communication of genetic testing results and/or cancer predisposition cascade genetic testing for HBOC and LS. We conducted a systematic review and meta-analysis of randomized trials that assessed intervention efficacy for these two outcomes. Additional outcomes were also recorded and synthesized when possible. Fourteen articles met the inclusion criteria and were included in the narrative synthesis and 13 in the meta-analysis. Lack of participant blinding was the most common risk of bias. Interventions targeted HBOC (n = 5); both HBOC and LS (n = 4); LS (n = 3); or ovarian cancer (n = 2). All protocols (n = 14) included a psychoeducational and/or counseling component. Additional components were decision aids (n = 4), building communication skills (n = 4), or motivational interviewing (n = 1). The overall effect size for family communication was small (g = 0.085) and not significant (p = 0.344), while for cascade testing, it was small (g = 0.169) but significant (p = 0.014). Interventions show promise for improving cancer predisposition cascade genetic testing for HBOC and LS. Future studies should employ family-based approaches and include racially diverse samples.

No Evidence of Increased Risk of Breast Cancer in Women With Lynch Syndrome Identified by Multigene Panel Testing.

Prior estimates of breast cancer risk in women with Lynch syndrome (LS) range from population risk to 18-fold increased risk with reported differences by gene. Here, breast cancer rates were determined in a large cohort of women with pathogenic variants (PVs) in a mismatch repair (MMR) gene detected through multigene panel testing and compared with rates in the US population and women undergoing panel testing. MMR gene PV carriers were identified among women tested for suspicion of LS or hereditary breast and ovarian cancer (HBOC) who met inclusion criteria. Standardized incidence ratios (SIRs) and 95% CIs of breast cancer were calculated compared with age-matched incidence in the general US female population and with women negative for PVs stratified by the test indication. In total, 0.8% of women (30,362 of 441,966 women) carried MMR gene PVs. PVs in PMS2 (37.5%) and MSH6 (29.3%) were more common than in MLH1 (13.7%) and MSH2/EPCAM (19.4%). Women with PVs in PMS2 and MSH6 were tested more frequently for HBOC, whereas those with PVs in MLH1 and MSH2/EPCAM were tested more frequently for LS. Breast cancer rates in women with LS were lower than those in the general female population (SIR, 0.88; 95% CI, 0.81 to 0.96) and did not differ compared with women with negative panel testing for HBOC (SIR, 0.90; 95% CI, 0.82 to 0.99) or LS (SIR, 1.02; 95% CI, 0.78 to 1.30). In this large cohort of women with LS identified through panel testing, there was no evidence for increased risk of breast cancer compared with the general US population or women undergoing panel testing. These findings support average-risk breast cancer screening in women with LS.

"It wasn't just for me": Motivations and implications of genetic testing for women at a low risk of hereditary breast and ovarian cancer syndrome.

Genetic testing for hereditary breast and ovarian cancer (HBOC) due to pathogenic variants in BRCA1 or BRCA2 is why most women present to familial cancer centers. Despite being assessed as low risk for HBOC, many women proceed with genetic testing. This study explored the genetic testing experiences of unaffected women at low risk of HBOC to clarify what motivates these women to have testing, and what are the implications of the results. A qualitative approach was taken. Participants included women who had genetic testing for HBOC from 2016-2018 at the Parkville Familial Cancer Centre in Melbourne, Australia. In-depth, semi-structured interviews were conducted, and thematic analysis was undertaken on transcripts; transcripts were coded, codes were organized into a hierarchical system of categories/subcategories, and key themes were identified. Analysis of 19 transcripts identified five themes: family underpinned all motivators for HBOC genetic testing; health professionals were influential throughout the process; participants were planning for a positive result; results influenced screening-anxiety and frequency; and negative results gave participants relief in many different ways. The three participants with positive results reported feeling shocked at the results and empowered giving this information to family members. Women at low HBOC risk may be motivated to seek genetic testing, and access to this is increasingly offered through non-genetic health professionals. Professionals can support clients through genetic testing by recognizing familial experiences, providing accurate information, addressing risk perceptions, and understanding cancer anxiety felt by many women.

Abstract P6-08-03: Germline mutational landscape in 5422 individuals at risk for hereditary breast and ovarian cancer who underwent multi-gene panel testing

Abstract Background: The introduction of multi-gene panel testing and improved awareness under patients and physicians has led to an increase of individuals with known germline pathogenic variants in hereditary breast and ovarian cancer (HBOC) genes. Significant regional differences exist in germline mutational landscape. We aimed to report the findings from multi-gene panel testing in a large Belgian cohort of individuals at risk for HBOC. Methods: All individuals who underwent multi-gene panel testing for HBOC at the Center for Human Genetics of the University Hospitals Leuven since the introduction of the panel were included (March 2016-April 2019). All included individuals were considered candidates for HBOC-panel testing by the requesting physician based on a personal or familial history of breast and/or ovarian cancer. Testing criteria from the Belgian Society of Human Genetics (www.beshg.be/download/guidelines/Guidelines_HBOC_2018.pdf) were met in the vast majority. The panel used was the BRCA Hereditary Cancer MASTR Plus® (Agilent, Belgium), with sequencing of BARD1, BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, TP53, MRE11A, RAD50, NBN, FAM175A, ATM, PALB2, STK11, MEN1, PTEN, CDH1, MUTYH, CHEK2, BLM, XRCC2, EPCAM, MLH1, MSH6, PMS2 and MSH2. Sequencing was performed by NGS on a Miseq platform (Illumina). Genomic deletions and duplications in BRCA1 and BRCA2 were investigated with multiplex ligation-dependent probe amplification. We hereby report on the frequency of pathogenic and likely pathogenic germline variants in this population. Results: In 5422 individuals who underwent multi-gene panel testing, we detected 665 pathogenic or likely pathogenic variants in 639 patients (11,7%). In 25 patients (0.46%), more than one relevant alteration was detected with double heterozygosity in 24 individuals and triple heterozygosity in one. Germline variants in BRCA1 and BRCA2 were detected in 178 (3.3%) and 144 (2.7%) patients, resulting in a fraction of 26,4% and 21,4% of detected variants respectively. Relevant alterations in CHEK2, ATM, PALB2 and TP53 were observed in 135 (2.5%), 93 (1.7%), 26 (0.5%) and 11 (0.2%) patients respectively, accounting together for 39.3% of detected variants. Alterations in BRIP1/RAD51C/RAD51D were retrieved in 64 patients (1.2%) and alterations in mismatch-repair genes MSH6/MLH1/PMS2/MSH2 were detected in 0.3% of patients. These patients where dominantly referred for familial history of ovarian cancer. Furthermore, germline alterations in PTEN, CDH1 and BLM were observed in 3, 2 and 1 cases respectively. Double heterozygosity for ATM+CHEK2 and for ATM+BRCA2 were both observed in 3 cases. In the patient with triple heterozygosity, co-occurrence of pathogenic variants in BRCA2, ATM and CHEK2 was detected. Conclusions: In a large Belgian cohort of 5422 individuals at risk for HBOC who underwent multi-gene panel testing, a pathogenic or likely pathogenic germline variant was detected in 11,7% of patients, and in 0,46% of patients double or triple heterozygosity for HBOC-variants was observed. Almost 40% of detected variants were alterations beyond BRCA correlated with hereditary breast cancer (CHEK2, ATM, PALB2 and TP53). Given the time-lag to predictive testing in families, a significant rise in healthy carriers with these non-BRCA alterations is expected in the upcoming years. Citation Format: Kevin Punie, Griet Hoste, Griet Van Buggenhout, Ellen Denayer, Hilde Brems, Hilde Peeters, Ann Smeets, Ines Nevelsteen, Patrick Neven, Jan Ardui, Renate Prevos, Machteld Keupers, Chantal Van Ongeval, Giuseppe Floris, Christine Desmedt, Hans Wildiers, Geneviève Michils, Hilde Van Esch, Eric Legius. Germline mutational landscape in 5422 individuals at risk for hereditary breast and ovarian cancer who underwent multi-gene panel testing [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-03.

Population prevalence of individuals meeting criteria for hereditary breast and ovarian cancer testing

BackgroundPersonal cancer diagnosis and family cancer history factor into which individuals should undergo genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome. Family history is often determined in the research setting through kindreds with disease clusters, or clinically from self‐report. The population prevalence of individuals with diagnostic characteristics and/or family cancer history meeting criteria for HBOC testing is unknown.MethodsUtilizing Surveillance, Epidemiology, and End Results (SEER) cancer registry data and a research resource linking registry records to genealogies, the Utah Population Database, the population‐based prevalence of diagnostic and family history characteristics meeting National Comprehensive Cancer Network (NCCN) criteria for HBOC testing was objectively assessed.ResultsAmong Utah residents with an incident breast cancer diagnosis 2010‐2015 and evaluable for family history, 21.6% met criteria for testing based on diagnostic characteristics, but the proportion increased to 62.9% when family history was evaluated. The proportion of cases meeting testing criteria at diagnosis was 94% for ovarian cancer, 23% for prostate cancer, and 51.1% for pancreatic cancer. Among an unaffected Utah population of approximately 1.7 million evaluable for family history, 197,601 or 11.6% met testing criteria based on family history.ConclusionsThis study quantifies the population‐based prevalence of HBOC criteria using objectively determined genealogy and cancer incidence data. Sporadic breast cancer likely represents a portion of the high prevalence of family cancer history seen in this study. These results underline the importance of establishing presence of a deleterious mutation in an affected family member, per NCCN guidelines, before testing unaffected relatives.

Assessment of High Risk of Hereditary Breast and Ovarian Cancer (HBOC) and Acceptance for Genetic Testing Among Cases of Ovarian and Breast Cancer in Indian Set-up

To identify cases needing genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome among cases of breast and ovarian cancer and assess their acceptability for genetic testing. One hundred patients of breast and/or ovarian cancer were recruited. A series of family meetings were done with patient and close family members. The first meeting was for pedigree chart preparation and identification of cases for genetic testing (HBOC) as per NCCN 2013 criteria. Second family meeting was held for counselling about genetic testing. Third meeting was held for recording acceptance or refusal for genetic testing. For those refusing the test, reasons for refusal were recorded. Outcome measures including prevalence of high-risk cases, acceptance rate for genetic testing and factors affecting the above acceptance rates among high-risk women were statistically analysed. Out of 100 patients of breast and ovarian cancer recruited in the study, 88 were found to be at high risk of HBOC. The most common criterion for high risk among breast cancer cases was age below 45 years. Family history of breast or ovarian cancer was present in 3.03% cases of ovarian cancer and 11.76 cases of breast cancer. Eleven (16.66%) cases of epithelial ovarian carcinoma and six (27.27%) cases of breast carcinoma accepted genetic testing. Socioeconomic status was found to have statistically significant correlation (p < 0.001 and p = 0.030) with acceptance for genetic testing. Though it is a small sample study, there is huge burden of women needing genetic testing for HBOC. There is lack of awareness about familial nature of disease and low acceptance for genetic testing in our population. There is a significant effect of socioeconomic status on acceptance for genetic testing.

Abstract P5-09-05: Hereditary breast cancer beyond BRCA: Clinical and histopathological characteristics in patients with germline CHEK2, ATM, PALB2 and TP53-mutations

Abstract Background The introduction of multi-gene panel testing in the diagnosis of hereditary breast and ovarian cancer (HBOC) has led to an important increase in the detection of breast cancer predisposition genes other than BRCA1 and BRCA2. Methods All individuals who underwent HBOC-testing at our institution since the introduction of multi-gene panel testing were included (March 2016-August 2017). In this retrospective analysis, the BRCA Hereditary Cancer MASTR Plus® panel is used (Multiplicom, Belgium), with sequencing of BARD1, BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, TP53, MRE11A, RAD50, NBN, FAM175A, ATM, PALB2, STK11, MEN1, PTEN, CDH1, MUTYH, CHEK2, BLM, XRCC2, EPCAM, MLH1, MSH6, PMS2, MSH2. In breast cancer patients with a recurrent germline alteration, age and TNM stage at diagnosis, histological subtype, grade of differentiation and molecular surrogate subtype were recorded. Given the low numbers of TP53-carriers diagnosed by HBOC testing, also patients with a germline TP53-mutation diagnosed by targeted sequencing at our institution were included. Statistical analysis were performed with SPSS version 25. Results In 11.9 % of 2806 patients who underwent panel testing, a germline pathogenic alteration was detected. BRCA1 and BRCA2 were the most prevalent alterations, detected in respectively 3.35 and 2.92 % of patients. Germline alterations in CHEK2, ATM , PALB2 and TP53 were detected in respectively 2.5 %, 1.1 %, 0.5 % and 0.1 %. In 1 % of patients, germline alterations were retrieved that only contribute to ovarian cancer risk (BRIP, RAD51C, RAD51D). Germline DNA mismatch repair alterations were detected in 0.39 % of patients. The median age at onset of breast cancer in patients with germline CHEK2-, ATM-, PALB2- and TP53-mutations was 47, 53, 39 and 33 years respectively. The age of breast cancer diagnosis in patients with germline TP53-alterations was significantly younger compared to patients with CHEK2-mutations (p = 0.01), ATM-mutations (p = 0.01) and PALB2-mutations (p = 0.04). In situ carcinomas were diagnosed in respectively 9 %, 11 % and 11 % of patients with CHEK2-, PALB2- and TP53-mutations. Patients with CHEK2, ATM, PALB2 and TP53-alterations were diagnosed with ≥T3-tumors in respectively 13 %, 12 %, 33 % and 22 %. Nodal status at diagnosis was negative in 40-60 % in these 4 subgroups. Upfront metastatic disease was diagnosed only in 2/43 CHEK2-carriers. More than half of the breast cancer diagnoses were luminal tumors in CHEK2-, ATM- and PALB2-carriers, while cases with germline TP53-alterations only presented with luminal cancers in 22 % in our series. Conclusion Almost half of the pathogenic mutations detected in HBOC-genes are alterations in genes other than BRCA1 and BRCA2. CHEK2-mutations are by far the most prevalent, followed by ATM, PALB2 and TP53. The range of the CHEK2- and ATM-population was wider then expected at the lower-age boundary. The age of breast cancer diagnosis in patients with germline TP53-mutations was significantly younger compared to patients with CHEK2-, ATM- and PALB2-mutations. The distribution of the histological subtypes and grade of differentiation was not suggestive of a specific correlation with germline mutation status. Citation Format: Hoste G, D'Hoore P, Legius E, Van Buggenhout G, Floris G, Wildiers H, Han SN, Van Nieuwenhuysen E, Berteloot P, Smeets A, Nevelsteen I, Weltens C, Janssen H, Van Limbergen E, Neven P, Punie K. Hereditary breast cancer beyond BRCA: Clinical and histopathological characteristics in patients with germline CHEK2, ATM, PALB2 and TP53-mutations [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-05.

Changing landscape of hereditary breast and ovarian cancer germline genetic testing in Australia.

Federal funding for germline genetic testing in hereditary breast and ovarian cancer (HBOC) was recently introduced. Germline testing for HBOC under Medicare Benefits Schedule items 73296/73297 can be requested by any specialist, whereas the previous state- and territory-funded testing was limited to those operating within a familial cancer service. The impact of this decentralisation of HBOC testing on health and economic outcomes is uncertain, primarily as it has potential to significantly disrupt the clinical framework that generated the evidence used to justify clinical implementation of the Medicare Benefits Schedules.

Underdiagnosis of Hereditary Breast and Ovarian Cancer in Medicare Patients: Genetic Testing Criteria Miss the Mark.

An estimated 5-10% of breast and ovarian cancers are due to hereditary causes such as hereditary breast and ovarian cancer (HBOC) syndrome. Medicare, the third-party payer that covers 44 million patients in the United States, has implemented a set of clinical criteria to determine coverage for the testing of the BRCA1 and BRCA2 genes. These criteria, developed to identify carriers of BRCA1/2 variants, have not been evaluated in the panel testing era. This study investigated a series of Medicare patients undergoing genetic testing for HBOC to determine the efficacy of genetic testing criteria in identifying patients with hereditary risk. This study retrospectively examined de-identified data from a consecutive series of Medicare patients undergoing genetic testing based on personal and family history of breast and gynecologic cancer. Ordering clinicians indicated whether patients did or did not meet established criteria for BRCA1/2 genetic testing. The genetic test results were compared between the group that met the criteria and the group that did not. Patients in families with known pathogenic (P) or likely pathogenic (LP) variants were excluded from the primary analysis. Among 4196 unique Medicare patients, the rate of P/LP variants for the patients who met the criteria for genetic testing was 10.5%, and for those who did not, the rate was 9% (p = 0.26). The results of this study indicate that a substantial number of Medicare patients with clinically actionable genetic variants are being missed by current testing criteria and suggest the need for significant expansion and simplification of the testing criteria for HBOC.

Inherited germline mutations in men with prostate cancer.

357 Background: Recent studies have demonstrated a high prevalence of pathogenic variants (PVs) in genes that confer hereditary cancer risk among men with metastatic prostate cancer (PC); however, PC does not currently receive attention as an indication for genetic testing. We assessed the clinical features of men with PC who received clinical testing as well as the distribution of PVs identified. Methods: Men with PC who underwent testing with a multi-gene hereditary cancer panel (Myriad Genetic Laboratories) from September 2013–September 2017 were included. Clinical information was obtained from provider-completed test request forms. Individuals with PC only were evaluated separately from those who had ≥1 additional malignancy. Personal/family history was evaluated relative to the 2013 NCCN guidelines for hereditary breast and ovarian cancer (HBOC) testing. Results: Overall, 1004 men with a personal history of PC were identified: 606 (60.4%) with only PC and 398 (39.6%) with PC and ≥1 additional malignancy. The most common additional malignancies were breast (136) and colorectal cancer (134). The median age of diagnosis in men with only PC was 59, which is younger than tested men who had an additional malignancy (63) and the SEER data (2009-2013) for all men with PC (66). HBOC testing criteria were met by 78.0% of men, including 68 (6.8%) who met based only on a personal/family history of PC and 330 (32.9%) who met in part due to a personal/family history of PC. PVs were identified in 12.9% of all men: 11.2% of men with PC only and 15.4% of men with PC and a second malignancy (Table). Conclusions: PC patients selected for genetic testing here were younger than men diagnosed with PC from the general population (SEER), and about a third had a diagnosis of an additional malignancy. They also have a high positive mutation rate across a broad spectrum of genes. [Table: see text]

Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy.

Approximately 10% of pancreatic adenocarcinoma (PC) cases are attributed to hereditary causes. Individuals with PC and a personal history of another cancer associated with hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS) may be more likely to carry germline mutations. Participants with PC and a history of cancer were selected from a pancreatic disease registry. Of 1296 individuals with PC, 149 had a relevant history of cancer. If banked DNA was available, a multigene panel was performed for individuals who had not 1) previously had a mutation identified through clinical testing or 2) undergone clinical multigene panel testing with no mutations detected. Twenty-two of 124 individuals with PC and another HBOC- or LS-related cancer who underwent genetic testing had a mutation identified in a PC susceptibility gene (18%). If prostate cancer is excluded, the mutation prevalence increased to 23% (21/93). Mutation carriers were more likely to have more than 1 previous cancer diagnosis (P = .001), to have had clinical genetic testing (P = .001), and to meet National Comprehensive Cancer Network (NCCN) genetic testing criteria (P < .001). Approximately 23% of mutation carriers did not meet NCCN HBOC or LS testing guidelines based on their personal cancer history and reported cancer history in first-degree relatives. At least 18% of individuals with PC and a personal history of other HBOC- or LS-related cancers carry mutations in a PC susceptibility gene based on our data, suggesting that criteria for genetic testing in individuals with PC should include consideration of previous cancer history. Cancer 2018;124:1691-700. © 2018 American Cancer Society.

BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?

BackgroundGermline pathogenic variants in BRCA1 and BRCA2 (BRCA) are the main cause of Hereditary Breast and Ovarian Cancer syndrome (HBOC).MethodsIn this study we evaluated the mutational profile and prevalence of BRCA pathogenic/likely pathogenic variants among probands fulfilling the NCCN HBOC testing criteria. We characterized the clinical profile of these individuals and explored the performance of international testing criteria.ResultsA pathogenic/likely pathogenic variant was detected in 19.1% of 418 probands, including seven novel frameshift variants. Variants of uncertain significance were found in 5.7% of individuals. We evaluated 50 testing criteria and mutation probability algorithms. There was a significant odds-ratio (OR) for mutation prediction (p ≤ 0.05) for 25 criteria; 14 of these had p ≤ 0.001. Using a cutoff point of four criteria, the sensitivity is 83.8%, and the specificity is 53.5% for being a carrier. The prevalence of pathogenic/likely pathogenic variants for each criterion ranged from 22.1% to 55.6%, and criteria with the highest ORs were those related to triple-negative breast cancer or ovarian cancer.ConclusionsThis is the largest study of comprehensive BRCA testing among Brazilians to date, and the first to analyze clinical criteria for genetic testing. Several criteria that are not included in the NCCN achieved a higher predictive value. Identification of the most informative criteria for each population will assist in the development of a rational approach to genetic testing, and will enable the prioritization of high-risk individuals as a first step towards offering testing in low-income countries.