The uptake rate of risk-reducing salpingo-oophorectomy among Thai women with breast cancer and germline BRCA pathogenic or likely pathogenic variants.

Background: Carriers of pathogenic variants in BRCA1 and BRCA2 have an elevated lifetime risk of breast, ovarian and other cancers. Current NCCN guidelines recommend specific screening for early cancer detection and risk reducing surgeries. Previous studies investigating the choices women make following the identification of pathogenic germline BRCA1 or BRCA2 variants reveal racial disparities in uptake of recommendations with black patients having lower rates of risk-reducing surgical procedures. We report on screening and prevention practices among 128 women identified with a pathogenic BRCA1 or BRCA2 variant at a large, urban comprehensive cancer center in Detroit, Michigan to evaluate racial differences in compliance with screening and prevention practices and to identify potential barriers to guideline-recommended care. Methods: The study population included women evaluated for genetic counseling and testing at the Karmanos Cancer Institute (KCI) from January 1, 2000 through December 31, 2017, who tested positive for a pathogenic variant in BRCA1 or BRCA2. A 54-item mail or telephone-based questionnaire was used to measure sociodemographics, medical history, cancer screening and risk reducing surgery, and cancer worries and fears. The primary and secondary outcomes were rate of risk reducing salpingo-oophorectomy (RRSO) and risk reducing mastectomy (RRM). Univariable logistic regression analyses were performed to identify potential predictors of RRSO and RRM, including race, personal cancer history, age at survey, time interval since BRCA1 or BRCA2 diagnosis, education, income, marital status and family history of a pathologic BRCA variant. P values less than 0.05 were considered statistically significant. Results: Of 374 women with pathogenic BRCA1 or BRCA2 variants during the study period, 129 (35%) completed the study survey (75 written, 54 telephone) with one ineligible. Of the 128 BRCA1 or BRCA2 carriers, 94 (73%) and 76 (59%) underwent RRSO and RRM, respectively and 13 (38%) and 10 (19%) planned to complete those procedures in the future. The rate of RRSO was 72% for white and 71% for black carriers. Black women tended to be less likely to have RRM compared to white women, but this difference did not reach statistical significance (OR 0.5 [95% CI 0.17 - 1.43], p = 0.193). Women who had RRM were 3 times more likely to have RRSO (and vice versa) (OR = 3.28, p = 0.004). With each increasing year of age at the time of genetic counseling, the odds of RRSO increased by 6% (OR = 1.06, p = <0.001). The odds of having had RRM increased with the time interval between genetic diagnosis and the survey by 9% (OR = 1.09, p = 0.043) for each elapsed year. The occurrence of new breast or ovarian cancer since genetic testing had no impact on RRSO, however participants who developed a new ovarian cancer had higher odds of having RRM (OR = 2.63, p = 0.01). There was no association between rate of RRSO or RRM with education level, annual household income, marital status or family history of pathologic BRCA variant. Conclusion: There was no racial difference in the rate of RRSO or RRM between white and black carriers of pathogenic BRCA1 or BRCA2 variants. Further multivariable models will assess predictors of risk reducing surgeries and will include assessment of screening practices as well as cancer worries and fears. Citation Format: Maria Levitin, Hadeel Assad, Hyejeong Jang, Wei Chen, Nancie Petrucelli, Michael Simon. Uptake of screening and risk reducing recommendations among women with hereditary breast and ovarian cancer syndrome evaluated at a large urban comprehensive cancer center [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-70.

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

No. 366-Gynaecologic Management of Hereditary Breast and Ovarian Cancer.

Eligibility Criteria and Genetic Testing Results from a High-Risk Cohort for Hereditary Breast and Ovarian Cancer Syndrome in Southeastern Ontario

To establish an individualized surgical strategy for lymphadenectomy in ovarian cancer patients with the germline BRCA1 and BRCA2 pathogenic variants (BRCA1+ and BRCA2+), we investigated the clinicopathological characteristics that are involved in the increased risk of lymph node metastasis. We retrospectively reviewed the data of Japanese women registered in the database of the Japanese Hereditary Breast and Ovarian Cancer Consortium, who underwent BRCA1 and BRCA2 genetic testing. We evaluated the predictors of lymph node metastasis in all patients with the information of age at the diagnosis, disease site, histological subtype, 2014 FIGO stage, personal breast cancer history and family history; 233, 153 and 32 patients in the BRCA- (no pathogenic variant), BRCA1+ and BRCA2+ groups, respectively. The prevalence of lymph node metastasis was not markedly different between BRCA- (20.0%), BRCA1+ (18.4%) and BRCA2+ (26.2%). Multivariate analysis revealed an absence of a family history of ovarian cancer as an independent predictor for an increased risk of lymph node metastasis in BRCA1+, and the prevalence of lymph node metastasis was 11.7 and 42.0% in the groups with and without a family history of ovarian cancer, respectively. This subgroup without a family history of ovarian cancer did not show any correlation with a particular variant of BRCA1, including two common variants of c.188T>A and c.2800C>T. This study suggested that certain genetic factors related to the penetrance of hereditary breast and ovarian cancer syndrome altered the frequency of lymph node metastasis in BRCA1+ ovarian cancer, and family history may be useful to personalize the indication of lymphadenectomy.

With the increasing demand for BRCA genetic testing, most existing prediction models were developed using data from individuals of European descent. This study aimed to identify clinicopathological factors of hereditary breast and ovarian cancer (HBOC) syndrome and develop the first Japanese-specific prediction model for BRCA pathogenic variant carriers in Japan. We utilized data from 3072 Japanese patients with breast cancer aggregated by the Japanese Organization of Hereditary Breast and Ovarian Cancer registry. Prediction models were developed using 70% of the overall dataset and validated using the remaining 30%. Factors associated with the BRCA pathogenic variant status were identified using logistic univariate analysis, and significant factors were further analyzed using logistic multivariate analysis to develop prediction models for BRCA1/2 (BRCA1 and/or BRCA2), BRCA1, and BRCA2 pathogenic variants. BRCA1 showed associations with aggressive clinicopathological factors such as triple-negative breast cancer and nuclear grade 3. Moreover, the prediction model showed a high area under the curve (AUC) of 0.879. By contrast, BRCA2 exhibited fewer characteristic associated factors, and the AUC of the model was 0.669. Common factors shared by BRCA1/2, BRCA1, and BRCA2 were the age at diagnosis of breast cancer and the youngest age of relatives with breast cancer. Consistent with previous research, early-onset breast cancer appeared to be strongly associated with HBOC. We successfully developed prediction models for BRCA1/2, BRCA1, and BRCA2 pathogenic variants. By accurately stratifying patients' risk and guiding targeted screening and preventative interventions, these models will contribute to improved management and outcomes of HBOC.

Breast cancer among Emirati patients is characterized by early-onset disease and later stages at presentation. Little is known about the germline genetic variants that may contribute to these observations. The goal of this study is to characterize the rate and implications of germline genetic variants among a cohort of Emirati patients at risk for hereditary breast and ovarian cancer syndrome. A retrospective study was performed to analyze the results of clinical germline genetic testing (March 2020-January 2023) among a cohort of consecutive Emirati patients at risk for hereditary breast and ovarian cancer syndrome: group A: patients with personal history of breast or ovarian cancer (n = 135); group B: unaffected patients with family history of breast or ovarian cancer (n = 37); and group C: patients presenting for cascade testing (n = 20). Management of patients identified to have pathogenic/likely pathogenic (P/LP) variants was analyzed. The rate of P/LP germline variants for each group was: group A: 17.3%, group B: 16.6%, group C: 57.9%. BRCA1 gene was the most commonly identified gene harboring P/LP variants, followed by BRCA2, among this cohort. Four unrelated patients had a recurrent BRCA1 pathogenic variant: c.4065_4068del (p.Asn1355Lysfs*10). Only two patients in this series elected risk-reducing mastectomy and four patients elected risk-reducing bilateral salpingo-oophorectomy. A higher rate of P/LP variants is seen among Emirati patients at risk for hereditary breast and ovarian cancer syndrome compared with reports of similar patients from Western populations. Efforts to increase utilization and awareness of germline genetic testing are warranted among Emirati patients.

Double heterozygosity is an extremely rare occurrence in hereditary breast and ovarian cancer syndrome (HBOC [MIM 604370; MIM 612555]) where two pathogenic variants, one in BRCA1 and one in BRCA2, are found in an individual. To date, only a few case reports and case series have been reported in the literature (1-3). Furthermore, little is known about the clinical characteristics, family history, and tumor histology in these patients. In this study, we utilized targeted gene testing with next-generation sequencing (NGS) technology in an early-onset metastatic breast cancer patient from France. We evaluated germline variants using Pathway Genomics' BRCATrueTM NGS test, which analyzes variants covering all exons and exon flanking regions in both the BRCA1 and BRCA2 genes. All variant calls were determined after alignment and mapping to the GRCh37/hg19 reference genome. Variant calls were confirmed by Sanger sequencing. In this patient, a c.1016dupA (p.V340GfsX6) frameshift variant was found in BRCA1 along with a c.6814delA (p.R2272EfsX8) frameshift variant in BRCA2. Both frameshift variants are predicted to truncate the BRCA proteins. The BRCA1 c.1016dupA variant is considered a Norwegian founder mutation but has also been observed in individuals who are of French-Canadian, French, Italian or Dutch ancestry (4-7). The BRCA2 c.6814delA (p.R2272Efs*8) pathogenic variant, also known as 7042delA, is predicted to truncate the BRCA2 protein and has been identified in individuals with a personal or family history of breast and/or ovarian cancer (8,9). To the best of our knowledge, the combination of these two pathogenic variants in an individual has not been previously reported. In a clinical diagnostic setting, the possibility of double heterozygosity of pathogenic variants in more than one susceptibility gene should be considered, especially in patients with early-onset metastatic cancers. Furthermore, genetic testing and genetic counseling should also be indicated for high-risk family members. 1. Heidemann, S. et al. (2012) Breast cancer research and treatment 134, 1229-1239 2. Lavie, O., et al. (2011) Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 22, 964-966 3. Nomizu, T., et al. (2012). Breast cancer 4. Andersen, T. I., Borresen, A. L., and Moller, P. (1996) American journal of human genetics 59, 486-487 5. Caputo, S., et al. (2012) Nucleic acids research 40, D992-1002 6. Dorum, A., et al. (1999). American journal of human genetics 65, 671-679 7. Simard, J., et al. (1994). Nature genetics 8, 392-398 8. Novakovic, S., et al. (2012) International journal of oncology 41, 1619-1627 9. Tea, M. K., et al. (2014) Maturitas 77, 68-72. Citation Format: Curtit E, Meynard G, Villanueva C, Mansi L, Chaix M, Vilalta A, Kuo JZ, Villa M, Neidich J, Tomar A, Arianpour A, Lebahar P, Pivot X. Double heterozygosity for BRCA1 and BRCA2 pathogenic variants in a French metastatic breast cancer patient. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-10.

Rates of breast and ovarian cancer are high in the Caribbean; however, to date, few published data quantify the prevalence of inherited cancer in the Caribbean population. To determine whether deleterious variants in genes that characterize the hereditary breast and ovarian cancer syndrome are associated with the development of breast and ovarian cancer in the English- and Creole-speaking Caribbean populations. This multisite genetic association study used data from germline genetic test results between June 2010 and June 2018 in the Bahamas, Cayman Islands, Barbados, Dominica, Jamaica, Haiti, and Trinidad and Tobago. Next-generation sequencing on a panel of 30 genes and multiplex ligation-dependent probe amplification (BRCA1 and BRCA2) were performed. Medical records were reviewed at time of study enrollment. Women and men diagnosed with breast and ovarian cancer with at least 1 grandparent born in the participating study sites were included; 1018 individuals were eligible and consented to participate in this study. Data were analyzed from November 4, 2019, to May 6, 2020. Breast and/or ovarian cancer diagnosis. Rate of inherited breast and ovarian cancer syndrome and spectrum and types of variants. Of 1018 participants, 999 (98.1%) had breast cancer (mean [SD] age, 46.6 [10.8] years) and 21 (2.1%) had ovarian cancer (mean [SD] age, 47.6 [13.5] years). Three individuals declined to have their results reported. A total of 144 of 1015 (14.2%) had a pathogenic or likely pathogenic (P/LP) variant in a hereditary breast and ovarian cancer syndrome gene. A total of 64% of variant carriers had P/LP variant in BRCA1, 23% in BRCA2, 9% in PALB2 and 4% in RAD51C, CHEK2, ATM, STK11 and NBN. The mean (SD) age of variant carriers was 40.7 (9.2) compared with 47.5 (10.7) years in noncarriers. Individuals in the Bahamas had the highest proportion of hereditary breast and ovarian cancer (23%), followed by Barbados (17.9%), Trinidad (12%), Dominica (8.8%), Haiti (6.7%), Cayman Islands (6.3%), and Jamaica (4.9%). In Caribbean-born women and men with breast cancer, having a first- or second-degree family member with breast cancer was associated with having any BRCA1 or BRCA2 germline variant (odds ratio, 1.58; 95% CI, 1.24-2.01; P < .001). A BRCA1 vs BRCA2 variant was more strongly associated with triple negative breast cancer (odds ratio, 6.33; 95% CI, 2.05-19.54; P = .001). In this study, among Caribbean-born individuals with breast and ovarian cancer, 1 in 7 had hereditary breast and ovarian cancer. The proportion of hereditary breast and ovarian cancer varied by island and ranged from 23% in the Bahamas to 4.9% in Jamaica. Each island had a distinctive set of variants.

Introduction/BackgroundTo establish an individualized surgical strategy for ovarian cancer in patients with the germline BRCA1 and BRCA2 pathogenic variants (BRCA1+ and BRCA2+), we investigated the clinicopathological characteristics that are involved...

Women with pathogenic variants in BRCA1 and BRCA2 are at high risk of developing breast and ovarian cancers. They usually undergo intensive cancer surveillance and may also consider surgical interventions, such as risk-reducing mastectomy or risk-reducing salpingo-oophorectomy (RRSO). Risk-reducing salpingo-oophorectomy has been shown to reduce ovarian cancer risk, but its association with breast cancer risk is less clear. To assess the association of RRSO with the risk of breast cancer in women with BRCA1 and BRCA2 pathogenic variants. This case series included families enrolled in the Breast Cancer Family Registry between 1996 and 2000 that carried an inherited pathogenic variant in BRCA1 (498 families) or BRCA2 (378 families). A survival analysis approach was used that was designed specifically to assess the time-varying association of RRSO with breast cancer risk and accounting for other potential biases. Data were analyzed from August 2019 to November 2020. Risk-reducing salpingo-oophorectomy. In all analyses, the primary end point was the time to a first primary breast cancer. A total of 876 families were evaluated, including 498 with BRCA1 (2650 individuals; mean [SD] event age, 55.8 [19.1] years; 437 White probands [87.8%]) and 378 with BRCA2 (1925 individuals; mean [SD] event age, 57.0 [18.6] years; 299 White probands [79.1%]). Risk-reducing salpingo-oophorectomy was associated with a reduced risk of breast cancer for BRCA1 and BRCA2 pathogenic variant carriers within 5 years after surgery (hazard ratios [HRs], 0.28 [95% CI, 0.10-0.63] and 0.19 [95% CI, 0.06-0.71], respectively), whereas the corresponding HRs were weaker after 5 years postsurgery (HRs, 0.64 [95% CI, 0.38-0.97] and 0.99 [95% CI; 0.84-1.00], respectively). For BRCA1 and BRCA2 pathogenic variant carriers who underwent RRSO at age 40 years, the cause-specific cumulative risk of breast cancer was 49.7% (95% CI, 40.0-60.3) and 52.7% (95% CI, 47.9-58.7) by age 70 years, respectively, compared with 61.0% (95% CI, 56.7-66.0) and 54.0% (95% CI, 49.3-60.1), respectively, for women without RRSO. Although the primary indication for RRSO is the prevention of ovarian cancer, it is also critical to assess its association with breast cancer risk in order to guide clinical decision-making about RRSO use and timing. The results of this case series suggest a reduced risk of breast cancer associated with RRSO in the immediate 5 years after surgery in women carrying BRCA1 and BRCA2 pathogenic variants, and a longer-term association with cumulative breast cancer risk in women carrying BRCA1 pathogenic variants.

Background: Hereditary cancer syndromes explain 5-10% of all cancer cases. Germline pathogenic variants in BRCA1 and BRCA2 genes (BRCA) are present in 2-3% of all breast cancer (BC), and 15% of all ovarian cancer (OC) cases. BRCA1 and BRCA2 pathogenic variants (PV) represent 25-28% of BC and 40% of OC patients with a positive familial history. BRCAs are the most studied genes for the prevalence, family history, preventive surgeries, and target treatment options in both BC and OC. There are other genes, important in the diagnosis, pathogenesis, and treatment options of the patients: TP53, PALB2, CHEK2, among others. This study aims to identify the prevalence of non- BRCA genes related to the development of hereditary breast and ovarian cancer syndrome in patients of Northeast Mexico. Methods: This is a multicenter study that recruited patients from two reference oncology centers in Nuevo Leon, Mexico: the CECIL (The CUCC Early Cancer Detection Clinic) Hereditary Cancer Registry and Hereditary Cancer Program from Tec Salud. From March of 2016 to March of 2023, a total of 872 patients meeting NCCN criteria were evaluated by Medical Geneticists from both centers and were tested with NGS multigene cancer panels. Results: A total of 665 (76.26%) patients with a clinical diagnosis of HBOC (Hereditary Breast Hereditary Cancer Syndrome) were included. We found 310 (46.6%) patients had at least one variant, 180 (58%) with at least one pathogenic variant, and 130 (41%) with a VUS (a variant of uncertain significance). BRCA1 was found in 79 (43.8%) and BRCA2 in 32 (17.7%) of all PV. Non-BRCA PV were found in 69 (38.3%) patients: 4 ATM, 2 BLM, 3 BRIP1, 22 CHEK2, 4 CDKN2A, 5 MUTYH, 10 PALB2, 4 RAD51C, 2 SDHA, 2 TP53, 2 WRN, CDH1, CDK4, DICER, MSH3, NBN, PTEN, RAD50, USH2A one of each. Is remarkable that 19 of the 22 patients with CHEK2 and 5 of the 10 patients with PALB2 had the recurrent PV c.707T&amp;gt;C and c.2167_2168del, respectively. Conclusions: Non-BRCA PV in Northern Mexico corresponds to one-third of the BC and OC cases, including HRD (homologous recombination deficiency) genes. HDR patient carriers are potential targets of iPARP therapies. This project reinforces the fact that multigene panels should be employed to ensure a complete diagnosis in hereditary cancer patients. Citation Format: Carlos H. Burciaga-Flores, Diana C. Perez-Ibave, Maria L. Garza-Rodriguez, Oscar Vidal-Gutierrez, Cynthia M. Villarreal-Garza, Dione Aguilar y Mendez. Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3947.

DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)

BackgroundHereditary breast and ovarian cancer (HBOC) is an autosomal dominant inherited cancer susceptibility disorder. Both BRCA1 and BRCA2 genes are considered as high penetrance genes of this syndrome. The identification of BRCA1/2 genetic alterations before cancer development, grant patients the chance to benefit from various medical cancer prevention approaches. Therefore, the appearance of recent advanced technologies in molecular analysis such as next generation sequencing has simplified full BRCA1/2 analysis.Many attempts took place in hope of understanding the molecular germline spectrum of these two genes in Moroccan HBOC patients. However, most of the past projects focused only on young breast cancer cases, lacked ovarian cancer cases in their cohort and only a limited number of these studies were able to analyze the entire exons or copy number variations for both genes.In attempt of gaining more information regarding the molecular profile of BRCA1/2 in HBOC, we conducted a study in which we analyze their molecular profile on selected Moroccan patients suspected of having HBOC syndrome.MethodsIn this study we obtained blood samples from 64 selected Moroccan patients, who suffered from Breast and/or ovarian cancer and had a strong family history for cancer. To analyze BRCA1/2 punctual variants and copy number variations, we used the Ion Personal Genome Machine (PGM) and Oncomine BRCA1/2 research assay panel. Afterward, we correlated the molecular results with the clinic-pathologic data using IBM SPSS Statistics ver 2.ResultsFrom the 64 selected cases, Forty-six had breast cancer, fifteen had ovarian cancer and three had both breast and ovarian cancer. The molecular analysis revealed that 18 patients from the 64 harbored a pathogenic variant (28%). Twelve had six different BRCA1 pathogenic variants and six had six different BRCA2 pathogenic variants. In this study, we report four pathogenic variants that to the best of our knowledge has never been reported in the Moroccan population before. Regarding copy number variation analysis, No CNV was detected in both genes for all the 64 successfully sequenced and analyzed patients in our cohort.ConclusionWork like the present has an important implication on public health and science. It is critical that molecular profiling studies are performed on underserved and understudied population like Morocco.

Background: Hereditary breast and ovarian cancer (HBOC) is a common indication for referral to cancer genetic counselors. Next generation sequencing panels allow for the efficient evaluation of many genes associated with increased risk of these cancers. The purpose of this study is to compare clinical histories of those with pathogenic variants in high risk versus low/moderate risk genes in order to determine which patients might benefit from more extensive testing by a panel approach. Methods: We queried the results of patients tested at GeneDx for a panel of 21 genes causing increased breast and/or ovarian cancer risk. Data regarding personal and family history of cancer provided on the test requisition forms were analyzed and classified according NCCN guidelines for testing criteria for HBOC syndrome. Results: Of 1709 individuals referred for testing, 146 (8.5%) tested positive for a pathogenic variant. Of these, 33% percent were found to carry a pathogenic BRCA1/2 variant while 67% tested positive for a pathogenic variant in a gene other than BRCA1/2 (CHEK2: 17%; ATM: 12%; PALB2: 10%; BRIP1: 7%; BARD1: 3%; PTEN: 3%; each of FANCC, MSH2, MSH6, NBN, PMS2, RAD51C, RAD51D: 2%; MLH1: 1%). Eighty-six percent of these individuals were affected with cancer. In the probands with a pathogenic BRCA1/2 variant, 66% were diagnosed with breast cancer and 22% with ovarian cancer compared to the probands with a pathogenic variant in a gene other than BRCA1/2 of whom 84% had a history of breast cancer and 17% had ovarian cancer. The highest number of breast cancer diagnoses were found, in decreasing order, in association with pathogenic variants in BRCA1 (20), CHEK2 (20), ATM (17), PALB2 (14), BRCA2 (13), and BRIP1 (12). The greatest number of ovarian cancers were identified, in decreasing order, in association with pathogenic variants in BRCA2 (8), BRCA1 (3), CHEK2 (3), and ATM (3). Furthermore, all of the individuals with pathogenic variants met NCCN guidelines for HBOC. Conclusion: A high yield of pathogenic variants were found in genes other than BRCA1/2. Data analysis also shows that individuals with a pathogenic variant in genes other than BRCA1/2 did not have a notably less severe clinical history than those pathogenic variants in BRCA1/2. As all individuals tested meet NCCN guidelines for HBOC testing, panel testing should be considered in this population. Citation Format: Erica Vaccari, Lauren Yackowski, Melanie Hussong, Patricia Murphy, Maria L Cremona, Jessica Booker, Kathleen Hruska. Characterizing the clinical presentation of individuals with pathogenic variants in a breast/ovarian cancer gene panel [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-01.