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Purpose: We compared 21-gene recurrence score (RS) distribution and expression of the single-gene/gene groups within this assay between BC patients with pathogenic variants (PV) in BRCA1/2 vs the general 21-gene-tested BC population., Methods: This retrospective study included consecutive 21-gene-tested female ER + HER2-negative BC patients with germline PVs in BRCA1/2. RS/gene expression data were compared to a previously described commercial use database (CDB, N = 799,986). Chi-square and 1-sample t test were used to compare RS distribution and single-gene/gene group scores between the study group and the CDB., Results: Study group patients (N = 81) were younger and their RS results were higher compared to the CDB (age: median [IQR], 56 [47-61.5] vs 60 [51-67] years; p < 0.001; proportion of patients with RS ≥ 26: 49.4% vs 16.4%, p < 0.001). Expression of 12/16 cancer genes in the assay and the ER, proliferation, and invasion gene group scores differed significantly between the study group and the CDB, all in a direction contributing to higher RS. The differences between the study group and the CDB were mostly retained, upon stratifying the patients by menopausal status., Conclusion: BC patients with PVs in BRCA1/2 have higher RS results that stem from distinct gene expression profiles in the majority of genes in the 21-gene assay., (© 2024. The Author(s).)

Purpose: To evaluate the total biopsy and positive biopsy rates in women at high risk of breast cancer compared to the general population., Methods: The study group consisted of 330 women with pathogenic variants (PVs) in BRCA1/2 attending the dedicated multidisciplinary breast cancer clinic of a tertiary medical center in Israel. Clinical, genetic, and biopsy data were retrieved from the central healthcare database and the medical files. Patients aged 50 years or older during follow-up were matched 1:10 to women in the general population referred for routine breast cancer screening at the same age, as recommended by international guidelines. The groups were compared for rate of biopsy studies performed and percentage of positive biopsy results. Matched analysis was performed to correct for confounders., Results: The total biopsy rate per 1000 follow-up years was 61.7 in the study group and 22.7 in the control group (p < 0.001). The corresponding positive biopsy rates per 1000 follow-up years were 26.4 and 2.0 (p < 0.001), and the positive biopsy percentages, 42.9% and 8.7% (p < 0.0001)., Conclusion: Women aged 50 + years with PVs in BRCA1/2 attending a dedicated clinic have a 2.7 times higher biopsy rate per 1000 follow-up years, a 13.2 times higher positive biopsy rate per 1000 follow-up years, and a 4.9 times higher positive biopsy percentage than same-aged women in the general population., (© 2022. The Author(s).)

Purpose: BRCA1/2 founder pathogenic variants (PVs) occur in various populations, but data on the mutational spectrum in Africans are limited. We examined BRCA1/2 PVs in breast cancer patients of Ethiopian Jewish (EJ) origin., Methods: We retrospectively analyzed BRCA1/2 test results and clinical features of EJ breast cancer patients from seven medical institutions. We obtained heterozygote carrier rates in affected individuals from the laboratories of the largest Israeli HMO (Clalit). Population carrier frequency was determined in EJ controls., Results: We identified three recurrent BRCA2 PVs in 11 EJ breast cancer patients (9 females, 2 males): c.7579delG, c.5159C > A, and c.9693delA. Only c.5159C > A was previously reported in Africans. In women, mean age at diagnosis was 35.7y; 8/9 were diagnosed with advanced disease. All tumors were invasive, 4/9 were triple negative. Only 3/11 carriers had relevant family history. Carrier rate in high-risk breast cancer patients was 11% (3/28; 95%CI [2.3%, 28.2%]). Combined carrier rate among controls was 1.8% (5/280; 95%CI [0.6%, 4.1%])., Conclusion: EJs harbor 3 recurrent BRCA2 PVs presenting with relatively severe breast cancer morbidity. Combined with the high BRCA2 carrier rate in the EJ population, these findings merit increasing awareness in this community and suggest that a culturally adapted population screening approach may be warranted., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes., Methods: Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed., Results: Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984&#95;3987dupGTCA founder PV; 3 patients had the MSH6 c.3956&#95;3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1-2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36-76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines., Conclusions: This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Carriers of pathogenic variants (PVs) in moderate-high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear., Methods: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018., Results: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals., Conclusions: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.

Oncotype-DX assay has never been validated for BRCA mutation carriers. This study compares the recurrence score (RS) distribution in BRCA-positive breast cancer patients with that of a general population (GP) of patients and reports their outcomes. Eligible patients were BRCA carriers who performed the Oncotype-DX assay. Two sets of databases were cross-linked: BRCA carriers at Rabin Medical Center and Sheba Medical Center with Oncotype-DX tests performed through Clalit Health Services HMO, from 2003 to 2015. Fifty-eight BRCA patients were included (20 BRCA1, 38 BRCA2). The GP included 1020 patients. Compared to the GP, BRCA1 patients were younger, had higher rate of grade three tumors, and higher Ki67. BRCA2 patients had lower PR index, higher rate of grade three tumors, and higher Ki67. Among the GP, 52.9, 37.9, and 9.1 % had low, intermediate, and high risk RS, respectively. Corresponding rates were 15, 35, and 50 % in BRCA1 patients, and 18.4, 52.6, and 29 % in BRCA2 patients. Subgroup analysis revealed a similar RS distribution pattern regardless of the nodal status. Median follow-up was 45 months. Four BRCA patients (7 %) developed disease recurrence. RS of these patients were in the intermediate and low range. All recurrences occurred in chemo-naïve patients who had not undergone bilateral oophorectomy. This study revealed significantly different RS distributions between BRCA patients and the GP. RS values shifted toward high and intermediate risk categories. This pattern held regardless of the nodal status and was more pronounced in the BRCA1 group.