The association between age at breast cancer diagnosis and prevalence of pathogenic variants.

Purpose: Young age at breast cancer (BC) diagnosis and family history of BC are strongly associated with high prevalence of pathogenic variants (PVs) in BRCA1 and BRCA2 genes. There is limited evidence for such associations with moderate/high penetrance BC-risk genes such as ATM, CHEK2, and PALB2.

Methods: We analyzed multi-gene panel testing results (09/2013-12/2019) for women unaffected by any cancer (N = 371,594) and those affected with BC (N = 130,151) ascertained for suspicion of hereditary breast and/or ovarian cancer.

Development and Validation of a Breast Cancer Polygenic Risk Score on the Basis of Genetic Ancestry Composition.

Purpose: Polygenic risk scores (PRSs) for breast cancer (BC) risk stratification have been developed primarily in women of European ancestry. Their application to women of non-European ancestry has lagged because of the lack of a formal approach to incorporate genetic ancestry and ancestry-dependent variant frequencies and effect sizes. Here, we propose a multiple-ancestry PRS (MA-PRS) that addresses these issues and may be useful in the development of equitable PRSs across other cancers and common diseases.

Performance of the IBIS/Tyrer-Cuzick model of breast cancer risk by race and ethnicity in the Women's Health Initiative.

Background: The IBIS/Tyrer-Cuzick model is used clinically to guide breast cancer screening and prevention, but was developed primarily in non-Hispanic White women. Little is known about its long-term performance in a racially/ethnically diverse population.

Methods: The Women's Health Initiative study enrolled postmenopausal women from 1993-1998.

Age of ovarian cancer diagnosis among BRIP1, RAD51C, and RAD51D mutation carriers identified through multi-gene panel testing.

Background: Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013-May 2019 were included (N = 631,950).

Multigene assessment of genetic risk for women for two or more breast cancers.

Purpose: The prevalence, penetrance, and spectrum of pathogenic variants that predispose women to two or more breast cancers is largely unknown.

Methods: We queried clinical and genetic data from women with one or more breast cancer diagnosis who received multigene panel testing between 2013 and 2018. Clinical data were obtained from provider-completed test request forms.

Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated () Gene are Associated with High and Moderate Risks for Multiple Cancers.

Pathogenic variants (PVs) in are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel ( = 627,742).

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

Purpose: 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.

Methods: MMR gene PV carriers were identified among women tested for suspicion of LS or hereditary breast and ovarian cancer (HBOC) who met inclusion criteria.

Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer.

This study uses Women’s Health Initiative data to compare the prevalence of pathogenic variants (PVs) in breast cancer susceptibility genes in postmenopausal women with vs without breast cancer to guide decisions about who should undergo PV testing.

High risk of breast cancer in women with biallelic pathogenic variants in CHEK2.

Purpose: Compared to breast cancer risk genes such as BRCA2, ATM, PALB2, and NBN, no defined phenotype is currently associated with biallelic pathogenic variants (PVs) in CHEK2. This study compared the prevalence of breast and other cancers in women with monoallelic and biallelic CHEK2 PVs.

Methods: CHEK2 PV carriers were identified through commercial hereditary cancer panel testing (09/2013-07/2019).

Association of Tumor-Infiltrating Lymphocytes with Homologous Recombination Deficiency and Status in Patients with Early Triple-Negative Breast Cancer: A Pooled Analysis.

Purpose: Patients with triple-negative breast cancer (TNBC) with homologous recombination deficient tumors achieve significantly higher pathologic complete response (pCR) rates when treated with neoadjuvant platinum-based therapy. Tumor-infiltrating lymphocytes (TIL) are prognostic and predictive of chemotherapy benefit in early stage TNBC. The relationship between TILs, mutation status, and homologous recombination deficiency (HRD) status in TNBC remains unclear.

Detection of large rearrangements in a hereditary pan-cancer panel using next-generation sequencing.

Background: Healthcare providers increasingly use information about pathogenic variants in cancer predisposition genes, including sequence variants and large rearrangements (LRs), in medical management decisions. While sequence variant detection is typically robust, LRs can be difficult to detect and characterize and may be underreported as a cause for hereditary cancer risk. This report describes the outcomes of hereditary cancer genetic testing using a comprehensive strategy that employs next-generation sequencing (NGS) for LR detection, coupled with LR confirmation using repeat hybrid capture NGS, microarray comparative genomic hybridization (microarray-CGH), and/or multiplex ligation-dependent probe amplification (MLPA).

A substantial proportion of apparently heterozygous TP53 pathogenic variants detected with a next-generation sequencing hereditary pan-cancer panel are acquired somatically.

Previous analysis of next-generation sequencing (NGS) hereditary pan-cancer panel testing demonstrated that approximately 40% of TP53 pathogenic and likely pathogenic variants (PVs) detected have NGS allele frequencies between 10% and 30%, indicating that they likely are acquired somatically. These are seen more frequently in older adults, suggesting that most result from normal aging-related clonal hematopoiesis. For this analysis, apparent heterozygous germline TP53 PV carriers (NGS allele frequency 30-70%) were offered follow-up testing to confirm variant origin.

Clinical outcomes in men with prostate cancer who selected active surveillance using a clinical cell cycle risk score.

To evaluate active surveillance (AS) selection, safety and durability among men with low-risk prostate cancer assessed using the clinical cell cycle risk (CCR) score, a combined clinical and molecular score. Initial treatment selection (AS vs treatment) and duration of AS were evaluated for men with low-risk prostate cancer according to the CCR score and National Comprehensive Cancer Network guidelines. Adverse events included biochemical recurrence and metastasis.

Prediction of Distant Recurrence Using EndoPredict Among Women with ER, HER2 Node-Positive and Node-Negative Breast Cancer Treated with Endocrine Therapy Only.

Purpose: Prognostic molecular assays may aid in treatment decisions for women with estrogen receptor (ER)-positive, HER2-negative breast cancer. The prognostic value of a 12-gene expression assay (EndoPredict) was reevaluated in the combined ABCSG-6/8 cohorts with longer clinical follow-up.

Experimental Design: EndoPredict (EP; molecular score, EPclin score) was evaluated in women with ER-positive, HER2-negative node-positive and node-negative breast cancer who received 5 years of endocrine therapy only (median follow-up, 9.

Prevalence and characteristics of likely-somatic variants in cancer susceptibility genes among individuals who had hereditary pan-cancer panel testing.

Next-generation sequencing (NGS) hereditary pan-cancer panel testing can identify somatic variants, which exhibit lower allele frequencies than do germline variants and may confound hereditary cancer predisposition testing. This analysis examined the prevalence and characteristics of likely-somatic variants among 348,543 individuals tested using a clinical NGS hereditary pan-cancer panel. Variants showing allele frequencies between 10% and 30% were interpreted as likely somatic and identified in 753 (0.

Hereditary Cancer Risk Assessment and Genetic Testing in the Community-Practice Setting.

Objective: To evaluate the feasibility and results of incorporating routine hereditary cancer risk assessment, counseling, and follow-up genetic testing in the community obstetrics and gynecology practice setting without referral to a genetic counselor.

Methods: This prospective process intervention study was conducted with two obstetrics and gynecology practice groups (five sites). The intervention included baseline process assessment, refinement of clinic-specific patient screening workflows and tools, and training in hereditary cancer risk screening and follow-up.

A genealogical assessment of familial clustering of anorectal malformations.

Familial recurrence of anorectal malformations (ARMs) has been reported in single institution case series and in two population-based studies. Here, we investigate the familial aggregation of ARMs using well-established, unbiased methods in a population genealogy of Utah. Study subjects included 255 ARM cases identified from among the two largest healthcare providers in Utah with linked genealogy data using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes.

Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories.

Genetic testing for inherited cancer risk is now widely used to target individuals for screening and prevention. However, there is limited evidence available to evaluate the clinical utility of various testing strategies, such as single-syndrome, single-cancer, or pan-cancer gene panels. Here we report on the outcomes of testing with a 25-gene pan-cancer panel in a consecutive series of 252,223 individuals between September 2013 and July 2016.

A population-based description of familial clustering of Hirschsprung disease.

Background: Familial recurrence of Hirschsprung disease (HSCR) is well documented, and risk estimates for relatives have been reported from various populations. We describe the familial clustering of HSCR cases using well-established unbiased familial aggregation techniques within the context of a population genealogy.

Methods: Patients included 264 HSCR cases identified using ICD-9 diagnosis coding from the two largest healthcare providers in Utah who also had linked genealogy data.