A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes (original) (raw)
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Expert Review of Anticancer Therapy, 2019
In the past five years, multi-gene panels have replaced the practice of BRCA1 and BRCA2 genetic testing in cases of suspected inherited breast cancer susceptibility. A variety of genes have been included on these panels without certainty of their clinical utility. Pertinent current and historical literature was reviewed to provide an up-to-date snapshot of the changing landscape of the use of gene panel tests in the context of breast cancer. Areas covered: Following a recent review of the evidence, ten genes have been found to have definitive evidence of increased breast cancer risk with variable penetrance. Here, we review the recent changes to the practice of multi-gene panel use in breast cancer diagnoses, including an update on next generation sequencing, alternative models of genetic testing, considerations when ordering these panel tests, and recommendations for management in identified carriers for a variety of genes. A comparison of screening recommendations and carrier frequencies from recent studies are also explored. Lastly, we consider what the future of hereditary oncologic genetic testing holds.
Multi gene panel testing for hereditary breast cancer - is it ready to be used?
Medicine and Pharmacy Reports
Breast cancer is one of the most common malignancies and the leading cause of death among women worldwide. About 20% of breast cancers are hereditary. Approximately 30% of the mutations have remained negative after testing BRCA1/2 even in families with a Mendelian inheritance pattern for breast cancer. Additional non-BRCA genes have been identified as predisposing for breast cancer. Multi gene panel testing tries to cover and explain the BRCA negative inherited breast cancer, improving efficiency, speed and costs of the breast cancer screening. We identified 23 studies reporting results from individuals who have undergone multi gene panel testing for hereditary breast cancer and noticed a prevalence of 1-12% of non-BRCA genes, but also a high level of variants of uncertain significance. A result with a high level of variants of uncertain significance is likely to be more costly than bring benefits, as well as increase the anxiety for patients. Regarding further development of multi ...
Gene Panel Testing in Hereditary Breast Cancer
Archives of Iranian medicine, 2020
BACKGROUND Breast cancer (BC) is a highly complex, heterogeneous and multifactorial disease and is the most commonly diagnosed cancer and the leading cause of cancer-related mortality in women worldwide. Family history and genetic mutations are important risk factors for BC. While studies in twins have estimated that about 10%-30% of BC are due to hereditary factors, only 4%-5% of them are due to mutations in BRCA1 or BRCA2 genes. Our aim was to investigate the role of other BC genes in familial BC among the Iranian population. METHODS We selected 61 BC patients who were wild-type for BRCA1 and BRCA2 mutations but who met the criteria for hereditary BC based on the American College of Medical Genetics and Genomics (ACMG) and the National Comprehensive Cancer Network (NCCN) guidelines. We performed targeted sequencing covering the exons of 130 known cancer susceptibility genes based on the Cancer Gene Census list. RESULTS We found seven mutations in seven known BC susceptibility gene...
Breast cancer is an important public health problem in Nigeria. With an estimated age-standardized rate of approximately 50 per 100,000 per year, it is the most common cancer in women, representing approximately 40% of all cancers and approximately one third of cancer deaths among women. In 2012, this amounted to . 27,000 new cases and 13,000 deaths, reflecting a high case fatality ratio. 1 Projections to 2030 indicate that new cases per year will increase by at least 60% because of the demographic transition alone, with potential further increases due to changes in risk factors.
Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle?
Journal of Clinical Oncology, 2018
Purpose An estimated 10% of breast and ovarian cancers result from hereditary causes. Current testing guidelines for germ line susceptibility genes in patients with breast carcinoma were developed to identify carriers of BRCA1/ 2 variants and have evolved in the panel-testing era. We evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing. Methods An institutional review board–approved multicenter prospective registry was initiated with 20 community and academic sites experienced in cancer genetic testing and counseling. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Consecutive patients 18 to 90 years of age were consented and underwent an 80-gene panel test. Health Insurance Portability and Accountability Act–compliant electronic case report forms collected in...
Annals of Surgical Oncology, 2019
Background. The purpose of this consensus guideline is to outline recommendations for genetic testing that medical professionals can use to assess hereditary risk for breast cancer. Methods. Literature review included large datasets, basic and clinical science publications, and recent updated national guidelines. Genetic testing to assess hereditary risk of cancer is a complex, broad, and dynamic area of medical research. The dominant focus of this guideline is limited in scope to breast cancer. Results. There is a lack of consensus among experts regarding which genes among many should be tested in different clinical scenarios. There is also variation in the degree of consensus regarding the understanding of risk and appropriate clinical management of mutations in many genes. Conclusions. Genetic testing should be made available to all patients with a personal history of breast cancer. Recent data are reviewed that support genetic testing being offered to each patient with breast cancer (newly diagnosed or with a personal history). If genetic testing is performed, such testing should include BRCA1/BRCA2 and PALB2, with other genes as appropriate for the clinical scenario and family history. For patients with newly diagnosed breast cancer, identification of a mutation may impact local treatment recommendations. Patients who had genetic
Breast cancer research and treatment, 2017
BRCA mutations contribute to about 20% of all hereditary breast cancers. With full-genome sequencing as the emerging standard for genetic testing, other breast cancer susceptibility genes have been identified and may collectively contribute to up to 30% of all hereditary breast cancers. We re-assessed women who had previously tested negative for a BRCA mutation when outdated techniques were used, and discuss the implications of identifying a mutation several years after initial genetic testing. We evaluated the prevalence of mutations in 12 breast cancer susceptibility genes (including BRCA1 and BRCA2) in 190 breast cancer patients with a strong family history of breast cancer. These women had previously tested negative for mutations in the large coding exons of BRCA1 and BRCA2 using the protein truncation test (PTT) between the years of 1996 and 2013. We identified pathogenic mutations in 17 of 190 (9%) women. Six mutations were detected in BRCA1 (n = 2) and BRCA2 (n = 4). Eleven m...
Cancers
Patients with unilateral breast cancer (UBC) have an increased risk of developing bilateral breast cancer (BBC). The annual risk of contralateral BC is about 0.5%, but increases by up to 3% in BRCA1 or BRCA2 pathogenic variant (PV) carriers. Our study was aimed to evaluate whether all BBC patients should be offered multi-gene panel testing, regardless their cancer family history and age at diagnosis. We retrospectively collected all clinical information of 139 BBC patients genetically tested for germline PVs in different cancer susceptibility genes by NGS-based multi-gene panel testing. Our investigation revealed that 52 (37.4%) out of 139 BBC patients harbored germline PVs in high- and intermediate-penetrance breast cancer (BC) susceptibility genes including BRCA1, BRCA2, PTEN, PALB2, CHEK2, ATM, RAD51C. Nineteen out of 53 positively tested patients harbored a PV in a known BC susceptibility gene (no-BRCA). Interestingly, in the absence of an analysis performed via multi-gene panel...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2018
Breast cancer is an important public health problem in Nigeria. With an estimated age-standardized rate of approximately 50 per 100,000 per year, it is the most common cancer in women, representing approximately 40% of all cancers and approximately one third of cancer deaths among women. In 2012, this amounted to. 27,000 new cases and 13,000 deaths, reflecting a high case fatality ratio. 1 Projections to 2030 indicate that new cases per year will increase by at least 60% because of the demographic transition alone, with potential further increases due to changes in risk factors. In the article that accompanies this editorial, Zheng and colleagues 2 describe a case-control study of hereditary breast cancer in Nigeria. Cases were 1,136 women with breast cancer unselected for age or family history, and controls were 997 unaffected community controls who underwent multigene panel testing, conducted at the at University of Washington, Seattle, Washington. Genetic testing was performed on a research basis, with results not being disclosed to study participants, per institutional review board. Approximately 15% of cases carried a pathogenic variant (mutation), including BRCA1 (7.0%), BRCA2 (4.2%), PALB2 (1.0%), TP53 (0.4%), and 12 other genes implicated in breast cancer risk. When limited to mutations in the four high-risk genes (BRCA1, BRCA2, PALB2, and TP53), 11% to 12% of cases in this study carried a loss-of-function variant. There was considerable allelic heterogeneity, with no strong founder effect. The background rate among controls was 1.8% for all mutations and 0.7% for the four high-risk genes. A previous study of among unselected women with breast cancer in Nigeria yielded similar results for BRCA1 and BRCA2. 3 These results suggest a pathogenic variant frequency of approximately one in 150 Nigerian women for these four actionable genes for which the National Comprehensive Cancer Network includes tailored management recommendations (ie, enhanced screening with breast magnetic resonance imaging, risk-reducing bilateral mastectomy, and risk-reducing bilateral salpingooophorectomy). The findings from Zheng et al 2 raise questions about practical implications for adopting a high-risk approach as one strategy to reduce breast cancer incidence and mortality in Nigeria. Nigeria has an estimated 32,407,926 women age 25 to 64 years, arguably the target ages for a hereditary breast cancer
Cancers
Background: Hereditary cancer predisposition syndromes are responsible for approximately 5–10% of all diagnosed cancer cases. In order to identify individuals at risk in a cost-efficient manner, family members of individuals carrying pathogenic alterations are tested only for the specific variant that was identified in their carrier relative. The purpose of this study was to investigate the clinical use and implementation of cascade family testing (CFT) in families of breast cancer patients with pathogenic/likely pathogenic variants (PVs/LPVs) in cancer-related predisposition genes. Methods: Germline sequencing was carried out with NGS technology using a 52-gene panel, and cascade testing was performed by Sanger sequencing or MLPA. Results: In a cohort of 1785 breast cancer patients (families), 20.3% were found to have PVs/LPVs. Specifically, 52.2%, 25.1%, and 22.7% of patients had positive findings in high-, intermediate-, and low-penetrance breast cancer susceptibility genes, resp...