Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!

Abdel‐Razeq, Hikmat

doi:10.4081/oncol.2021.544

Cited by 4 publications

(4 citation statements)

References 49 publications

(63 reference statements)

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“…A criticism of providing MGPT for all patients with cancer is the wide variability in panel composition, which may lead to inclusion of moderate- and low-penetrance genes, 81 , 85 potentially limiting the clinical implications of including such genes for testing. However, published management guidelines for several moderate- and even low-penetrance cancer risk genes do exist.…”

Section: Innovating Implementation Strategiesmentioning

confidence: 99%

Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer

Nielsen

Bristow

Garber

et al. 2022

JCO Precision Oncology

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Section: Innovating Implementation Strategiesmentioning

confidence: 99%

Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer

Nielsen

Bristow

Garber

et al. 2022

JCO Precision Oncology

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“…16 Several studies have performed cost modeling of expanding testing that accounts for appropriate screenings and risk-reducing interventions. 17 An analysis of population-based germline genetic testing of unselected women aged 50 years and younger in the United Kingdom and US using a panel comprising BRCA1/2, PALB2, RAD51C, RAD51D, and BRIP1 was found to reduce breast cancer incidence and was more cost-effective than a guideline-based strategy. 18 To fully assess the changes resulting from germline testing, it is vital to monitor treatment decisions and patient outcomes.…”

Section: Introductionmentioning

confidence: 99%

Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer

et al. 2022

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ImportanceNational Comprehensive Cancer Network guidelines currently recommend germline testing for high-risk genes in selected patients with breast cancer. The clinical utility of recommending testing all patients with breast cancer with multigene panels is currently under consideration.ObjectiveTo examine the implications of universal testing of patients with breast cancer with respect to clinical decision-making.Design, Setting, and ParticipantsPatients from a previously reported cohort were assessed as in-criteria or out-of-criteria according to the 2017 guidelines and underwent testing with a multigene germline panel between 2017 to 2018. Patients were women and men aged 18 to 90 years, with a new and/or previous diagnosis of breast cancer who had not undergone either single or multigene testing. Clinicians from 20 community and academic sites documented patient clinical information and changes to clinical recommendations made according to test findings. Association between prevalence of pathogenic or likely pathogenic germline variants and previously unreported clinical features, including scores generated by the BRCAPRO statistical model, was determined. Data were analyzed from April 2020 to May 2022.ExposureNew and/or previous diagnosis of breast cancer.Main Outcomes and MeasuresDisease management recommendations that were changed as a result of genetic testing results are reported.ResultsClinicians were asked to assess changes to clinical management as a result of germline genetic testing for 952 patients. Informative clinician-reported recommendations were provided for 939 (467 in-criteria and 472 out-of-criteria) of the patients with breast cancer (936 [99.7%] female; 702 [74.8%] White; mean [SD] age at initial diagnosis, 57.6 [11.5] years). One or more changes were reported for 31 of 37 (83.8%) in-criteria patients and 23 of 34 (67.6%) out-of-criteria patients with a pathogenic or likely pathogenic variant. Recommendations were changed as a result of testing results for 14 of 22 (63.6%) out-of-criteria patients who had a variant in a breast cancer predisposition gene. Clinicians considered testing beneficial for two-thirds of patients with pathogenic or likely pathogenic variants and for one-third of patients with either negative results or variants of uncertain significance. There was no difference in variant rate between patients meeting the BRCAPRO threshold (≥10%) and those who did not (P = .86, Fisher exact test). No changes to clinical recommendations were made for most patients with negative results (345 of 349 patients [98.9%]) or variants of uncertain significance (492 of 509 patients [96.7%]).Conclusions and RelevanceIn this cohort study, germline genetic testing was used by clinicians to direct treatment for most out-of-criteria patients with breast cancer with pathogenic or likely pathogenic germline variants, including those with moderate-risk variants. Universal germline testing informs clinical decision-making and provides access to targeted treatments and clinical trials for all patients with breast cancer.

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“…Jordan, as an upper-middle-income country, where 43–55% of all identified BRCA events are potential founder events, has a real opportunity to benefit of a customized BRCA screening panel to detect healthy carriers prior to costly disease treatment. Indeed, adopting such an early detection approach would certainly decrease the current estimated incidence of late diagnoses of breast cancer in the country, which makes ~ 12% of new cases (double the rate of developed countries) [ 15 ]. This is the first report highlighting the preponderance of BRCA1/2 founder variants in Jordan.…”

Section: Discussionmentioning

confidence: 99%

“…TP3 ) [ 14 ], and genetic testing and counseling have become an integral part of routine clinical practice. Nevertheless, many experts are continuously calling for expanding current testing guidelines both horizontally by including more patients and vertically by expanding the panel of genes tested for [ 15 , 16 ]. Mary-Claire King, who was the first to describe BRCA1 , has suggested that genetic screening, of at least BRCA1/2 , should be offered to every woman at around the age of 30 years, in order to detect healthy carriers prior to cancer onset [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

BRCA1/2 potential founder variants in the Jordanian population: an opportunity for a customized screening panel

Ahmad

Sutter

Hirsch

et al. 2023

Hered Cancer Clin Pract

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A founder variant is a genetic alteration, that is inherited from a common ancestor together with a surrounding chromosomal segment, and is observed at a high frequency in a defined population. This founder effect occurs as a consequence of long-standing inbreeding of isolated populations. For high-risk cancer predisposition genes, such as BRCA1/2, the identification of founder variants in a certain population could help designing customized cost-effective cancer screening panels. This advantage has been best utilized in designing a customized breast cancer BRCA screening panel for the Ashkenazi Jews (AJ) population, composed of the three BRCA founder variants which account for approximately 90% of identified BRCA alterations. Indeed, the high prevalence of pathogenic BRCA1/2 variants among AJ (~ 2%) has additionally contributed to make population-based screening cost-effective in comparison to family-history-based screening. In Jordan there are multiple demographic characteristics supporting the proposal of a founder effect. A high consanguinity rate of ~ 57% in the nineties of the last century and ~ 30% more recently is a prominent factor, in addition to inbreeding which is often practiced by different sub-populations of the country.This review explains the concept of founder effect, then applies it to analyze published Jordanian BRCA variants, and concludes that nine pathogenic (P) and likely pathogenic (LP) BRCA2 variants together with one pathogenic BRCA1 variant are potential founder variants. Together they make up 43% and 55% of all identified BRCA1/2 alterations in the two largest studied cohorts of young patients and high-risk patients respectively. These variants were identified based on being recurrent and either specific to ethnic groups or being novel. In addition, the report highlights the required testing methodologies to validate these findings, and proposes a health economic evaluation model to test cost-effectiveness of a population-based customized BRCA screening panel for the Jordanian population. The aim of this report is to highlight the potential utilization of founder variants in establishing customized cancer predisposition services, in order to encourage more population-based genomic studies in Jordan and similar populations.

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Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!

Cited by 4 publications

References 49 publications

Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer

Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer

Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer

BRCA1/2 potential founder variants in the Jordanian population: an opportunity for a customized screening panel

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