A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients

LaDuca, Holly; Polley, Eric C.; Yussuf, Amal; Hoang, Lily; Gutierrez, Stephanie; Hart, Steven N.; Yadav, Siddhartha; Hu, Chunling; Na, Jie; Goldgar, David E.; Fulk, Kelly; Smith, Laura P.; Horton, Carolyn; Profato, Jessica; Pesaran, Tina; Gau, Chia Ling; Pronold, Melissa; Davis, Brigette Tippin; Chao, Elizabeth; Couch, Fergus J.; Dolinsky, Jill S.

doi:10.1038/s41436-019-0633-8

Cited by 153 publications

(179 citation statements)

References 33 publications

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“…As a comparator, gross deletion and/or duplication analysis, which is routinely included as a component of DGT, identifies pathogenic variants in 1 of 142 patients tested. 30 Thus, if RGT were routinely performed alongside DGT, the potential consequences would exceed that of gross deletion and/or duplication analysis. This estimation also underestimates the overall number of individuals, since RGT may also detect intronic splicing variants outside the analytical range of clinical DGT that are currently not accounted for.…”

Section: Limitationsmentioning

confidence: 99%

Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer

et al. 2019

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IMPORTANCE Performing DNA genetic testing (DGT) for hereditary cancer genes is now a wellaccepted clinical practice; however, the interpretation of DNA variation remains a challenge for laboratories and clinicians. Adding RNA genetic testing (RGT) enhances DGT by clarifying the clinical actionability of hereditary cancer gene variants, thus improving clinicians' ability to accurately apply strategies for cancer risk reduction and treatment. OBJECTIVE To evaluate whether RGT is associated with improvement in the diagnostic outcome of DGT and in the delivery of personalized cancer risk management for patients with hereditary cancer predisposition. DESIGN, SETTING, AND PARTICIPANTS Diagnostic study in which patients and/or families with inconclusive variants detected by DGT in genes associated with hereditary breast and ovarian cancer, Lynch syndrome, and hereditary diffuse gastric cancer sent blood samples for RGT from March 2016 to April 2018. Clinicians who ordered genetic testing and received a reclassification report for these variants were surveyed to assess whether RGT-related variant reclassifications changed clinical management of these patients. To quantify the potential number of tested individuals who could benefit from RGT, a cohort of 307 812 patients who underwent DGT for hereditary cancer were separately queried to identify variants predicted to affect splicing. Data analysis was conducted from March 2016 and September 2018. MAIN OUTCOMES AND MEASURES Variant reclassification outcomes following RGT, clinical management changes associated with RGT-related variant reclassifications, and the proportion of patients who would likely be affected by a concurrent DGT and RGT multigene panel testing approach. Author affiliations and article information are listed at the end of this article. Open Access. This is an open access article distributed under the terms of the CC-BY-NC-ND License.

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Section: Limitationsmentioning

confidence: 99%

Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer

et al. 2019

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“…To put this into perspective, let's look at a real‐world example related to breast cancer prevention and treatment. With the dramatic drop in the cost of DNA sequencing and the wide availability of multigene‐cancer panels, a rapidly increasing number of patients are receiving germline genetic testing, and many are found to have pathogenic variants in genes other than BRCA1 and BRCA2 . Providing patients with accurate risk estimates of developing cancer for each cancer susceptibility gene (penetrance) has become an emergent need for practicing physicians, as this is considered the foundation for personalizing prevention strategies for patients and their families …”

Section: The Explosion Of Medical Literature: History and Realitymentioning

confidence: 99%

Natural language processing to facilitate breast cancer research and management

et al. 2019

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The medical literature has been growing exponentially, and its size has become a barrier for physicians to locate and extract clinically useful information. As a promising solution, natural language processing (NLP), especially machine learning (ML)-based NLP is a technology that potentially provides a promising solution. ML-based NLP is based on training a computational algorithm with a large number of annotated examples to allow the computer to "learn" and "predict" the meaning of human language.Although NLP has been widely applied in industry and business, most physicians still are not aware of the huge potential of this technology in medicine, and the implementation of NLP in breast cancer research and management is fairly limited. With a real-world successful project of identifying penetrance papers for breast and other cancer susceptibility genes, this review illustrates how to train and evaluate an NLPbased medical abstract classifier, incorporate it into a semiautomatic meta-analysis procedure, and validate the effectiveness of this procedure. Other implementations of NLP technology in breast cancer research, such as parsing pathology reports and mining electronic healthcare records, are also discussed. We hope this review will help breast cancer physicians and researchers to recognize, understand, and apply this technology to meet their own clinical or research needs. K E Y W O R D Sbreast cancer, genetics, medical literature, natural language processing

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“…For example, application of the NCCN version 2.2017 criteria to a cohort of 1371 newly diagnosed breast cancer patients from Norway who were tested for BRCA1 and BRCA2 mutations, revealed that 32 of 38 (88.9%) mutation carriers would have been classified as high-risk [13]. More recently, evaluation of 165,000 high-risk patients found that 5.8% of patients with BRCA1/2 mutations did not meet NCCN version 1.2018 guidelines [14]. Within our study, 6.5% of patients with BRCA1/2 mutations were classified as low-risk.…”

Section: Discussionmentioning

confidence: 99%

Should Genetic Testing for Cancer Predisposition Be Standard-of-Care for Women with Invasive Breast Cancer? The Murtha Cancer Center Experience

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Lovejoy

Turner

et al. 2020

Cancers

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Currently, genetic testing is offered only to women diagnosed with breast cancer who meet a defined set of criteria and is not included as standard-of-care treatment at the time of diagnosis. Thus, a significant number of women diagnosed with breast cancer may miss the opportunity for precision medical treatment and risk management. The effects of eligibility, timing, and uptake of genetic testing were evaluated in a cohort of women with invasive breast cancer diagnosed between 2001–2018. Risk status was estimated using NCCN BRCA1/2 testing criteria and panel testing was performed for all women who had genomic DNA available. Of the 1231 women, 57.8% were eligible for genetic testing. Uptake of testing within high-risk women was 42.7% of which 6.6% pursued clinical testing only after a second tumor event. Mutation frequencies were 15.8%, 5.5%, and 4.0% in high-risk women with clinical testing, high-risk women without clinical testing, and low-risk women, respectively. More than 4% of all patients harbored pathogenic or likely pathogenic mutations detected only in the research setting. Inclusion of panel testing at the time of diagnosis would allow for appropriate surveillance and treatment strategies to be employed to reduce the risk of secondary tumors and improve patient outcome.

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A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients

Cited by 153 publications

References 33 publications

Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer

Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer

Natural language processing to facilitate breast cancer research and management

Should Genetic Testing for Cancer Predisposition Be Standard-of-Care for Women with Invasive Breast Cancer? The Murtha Cancer Center Experience

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