The Future of Parallel Tumor and Germline Genetic Testing: Is There a Role for All Patients With Cancer?

Liu, Ying L.; Stadler, Zsofia K.

doi:10.6004/jnccn.2021.7044

Cited by 11 publications

(6 citation statements)

References 73 publications

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“…The widespread use of multigene panels and the expansion in preventative and treatment implications of germline findings have raised a question on whether universal genetic testing should be offered to all cancer patients [ 16 , 49 , 64 , 77 ]. The results of our study support that expanding patient and gene selection criteria for hereditary cancer predisposition testing would identify actionable findings and provide clinical benefit for larger groups of cancer patients and their families.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients

et al. 2022

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Background Genetic testing (GT) for hereditary cancer predisposition is traditionally performed on selected genes based on established guidelines for each cancer type. Recently, expanded GT (eGT) using large hereditary cancer gene panels uncovered hereditary predisposition in a greater proportion of patients than previously anticipated. We sought to define the diagnostic yield of eGT and its clinical relevance in a broad cancer patient population over a 5-year period. Methods A total of 17,523 cancer patients with a broad range of solid tumors, who received eGT at Memorial Sloan Kettering Cancer Center between July 2015 to April 2020, were included in the study. The patients were unselected for current GT criteria such as cancer type, age of onset, and/or family history of disease. The diagnostic yield of eGT was determined for each cancer type. For 9187 patients with five common cancer types frequently interrogated for hereditary predisposition (breast, colorectal, ovarian, pancreatic, and prostate cancer), the rate of pathogenic/likely pathogenic (P/LP) variants in genes that have been associated with each cancer type was analyzed. The clinical implications of additional findings in genes not known to be associated with a patients’ cancer type were investigated. Results 16.7% of patients in a broad cancer cohort had P/LP variants in hereditary cancer predisposition genes identified by eGT. The diagnostic yield of eGT in patients with breast, colorectal, ovarian, pancreatic, and prostate cancer was 17.5%, 15.3%, 24.2%, 19.4%, and 15.9%, respectively. Additionally, 8% of the patients with five common cancers had P/LP variants in genes not known to be associated with the patient’s current cancer type, with 0.8% of them having such a variant that confers a high risk for another cancer type. Analysis of clinical and family histories revealed that 74% of patients with variants in genes not associated with their current cancer type but which conferred a high risk for another cancer did not meet the current GT criteria for the genes harboring these variants. One or more variants of uncertain significance were identified in 57% of the patients. Conclusions Compared to targeted testing approaches, eGT can increase the yield of detection of hereditary cancer predisposition in patients with a range of tumors, allowing opportunities for enhanced surveillance and intervention. The benefits of performing eGT should be weighed against the added number of VUSs identified with this approach.

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Section: Discussionmentioning

confidence: 99%

Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients

et al. 2022

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“…Furthermore PGVs are detected in patients without clinical indication as shown in this study and by many other studies 6–18 . Evidence is cumulating that a tumour/germline based approach is necessary to increase PGV yields and thus there is an increasing need for a more universal approach 18, 48, 49 . However, directly analysing the germline requires genetic counselling and informed consent of the patient.…”

Section: Discussionmentioning

confidence: 99%

Impact of genetic counselling strategy on diagnostic yield and workload for genome sequencing-based tumour diagnostics

Koster

Schipper

Giesbertz

et al. 2023

Preprint

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Whole genome sequencing (WGS) enables comprehensive molecular analysis of tumours and identification of hereditary cancer predisposition. According to the guidelines, directly determining pathogenic germline variants (PGVs) requires pre-test genetic counselling, which is cost-ineffective. Referral for genetic counselling based on tumour variants alone could miss relevant PGVs and/or result in unnecessary referrals. Here we sought to determine the optimal strategy with high PGV yield and a low number-needed-to counsel (NTC). Therefore, we compared the PGV yield and NTC of three simulated strategies, using paired tumour-normal WGS data from 937 metastatic patients. In strategy-1 genetic counselling of all 937 patients prior to the WGS-tumour testing allowed direct PGV analysis using a tumour type-specific gene panel. In strategy-2 and -3, germline testing and referral for post-test genetic counselling is based on tumour variants using adjusted Dutch guidelines (strategy-2) or ESMO-Precision Medicine Working Group recommendations (strategy-3). In strategy-1, clinically relevant PGVs would be detected in 50 patients (NTC=18.7). In strategy-2, 86 patients would have been referred for genetic counselling and 43 would have clinically relevant PGVs (NTC=2). In strategy-3, 94 patients would have been referred for genetic counselling and 32 would have clinically relevant PGVs (NTC=2.9). Hence, in strategy-2 and -3, 43 and 62 patients, respectively, were unnecessarily referred based on a somatic variant, primarily in BRCA1/2, PALB2, MLH1, and MSH2/6 genes. Both post-tumour test counselling strategies (2 and 3) had significantly lower NTC compared to pre-tumour test counselling (strategy-1). The adjusted Dutch guidelines had the highest PGV yield per NTC since it was also based on clinical criteria. Both post-tumour test counselling strategies could be improved by using a hybrid approach of directly analysing hereditary predisposition with counselling through mainstreaming for BRCA1/2, PALB2, MLH1, and MSH2/6 genes, along with tumour type-specific strategies for other cancer predisposition genes.

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“…The clinical indications for germline genetic testing are expanding at a rapid pace, and germline genetic testing for all patients with solid tumors may soon be a reality (Liu, 2021). The traditional model of pre-test informed consent performed by a genetic counselor is not scalable given the limitations in the genetic counseling workforce (Esplin, 2022).…”

Section: Introductionmentioning

confidence: 99%

Development of an electronic decision aid tool to facilitate mainstream genetic testing in ovarian cancer patients

Shannon

Patel

Jonas

et al. 2023

Preprint

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Background: Multigene panel testing is an important component of cancer treatment plans and risk assessment, but there are many different panel options and choosing the most appropriate panel can be challenging for healthcare providers and patients. Electronic tools have been proposed to help patients make informed decisions about which gene panel to choose by considering their preferences and priorities. Materials and Methods: An electronic decision aid tool was developed in line with the International Patient Decision Aids Standards (IPDAS) collaboration. The multidisciplinary project team collaborated with an external healthcare communications agency and the MGH Cancer Center patient family advisory committee (PFAC) to develop the decision aid. Surveys of genetic counselors and patients were used to scope the content, and alpha testing was used to refine the design and content. Results: Surveys of genetic counselors (n=12) and patients (n=228) identified common themes in discussing panel size and strategies for helping patients decide between panels and in identifying confusing terms for patients and distribution of patients choices. The decision aid, organized into two major sections, provides educational text, graphics and videos to guide patients through the decision-making process. Alpha testing feedback from the PFAC (n=4), genetic counselors (n=3) and a group of lay people (n=8) identified areas to improve navigation, simplify wording and improve layout. Conclusion: The decision aid developed in this study has the potential to facilitate informed decision-making by patients regarding cancer genetic testing. The distinctive feature of this decision aid is that it addresses the specific question of which multigene panel may be most suitable for the patient. Its acceptability and effectiveness will be evaluated in future studies.

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The Future of Parallel Tumor and Germline Genetic Testing: Is There a Role for All Patients With Cancer?

Cited by 11 publications

References 73 publications

Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients

Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients

Impact of genetic counselling strategy on diagnostic yield and workload for genome sequencing-based tumour diagnostics

Development of an electronic decision aid tool to facilitate mainstream genetic testing in ovarian cancer patients

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