Diagnosing Hereditary Cancer Susceptibility Through Multigene Panel Testing

1585 Background: Genetic testing for hereditary cancer predisposition has rapidly changed over the past few years with the introduction of multigene panel testing. Multigene testing has evolved from disease-agnostic comprehensive (C) panels alone to include disease-specific but expanded (DSE) panels as well as guideline-based (GB) panels. We analyzed trends in utilization of genetic testing over a two-year period in one NCI-designated Cancer Center, hypothesizing that over time genetic testing usage would trend toward more disease-specific panels. Methods: We conducted a retrospective analysis of our program’s database for all germline genetic tests ordered from 9/1/2013 to 8/31/2015 (n = 619; 246 in year 1, and 373 in year 2). Tests were categorized into three groups based on specificity: GB (range: 2-12 genes tested), DSE (12-35 genes tested), and C (28-80 genes tested). The Chi-square test was used to analyze test types ordered in year 1 (9/1/2013-8/31/2014) and year 2 (9/1/2014 – 8/31/2015) and the proportions of resulting mutation types. Results: A total of 604 germline genetic tests met the inclusion criteria: 39 GB (20 year 1, 19 year 2), 171 DSE (43 year 1, 128 year 2), and 394 C (180 year 1, 214 year 2). Compared to year 1, a larger proportion of DSE tests (35% v. 18%, p < 0.001), and a smaller proportion of C tests (59% v. 74%, p < 0.001) and GB tests (5% vs. 8%, p = 0.146) were ordered. DSE panels revealed a pathogenic variant (PV) at a rate of 16% and a variant of unknown significance (VUS) at a rate of 24%. C tests revealed a PV and VUS at rates of 14% and 29%, respectively. GB tests revealed a PV and VUS at rates of 21% and 18%, respectively. No statistically significant differences in detection rates of mutation types (PV or VUS) were found between GB, DSE, or C tests. Conclusions: The rates of PV detection were not significantly different between test types, but the profile of tests ordered changed over time to favor DSE panels. Exploration of factors contributing to changing trends in genetic testing are warranted as counselors and clinicians adapt to the quickly expanding number of genes associated with hereditary cancer risks, many of them moderate-risk, and the evolving landscape of multigene panel testing.

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Mutation prevalence tables for hereditary cancer derived from multigene panel testing

Human Mutation ◽

10.1002/humu.24053 ◽

2020 ◽

Vol 41 (8) ◽

Cited By ~ 2

Author(s):

Steven N. Hart ◽

Eric C. Polley ◽

Amal Yussuf ◽

Siddhartha Yadav ◽

David E. Goldgar ◽

...

Keyword(s):

Hereditary Cancer ◽

Panel Testing ◽

Multigene Panel Testing ◽

Multigene Panel

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Adoption of multigene panel testing for hereditary cancer "CancerNext" in Tohoku University Hospital

Annals of Oncology ◽

10.1093/annonc/mdz338.040 ◽

2019 ◽

Vol 30 ◽

pp. vi99

Author(s):

Keigo Komine ◽

Masanobu Takahashi ◽

Sakura Hiraide ◽

Hideharu Yamada ◽

Mari Tsubata ◽

...

Keyword(s):

Hereditary Cancer ◽

University Hospital ◽

Panel Testing ◽

Multigene Panel Testing ◽

Multigene Panel

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Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

JCO Precision Oncology ◽

10.1200/po.21.00249 ◽

2021 ◽

pp. 1588-1602

Author(s):

Monica D. Levine ◽

Rachel Pearlman ◽

Heather Hampel ◽

Casey Cosgrove ◽

David Cohn ◽

...

Keyword(s):

Endometrial Cancer ◽

Cancer Susceptibility ◽

Susceptibility Genes ◽

Type Ii ◽

Newly Diagnosed ◽

Panel Testing ◽

Pathogenic Variants ◽

Cancer Susceptibility Genes ◽

Multigene Panel Testing ◽

Multigene Panel

PURPOSE Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

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Uptake of oophorectomy in women with findings on multigene panel testing: Results from the Prospective Registry of Multiplex Testing (PROMPT).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.1508 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 1508-1508 ◽

Cited By ~ 2

Author(s):

Susan M. Domchek ◽

Jamie Brower ◽

Heather Symecko ◽

Vanessa Marcell ◽

Michael Francis Walsh ◽

...

Keyword(s):

Cancer Susceptibility ◽

Personal History ◽

Variant Of Uncertain Significance ◽

Panel Testing ◽

Pathogenic Variants ◽

Increased Risk ◽

History Of ◽

Multigene Panel Testing ◽

Multiplex Testing ◽

Multigene Panel

1508 Background: With the expansion of multigene panel testing for cancer susceptibility, increasing numbers of patients are identified with pathogenic/likely pathogenic variants (P/LP V) in genes which do not have a clearly actionable increased risk of ovarian cancer (OC) (lifetime risk of OC >5%). However, there is concern that patients and/or providers may ascribe OC risk to such genetic findings with the potential for unnecessary oophorectomy (ooph). Methods: The Prospective Registry of Multiplex Testing (PROMPT) is an online registry for individuals with a genetic alteration detected on multiplex panel testing for cancer susceptibility. Participants self-enroll and complete baseline and annual follow-up questionnaires. PROMPT has enrolled 7388 participants (6936; 93.9% women) since September 2014. Results: 1566 women in the PROMPT registry reported ooph, the indications for which were reported as either cancer treatment (n=481, 30.7%) or benign disease (n=432, 27.6%). An additional 186 (12.8%) reported PV in genes associated with lifetime OC risk >5% ( BRCA1, BRCA2, RAD51C, RAD51D, BRIP, or Lynch syndrome genes). The remaining 467 did not have guideline based indications for ooph due to OC risk and are described further here. 92 (19.7%) had a variant of uncertain significance (VUS) in genes associated with OC, 241 (51.6%) had a personal history of breast cancer (BC) and no VUS in OC genes, and 119 (25.5%) had no personal history of BC and no VUS in OC genes. The majority of women had no family history (FH) of OC in first or second degree relatives (Table). Most ooph occurred prior to age 50. Of the 405 women with CHEK2 P/LP, 11.4% reported ooph (59% under age 50 when age known), as did 13.2% (of 228) with CHEK2 VUS, 8.8% (of 261) with ATM P/LP (66.7% under age 50), and 8.3% (of 387) with ATM VUS. In addition, of the 184 women with PALB2 P/LP, 14.1% reported ooph (35.3% under age 50) as did 11.6% (of 198) with PALB2 VUS. Of those who reported provider discussions, 47.2% stated “my provider recommended this” (including >60% in the OC gene VUS group) and an additional 25.2% stated “my provider presented this as an option, but not a requirement”. In those with no FH of OC, 45.8% stated that their provider recommended ooph. Conclusions: 10-15% of women with PV/VUS in genes not associated with a high risk of OC reported ooph without a clear indication. [Table: see text]

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