Use of Treatment-Focused Tumor Sequencing to Screen for Germline Cancer Predisposition

Lau, Tammy; May, Christina; Dashti, Zahra Jalali Sefid; Swanson, Lucas; Starks, Elizabeth; Parker, Jeremy; Moore, Richard A.; Tucker, Tracy; Bosdet, Ian; Young, Sean; Santos, Jennifer L.; Compton, Katie; Heidary, Nili; Hoang, Lien; Schrader, Kasmintan A.; Sun, Sophie; Kwon, Janice S.; Tinker, Anna V.; Karsan, Aly

doi:10.1016/j.jmoldx.2021.06.006

Cited by 2 publications

(4 citation statements)

References 44 publications

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“… 6 These studies were conducted before 2020, and with refined testing and bioinformatics algorithms, currently the likelihood of missing a germline mutation by screening the tumor is exceedingly low (essentially 0%). 4 , 5 Therefore, tumor testing may be almost equivalent to germline testing in identifying those with inherited PVs, with the added benefit of identifying somatic mutations as well. Tumor testing may also identify NTRK fusions and tumor mutation burden, which may be actionable targets for treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The model was populated with data from various sources, including data from SOLO-1 on survival outcomes with olaparib, 2 , 3 and published data on tumor testing performance. 4 , 5 For the base case, the proportion of ovarian cancer tissue samples sufficient for tumor testing was estimated at 95%. 4 , 5 Those with an insufficient tissue sample for testing would automatically have germline testing.…”

Section: Methodsmentioning

confidence: 99%

“… 4 , 5 For the base case, the proportion of ovarian cancer tissue samples sufficient for tumor testing was estimated at 95%. 4 , 5 Those with an insufficient tissue sample for testing would automatically have germline testing. The sensitivity of tumor testing to detect germline PVs was estimated to be 97.5%.…”

Section: Methodsmentioning

confidence: 99%

“…The sensitivity of tumor testing to detect germline PVs was estimated to be 97.5%. [3][4][5][6] We did not model reversion mutations in BRCA1/2, which could yield a false negative tumor test, but these reversion mutations are more likely to influence outcomes in the future as a mechanism of resistance to platinum-based therapy or olaparib [7][8][9] rather than the initial selection of patients for maintenance therapy. Costs were estimated from Medicare reimbursements (panel testing for tumor, germline, counseling with genetic counselor and/or physician), 10,11 and wholesale acquisition costs of olaparib, 12 in addition to estimated costs of monitoring and management of adverse effects during 24 months of treatment.…”

Section: Methodsmentioning

confidence: 99%

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Germline Testing and Somatic Tumor Testing forBRCA1/2Pathogenic Variants in Ovarian Cancer: What Is the Optimal Sequence of Testing?

Kwon

Tinker

Santos

et al. 2022

JCO Precision Oncology

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PURPOSE In 2020, ASCO recommended that all women with epithelial ovarian cancer have germline testing for BRCA1/2 mutations, and those without a germline pathogenic variant (PV) should have somatic tumor testing to determine eligibility for a poly (ADP-ribose) polymerase inhibitor. Consequently, the majority of patients with ovarian cancer will have both germline testing and somatic testing. An alternate strategy is tumor testing first and then germline testing if there is a PV in the tumor and/or significant family history. The objective was to conduct a cost-effectiveness analysis comparing the two testing strategies. METHODS The Markov model compared the costs (US dollars) and benefits of two testing strategies for newly diagnosed ovarian cancer: (1) ASCO strategy and (2) tumor testing triage for germline testing. Data were applied from SOLO-1, and costs were from wholesale acquisition prices, Medicare, and published sources. Sensitivity analyses accounted for uncertainty around various parameters. Monte Carlo simulation estimated the number tested and identified with germline and somatic BRCA PV for olaparib maintenance treatment annually in the US population. RESULTS The ASCO strategy was more effective but more costly than tumor testing triage in identifying patients for olaparib, with an incremental cost-effectiveness ratio of $281,296 US dollars per progression-free life year gained. Assuming 10,000 eligible patients with ovarian cancer annually, Monte Carlo simulation yielded comparable numbers of patients with BRCA PV in the germline and tumor with the ASCO and tumor testing triage strategies (2,080 v 2,062, respectively), but substantially higher number of patients tested using the ASCO strategy (8,052 v 3,076). CONCLUSION The ASCO strategy may identify more BRCA PVs but is not cost-effective. Tumor testing in epithelial ovarian cancer as triage for germline testing is the favored strategy in this health care system.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Germline Testing and Somatic Tumor Testing forBRCA1/2Pathogenic Variants in Ovarian Cancer: What Is the Optimal Sequence of Testing?

Kwon

Tinker

Santos

et al. 2022

JCO Precision Oncology

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Chronic Lymphocytic Leukemia IGHV Somatic Hypermutation Detection by Targeted Capture Next-Generation Sequencing

Grants,

May,

Bridgers

et al. 2024

Clinical Chemistry

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Background Somatic hypermutation (SHM) status of the immunoglobulin heavy variable (IGHV) gene plays a crucial role in determining the prognosis and treatment of patients with chronic lymphocytic leukemia (CLL). A common approach for determining SHM status is multiplex polymerase chain reaction and Sanger sequencing of the immunoglobin heavy locus; however, this technique is low throughput, is vulnerable to failure, and does not allow multiplexing with other diagnostic assays. Methods Here we designed and validated a DNA targeted capture approach to detect immunoglobulin heavy variable somatic hypermutation (IGHV SHM) status as a submodule of a larger next-generation sequencing (NGS) panel that also includes probes for ATM, BIRC3, CHD2, KLHL6, MYD88, NOTCH1, NOTCH2, POT1, SF3B1, TP53, and XPO1. The assay takes as input FASTQ files and outputs a report containing IGHV SHM status and V allele usage following European Research Initiative on CLL guidelines. Results We validated the approach on 35 CLL patient samples, 34 of which were characterized using Sanger sequencing. The NGS panel identified the IGHV SHM status of 34 of 35 CLL patients. We showed 100% sensitivity and specificity among the 33 CLL samples with both NGS and Sanger sequencing calls. Furthermore, we demonstrated that this panel can be combined with additional targeted capture panels to detect prognostically important CLL single nucleotide variants, insertions/deletions, and copy number variants (TP53 copy number loss). Conclusions A targeted capture approach to IGHV SHM detection can be integrated into broader sequencing panels, allowing broad CLL prognostication in a single molecular assay.

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Use of Treatment-Focused Tumor Sequencing to Screen for Germline Cancer Predisposition

Cited by 2 publications

References 44 publications

Germline Testing and Somatic Tumor Testing forBRCA1/2Pathogenic Variants in Ovarian Cancer: What Is the Optimal Sequence of Testing?

Germline Testing and Somatic Tumor Testing forBRCA1/2Pathogenic Variants in Ovarian Cancer: What Is the Optimal Sequence of Testing?

Chronic Lymphocytic Leukemia IGHV Somatic Hypermutation Detection by Targeted Capture Next-Generation Sequencing

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