scholarly journals Identification of Germline Cancer Predisposition Variants During Clinical Ctdna Testing

2021 ◽  
Author(s):  
Leigh Anne Stout ◽  
Nawal Kassem ◽  
Cynthia Hunter ◽  
Santosh Philips ◽  
Milan Radovich ◽  
...  
Keyword(s):  
Circulating Tumor Dna ◽  
Variant Allele Frequency ◽  
Germline Variants ◽  
Non Invasive ◽  
Invasive Method ◽  
Selection For ◽  
Ctdna Analysis ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. ctDNA variant allele frequency (VAF) is commonly reported and may aid in discerning whether a variant is germline or somatic. We report on the fidelity of VAF in ctDNA as a predictor for germline variant carriage. Two patient cohorts were studied. Cohort 1 included patients with known germline variants. Cohort 2 included patients with any variant detected by the ctDNA assay with VAF of 40–60%. In cohort 1, 36 of 91 (40%) known germline variants were identified through ctDNA analysis with a VAF of 39-87.6%. In cohort 2, 111 of 160 (69%) variants identified by ctDNA analysis with a VAF between 40–60% were found to be germline. Therefore, variants with a VAF between 40–60% should induce suspicion for germline status but should not be used as a replacement for germline testing.

scholarly journals Identification of germline cancer predisposition variants during clinical ctDNA testing

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Leigh Anne Stout ◽  
Nawal Kassem ◽  
Cynthia Hunter ◽  
Santosh Philips ◽  
Milan Radovich ◽  
...  
Keyword(s):  
Circulating Tumor Dna ◽  
Variant Allele Frequency ◽  
Germline Variants ◽  
Non Invasive ◽  
Invasive Method ◽  
Selection For ◽  
Ctdna Analysis ◽  
Tumor Dna ◽  
Generation Sequencing ◽  
Germline Testing

AbstractNext-generation sequencing of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. ctDNA variant allele frequency (VAF) is commonly reported and may aid in discerning whether a variant is germline or somatic. We report on the fidelity of VAF in ctDNA as a predictor for germline variant carriage. Two patient cohorts were studied. Cohort 1 included patients with known germline variants. Cohort 2 included patients with any variant detected by the ctDNA assay with VAF of 40–60%. In cohort 1, 36 of 91 (40%) known germline variants were identified through ctDNA analysis with a VAF of 39–87.6%. In cohort 2, 111 of 160 (69%) variants identified by ctDNA analysis with a VAF between 40 and 60% were found to be germline. Therefore, variants with a VAF between 40 and 60% should induce suspicion for germline status but should not be used as a replacement for germline testing.

scholarly journals Alectinib-Induced Pleural and Pericardial Effusions in ALK-Positive NSCLC

2021 ◽  
pp. 1323-1327
Author(s):  
Maiken Parm Ulhoi ◽  
Boe Sandahl Sorensen ◽  
Peter Meldgaard
Keyword(s):  
Progressive Disease ◽  
Heart Function ◽  
Circulating Tumor Dna ◽  
Driver Mutations ◽  
First Line ◽  
Alk Positive ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna ◽  
Generation Sequencing ◽  
Mild Toxicity

Alectinib is the first-line targeted treatment for advanced ALK-positive non-small-cell lung cancer. Although it has a relatively mild toxicity profile, adverse events (AEs) do occur. We present a case of alectinib-induced bilateral pleural effusions and pericardial effusion that has not previously been reported. The patient developed severe dyspnea 3 months after starting alectinib. He underwent thorough clinical examination including evaluations of heart function. The heart function was normal. There was no sign of pneumonitis or progressive disease on the CT scans. Cytology samples of the pleural fluid from multiple thoracocenteses were examined and showed no malignant cells. Next-generation sequencing (NGS) analysis of circulating tumor DNA from sequential blood samples was also carried out. NGS identified no known driver mutations associated with the effusions. Hence, the effusions were suspected to be an alectinib-induced AE. Alectinib was withdrawn, and the patient commenced brigatinib. The effusions subsequently regressed.

Comparison of tissue DNA to circulating tumor DNA in patients with brain metastases.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13546-e13546 ◽  
Author(s):  
Tyler A. Lanman ◽  
Santosh Kesari ◽  
Sandip Pravin Patel ◽  
Lyudmila Bazhenova ◽  
Barbara A. Parker ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Tumor Tissue ◽  
Late Complication ◽  
Median Number ◽  
Circulating Tumor Dna ◽  
Molecular Alterations ◽  
Dna Sampling ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna ◽  
Generation Sequencing

e13546 Background: Brain metastases are often a late complication of cancer, not easily amenable to biopsy, and may contain additional molecular alterations not found in the original tumor. We sought to analyze the concordance between tissue DNA and cell-free circulating tumor DNA (ctDNA) in patients who developed brain metastases, and determine how the ctDNA profile changed with time. Methods: We retrospectively analyzed 31 patients with brain metastases who underwent next-generation sequencing (NGS) from both ctDNA and tumor tissue DNA. Breast, lung, ovarian, renal, melanoma, and colon primaries were included (42, 32, 13, 7, 3, and 3%, respectively). Tissue DNA was from primary tumor, systemic metastasis or brain (39, 39, and 7%, respectively). A median number of five alterations was found in each tissue group. Alterations in ctDNA were compared to tumor DNA and analyzed for relative frequencies, concordance, and novel alterations. Overall survival (OS) and time between DNA sample collections was analyzed. Results: All 31 patients had detectable mutations in tumor tissue. 25 patients (80.6%) had detectable ctDNA alterations and 14 patients (45.2%) had at least one identical ctDNA alteration that was concordant with tissue DNA. The most commonly altered genes (in both ctDNA and tissue DNA) were TP53 and EGFR. Breast cancer had both the highest proportion of patients with ≥ 1 ctDNA alterations (92.3%) and the highest proportion of patients who had ≥ 1 alterations in common with tissue DNA (61.5%). 23 of the 25 patients (92%) with detectable ctDNA alterations had additional alterations not found in tissue DNA, which increased with time from tumor DNA sampling. Median time between ctDNA extraction and tissue biopsy was 6.5 months for cases with common alterations, and 12.4 months for those without common alterations. There was trend to decreased OS with increasing ctDNA burden. Conclusions: We found that ctDNA is comparable with tissue DNA sequencing in patients with brain metastases. This concordance decreases with increasing time from tissue diagnosis, reflecting the changing nature of tumor genetics and highlighting the utility of ctDNA as a feasible way to monitor changes and identify additional potentially targetable alterations.

Identification of germline cancer predisposition variants during clinical ctDNA testing.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15555-e15555
Author(s):  
Leigh Anne Anne Stout ◽  
Nawal Kassem ◽  
Cynthia Hunter ◽  
Santosh Philips ◽  
Milan Radovich ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Metastatic Cancer ◽  
Circulating Tumor Dna ◽  
Cancer Predisposition ◽  
Germline Variants ◽  
Predisposition Genes ◽  
Invasive Method ◽  
Ctdna Analysis ◽  
High Level ◽  
Germline Testing

e15555 Background: Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. Identification of inherited germline cancer predisposition mutations that have significant implications for at-risk relatives may be missed during routine ctDNA testing. Allele frequency has the potential to enhance the likelihood that a mutation is germline; and is often reported in many NGS tests from ctDNA. Here, we report on the fidelity of allele frequency in ctDNA as a predictor for pathogenic germline variant carriage. Methods: ctDNA sequencing of patients with metastatic cancer from the Indiana University Health Precision Genomics Program was performed using the FoundationOne Liquid assay. All variants detected by the ctDNA assay report were considered. All patients also had germline testing information and pathogenicity of germline variants were determined using ClinVar. Germline variants with conflicting interpretations were manually reviewed to determine pathogenicity. Comparisons between ctDNA results with known germline status were performed. Results: Of 91 previously identified germline cancer predisposition variants, 36 (40%) were also identified by ctDNA analysis. All germline variants that were tested for in the ctDNA assay (n = 36, 100%) were identified. When detected, the allele frequencies of detected germline variants in the ctDNA ranged from 39-87.6% with an average of 52.1%. Conversely, 111 of 160 (69%) variants identified by ctDNA analysis with allele frequency between 40-60% in a cancer predisposition gene were found to be germline in origin (regardless of pathogenicity). Variants in the BRCA2, BRCA1, and CDH1 genes were most likely to be germline in origin (26/27 [96%], 20/22 [91%], 13/15 [87%], respectively). Variants in the TP53 and APC genes were least likely to be germline in origin (9/36 [25%] and 1/6 [17%], respectively). There was an 85% (95/111) concordance in actionability between the somatic testing lab and ClinVar germline classifications. Of the 16 discordant variants, 100% were determined to be actionable by the somatic testing lab but not actionable in ClinVar. Conclusions: ctDNA allele frequency can alter the likelihood that a variant is germline. Importantly, however, this testing is far from comprehensive and should not be used as a replacement for germline testing. Variants with allele frequency between 40-60% in cancer predisposition genes should induce a high level of suspicion for germline status.

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