Impact of introducing cell‐free DNA screening into clinical care on first trimester ultrasound

Abstract Introduction Cell-free DNA (cfDNA) testing is increasingly used as a screening method not only for trisomy (T) 21 but also for T18 and T13, sex chromosome anomalies (SCA) and microdeletions. Based on cases with a positive cfDNA result in our specialised prenatal practice, this study aims to characterise the usage of cfDNA testing and to estimate the positive predictive value (PPV) in routine practice in Germany. Patients and Methods In this retrospective study we analysed the data of all pregnant women with a positive cfDNA result seen between 09/2013 and 12/2019. Women were either referred due to the positive result or the test was initiated in our practice. The primary parameter of interest was the concordance of cfDNA tests with confirmatory genetic testing. Results We encountered 81 cases with a positive cfDNA test (T21: 49.4%; T18: 9.9%; T13: 8.6%; SCA: 22.2%; 22q12del: 8.6%). The PPV was 95.0% for T21, but considerably lower for T18 (55.6%) and T13 (28.6%). For SCAs it was 23.1% and no case with DiGeorge syndrome was confirmed. 63% of the patients had not received a fetal anomaly scan before cfDNA testing. In first-trimester fetuses with a cfDNA test predicting an autosomal aneuploidy, fetal anomalies were detected in 90.3% of the cases. No false positive case had an abnormal US result. Conclusions Despite the excellent specificity of cfDNA tests, the PPV for aneuploidies other than T21 is low in routine practice. In discordance with the current guidelines, cfDNA test is often used without a previous detailed anomaly scan. Our data provide valuable information to assist patient counselling and shared decision making.

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First-Trimester Contingent Screening for Trisomy 21 by Fetal Nuchal Translucency and Maternal Serum Biomarkers and Maternal Blood Cell-Free DNA Testing

Journal of Fetal Medicine ◽

10.1007/s40556-018-0177-z ◽

2018 ◽

Vol 5 (3) ◽

pp. 139-143

Author(s):

Sarang Younesi ◽

Shahram Savad ◽

Soudeh Ghafouri-Fard ◽

Mohammad Mahdi Taheri-Amin ◽

Pourandokht Saadati ◽

...

Keyword(s):

Blood Cell ◽

Trisomy 21 ◽

First Trimester ◽

Nuchal Translucency ◽

Maternal Blood ◽

Maternal Serum ◽

Serum Biomarkers ◽

Dna Testing ◽

Cell Free Dna ◽

Free Dna

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FIRST SCREEN, NOT WORST SCREEN! (THE ROLE OF THE FIRST TRIMESTER SCREEN IN THE CELL FREE DNA ERA)

10.26226/morressier.60780408dc2fa1af56246910 ◽

2021 ◽

Author(s):

Tirtza Spiegel Strauss

Keyword(s):

First Trimester ◽

Cell Free Dna ◽

Free Dna

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Cell-Free DNA Screening for Fetal Aneuploidy

50 Studies Every Obstetrician-Gynecologist Should Know ◽

10.1093/med/9780190947088.003.0021 ◽

2021 ◽

pp. 115-120

Author(s):

Ashley N. Battarbee ◽

Neeta L. Vora

Keyword(s):

Trisomy 21 ◽

Dna Analysis ◽

Chromosomal Abnormalities ◽

Area Under The Curve ◽

First Trimester ◽

Outcome Data ◽

Cell Free Dna ◽

High Risk Women ◽

Free Dna ◽

Trimester Screening

In a prospective, multicenter blinded study at 35 international centers, the Noninvasive Examination of Trisomy (NEXT) study evaluated the performance of cell-free DNA screening for fetal trisomy compared to standard first trimester screening with nuchal translucency and serum analytes in a routine prenatal population. Among the 15,841 women who had standard screening and cell-free DNA analysis with neonatal outcome data, there were 68 chromosomal abnormalities (1 in 236). Of these, 38 were Trisomy 21 (1 in 417). Cell-free DNA analysis had a higher area under the curve (AUC) for trisomy 21, compared to standard screening (0.999 vs. 0.958, p = 0.001). Cell-free DNA analysis also had greater sensitivity, specificity, and positive predictive value compared to standard screening for trisomy 21, 18, and 13. While cell-free DNA analysis cannot detect all chromosome abnormalities, it performed better than standard screening for detection of trisomies 21, 18, and 13 in a routine population including low- and high-risk women.

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Circulating cell-free DNA: Translating prostate cancer genomics into clinical care

Molecular Aspects of Medicine ◽

10.1016/j.mam.2019.100837 ◽

2020 ◽

Vol 72 ◽

pp. 100837 ◽

Cited By ~ 2

Author(s):

Delila Gasi Tandefelt ◽

Johann de Bono

Keyword(s):

Prostate Cancer ◽

Cancer Genomics ◽

Clinical Care ◽

Cell Free Dna ◽

Free Dna ◽

Circulating Cell Free Dna

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Cell-free DNA in the supernatant of pleural effusion can be used to detect driver and resistance mutations, and can guide tyrosine kinase inhibitor treatment decisions

ERJ Open Research ◽

10.1183/23120541.00016-2019 ◽

2019 ◽

Vol 5 (1) ◽

pp. 00016-2019 ◽

Cited By ~ 9

Author(s):

Karlijn Hummelink ◽

Mirte Muller ◽

Theodora C. Linders ◽

Vincent van der Noort ◽

Petra M. Nederlof ◽

...

Keyword(s):

Pleural Effusion ◽

Clinical Care ◽

Molecular Profiling ◽

Driver Mutation ◽

Added Value ◽

Pleural Effusions ◽

Resistance Mutations ◽

Cell Free Dna ◽

Free Dna ◽

Cell Pellet

ObjectivesMolecular profiling of tumours has become the mainstay of diagnostics for metastasised solid malignancies and guides personalised treatment, especially in nonsmall cell lung cancer (NSCLC). In current practice, it is often challenging to obtain sufficient tumour material for reliable molecular analysis. Cell-free DNA (cfDNA) in blood or other bio-sources could present an alternative approach to obtain genetic information from the tumour. In a retrospective cohort we analysed the added value of cfDNA analysis in pleural effusions for molecular profiling.MethodsWe retrospectively analysed both the supernatant and the cell pellet of 44 pleural effusions sampled from 39 stage IV patients with KRAS (n=23) or EGFR (n=16) mutated tumours to detect the original driver mutation as well as for EGFR T790M resistance mutations. Patients were diagnosed with either NSCLC (n=32), colon carcinoma (n=4), appendiceal carcinoma (n=2) or adenocarcinoma of unknown primary (n=1). Samples collected in the context of routine clinical care were stored at the Netherlands Cancer Institute biobank. We used droplet digital PCR for analysis.ResultsThe driver mutation could be detected in 36 of the 44 pleural effusions by analysis of both the supernatant (35 out of 44 positive) and the cell pellet (31 out of 44 positive). In seven out of 20 pleural effusions from patients with EGFR mutation-positive tumours, a T790M mutation was detected. All seven supernatants and cell pellets were positive.ConclusionscfDNA in pleural effusion can be used to detect driver mutations as well as resistance mechanisms like EGFR T790M in pleural effusion with high accuracy and is therefore a valuable bio-source.

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