Patient-Paired Sample Congruence Between 2 Commercial Liquid Biopsy Tests

Torga, Gonzalo; Pienta, Kenneth J.

doi:10.1001/jamaoncol.2017.4027

Cited by 167 publications

(135 citation statements)

References 6 publications

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“…Discordance between different commercial tests and even repetitions of standard polymerase chain reaction (PCR) to detect and quantify rare alleles can often be linked to high false positive rates [25,26]. Consequently, we designed a locus-specific Illumina-compatible library design that incorporated 7-base unique molecular identifiers (UMIs) for tagging individual template molecules.…”

Section: Single Molecule Detectionmentioning

confidence: 99%

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

Hennigan

Trostel

Terrigino

et al. 2019

Preprint

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Section: Single Molecule Detectionmentioning

confidence: 99%

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

Hennigan

Trostel

Terrigino

et al. 2019

Preprint

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“…[3][4][5][6] Tumor-derived cell-free DNA (cfDNA) in serum or plasma likely originates from apoptotic, dead or dying tumor cells, and may constitute genetic information associated with tumor cell evolution and heterogeneity during treatment and metastatic progression. 7,8 Despite the utility of CTC and cfDNA analyses, there are several major challenges inherent in the development of CTC or cfDNA biomarkers 9 for treatment selection in clinical studies, namely reproducibility, defining actionable targets, and consistency across platforms. 10,11 While some studies have found concordance between selected cfDNA genomic alterations and paired tumor biopsies, 12,13 few studies have examined the consistency of whole-genome alterations across paired CTC and cfDNA samples.…”

mentioning

confidence: 99%

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Gupta

Hovelson

Kemeny

et al. 2019

Genes Chromosomes & Cancer

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Circulating tumor cell (CTC) and cell-free (cf) DNA-based genomic alterations are increasingly being used for clinical decision-making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low-pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium-223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR-V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC-specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA-discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR-V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.

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“…However, the path from Breakthrough Designation at the FDA to regulatory approval may not be as smooth as the Breakthrough Designations at the FDA may suggest. A recent paper comparing results for two of these LDT liquid biopsies concluded: Very low congruence for same patient‐paired samples Cannot determine which test is more accurate Reported gene alterations will not be the same across different platforms Patients could receive different treatments depending on the cfDNA platform …”

Section: Cfdna Liquid Biopsies At the Fdamentioning

confidence: 99%

“…However, the path from Breakthrough Designation at the FDA to regulatory approval may not be as smooth as the Breakthrough Designations at the FDA may suggest. A recent paper64 comparing results for two of these LDT liquid…”

mentioning

confidence: 99%

The Labyrinth of Product Development and Regulatory Approvals in Liquid Biopsy Diagnostics

Goodsaid

2019

Clinical Translational Sci

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The evolution of chemistries and instrument platforms for next‐generation sequencing has led to sequencing of genomic variants in both tumor biopsies as well as in circulating tumor cells (CTCs) and cell‐free DNA liquid biopsies. The transition of these analytical platforms into clinical ones has led to challenges in product development as well as regulatory strategies for the approval of diagnostic products with these platforms. Regulatory strategies for liquid biopsy diagnostics depend on a framework that has been developed over the past few years by the US Food and Drug Administration (FDA). This framework includes both guidances that cover enrichment biomarkers and companion diagnostics, as well as regulatory approval precedents, which can be used to design regulatory strategies for new liquid biopsy diagnostic products. However, the regulatory paths for these liquid biopsy diagnostics can also be tortuous, as is the example of CTC—platform liquid biopsies. The ultimate success of regulatory pathways of liquid biopsy diagnostics has been driven by the incremental value of FDA approval for Clinical Laboratory Improvement Amendment (CLIA)‐developed tests and by the inherent complexity of these diagnostics, which are practical barriers for the widespread replication of these tests throughout CLIA laboratories. The framework for FDA approval of sequence information from these liquid biopsies has been focused on single‐site approvals of diagnostics where sequencing information is considered at different diagnostic risk levels, ranging from novel or follow‐on companion diagnostics to variant calls in genomic targets considered independently valuable for therapeutic decision making.

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Patient-Paired Sample Congruence Between 2 Commercial Liquid Biopsy Tests

Cited by 167 publications

References 6 publications

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

The Labyrinth of Product Development and Regulatory Approvals in Liquid Biopsy Diagnostics

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