Validation of a whole exome/whole transcriptome liquid biopsy assay with correction for clonal hematopoiesis.

Medientyp: E-Artikel

Titel: Validation of a whole exome/whole transcriptome liquid biopsy assay with correction for clonal hematopoiesis

Beteiligte: Perdigones Borderias, Nieves; Abraham, Jim; Radovich, Milan; Oberley, Matthew James; Swensen, Jeffrey; Heath, Elisabeth I.; Dietrich, Martin Frederik; Liu, Stephen V.; Nabhan, Chadi; Hahn-Lowry, Robert; Lou, Emil; El-Deiry, Wafik S.; Shields, Anthony F.; Marshall, John; Miglarese, Mark Robert; Antani, Sourabh; Sledge, George W.; Halbert, David D.; Spetzler, David; Domenyuk, Valeriy

Erschienen: American Society of Clinical Oncology (ASCO), 2023

Sprache: Englisch

DOI: 10.1200/jco.2023.41.16_suppl.e15049

ISSN: 0732-183X; 1527-7755

Schlagwörter: Cancer Research ; Oncology

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Beschreibung: e15049 Background: Liquid biopsies have become integral to the management of patients with advanced malignancies, however significant deficiencies exist in currently used platforms. Liquid biopsy data often show unacceptably high discordance compared to gold standard tissue-based data; this is often due to false positives (FP) resulting from clonal hematopoiesis (CH) or increased false negatives due to inherently poor sensitivity as well as the confounding intra-patient or tumor stage dependent ‘non-shedder’ problem. Caris Assure is a novel whole exome (WES) and whole transcriptome (WTS) NGS assay performed on plasma and buffy coat (BC) fractions of whole blood that maximizes the number of unique nucleic acids, thereby increasing sensitivity as well as identifying incidental germline variants and correcting for CH. Methods: Matched tissue and whole blood specimens were obtained from 184 patients with solid tumors. Whole blood was collected in PAXgene ccfDNA tubes. DNA & RNA were co-extracted from matched plasma, BC, and FFPE tumor tissue specimens and prepared for NGS using hybrid bait capture methodology. Plasma and BC samples were tested using the Caris Assure WES/WTS assay as well as orthogonal assays. Tissue specimens were tested using Caris’ validated WES/WTS tissue assay. Results were compared between the plasma assays and matched tissues as well as using a majority-rules calling model. A positive plasma assay variant was counted a true positive if it was also identified in the matched tissue or the orthogonal plasma result. Similarly, a negative result was considered a true negative if either of the other two test results were also negative. Results: When data were analyzed from patients with metastatic disease and were focused on only those genes included in the limited orthogonal liquid panel, and tissue was treated as the gold standard, Caris Assure achieved a PPA for SNVs and INDELS of 81.4% and PPV of 85.1%, while the orthogonal assay achieved a PPA and PPV of 79.1% and 53.1%. When the majority rules approach was used, Assure PPA and PPV were 93.3% and 93.3%, respectively, compared to 91.1% and 64.1%. Germline variants detected by Caris Assure had 100% PPA & PPV when compared to the external germline assay. There were 444 pathogenic/likely pathogenic mutations detected across all assays. Of those, 77 (17.3%) were derived from CH and identified as such in the Caris Assure results, though they are inaccurately reported as tumor-derived variants using the comparator assay. Using Caris Assure corrected for CH-derived false positives, the correlation between plasma and tissue TMB was very strong (r = 0.9) when tissue and blood specimens were collected within 4 weeks of each other. Conclusions: The novel Caris Assure liquid biopsy platform demonstrates high sensitivity and specificity for somatic variants, while mitigating against FPs from CH, and identifying incidental germline pathogenic alterations.

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