Abstract 5233: Concordance of genomic alterations by next generation sequencing (NGS) in tumor tissue vs. cell-free DNA
Authors: Chae Young Kwang , Davis Andrew A. , Carneiro Benedito A. , Chandra Sunandana , Mohindra Nisha , Kalyan Aparna , Kaplan Jason , Matsangou Maria , Platanias Leonidas C. , Cristofanilli Massimo , Giles Francis J. 
Published: July 2016

Abstract
Introduction:
Genomic analysis of circulating tumor cell-free DNA (cfDNA) represents a non-invasive method of assessing genomic alterations using peripheral blood. We compared the concordance between cfDNA and tissue biopsies across genomic alterations in 65 genes in this pilot retrospective study.
Methods:
54 consecutive patients with cfDNA NGS testing (Guardant360) were identified. Of these, 28 had tissue DNA NGS testing (Foundation One). 65 genes were common to both assays. Concordance was defined as the absence or presence of the identical genomic sequencing alteration(s) in a single gene. The analysis included non-synonymous DNA mutations, rearrangements, and copy number variants regardless of clone percentage.
Results:
There were 14 lung cancers and 14 other advanced solid tumors. Including all alterations and variants of unknown significance (VUS), the average number of alterations per patient for tissue and cfDNA was 4.82 (SD 3.02) and 2.96 (SD 3.01), respectively. Concordance between the two assays was 91.9%. Among only genes with reported genomic alterations in either assay (n = 170), concordance was 12.4%. Concordance was similar when stratifying based on timeframe between biopsies (median time interval between assays; 89 days). 21.5% of alterations found in tissue were detected in cfDNA. 34.9% of alterations found in cfDNA were detected in tissue. Across the 5 most common genes, sensitivity and specificity were 40.0% and 94.2%, respectively (Table 1).
Discussion:
Concordance between tumor tissue and cfDNA NGS was 91.9%. The cfDNA assay had high specificity, but low sensitivity. In addition, more mutations were detected in tissue. Reasons for these findings may include different sequencing techniques, spatial and temporal factors, tumor heterogeneity, and inclusion of subclones.
[AD and YC contributed equally.]
Table 1: Diagnostic Accuracy across 5 Most Common Genes Tissue MutationsSensitivity (%)Specificity (%)PPV (%)NPV (%)Diagnostic Accuracy (%)cfDNA mutations(+)(-)TP53(+)82(-)8850.080.080.050.057.1EGFR(+)12(-)22333.392.033.392.085.7KRAS(+)41(-)22166.795.580.091.389.3APC(+)01(-)4230.095.80.085.282.1CDKN2A(+)10(-)52216.7100.0100.081.582.1Total positive146Total negative2197Total (positive + negative)3510340.094.270.082.280.4
PPV: positive predictive value
NPV: negative predictive value
Citation Format: Young Kwang Chae, Andrew A. Davis, Benedito A. Carneiro, Sunandana Chandra, Nisha Mohindra, Aparna Kalyan, Jason Kaplan, Maria Matsangou, Leonidas C. Platanias, Massimo Cristofanilli, Francis J. Giles. Concordance of genomic alterations by next generation sequencing (NGS) in tumor tissue vs. cell-free DNA. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5233.