Concordance between genomic alterations assessed by next-generation sequencing in tumor tissue or circulating cell-free DNA

Abstract

// Young Kwang Chae 1, 2, 3, * , Andrew A. Davis 2, * , Benedito A. Carneiro 1, 2, 3 , Sunandana Chandra 1, 2, 3 , Nisha Mohindra 2, 3 , Aparna Kalyan 1, 2, 3 , Jason Kaplan 1, 2, 3 , Maria Matsangou 1, 2, 3 , Sachin Pai 1, 3 , Ricardo Costa 1, 3 , Borko Jovanovic 2, 3 , Massimo Cristofanilli 1, 2, 3 , Leonidas C. Platanias 1, 2, 3, 4 , Francis J. Giles 1, 2, 3 1 Developmental Therapeutics Program of Division of Hematology Oncology, Northwestern University, Chicago, IL, USA 2 Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 3 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 4 Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA * These authors contributed equally to this work Correspondence to: Young Kwang Chae, email: young.chae@northwestern.edu Keywords: next-generation sequencing, cell-free DNA, genomic alterations, metastatic disease, lung cancer Received: April 14, 2016      Accepted: August 10, 2016      Published: August 30, 2016 ABSTRACT Genomic analysis of tumor tissue is the standard technique for identifying DNA alterations in malignancies. Genomic analysis of circulating tumor cell-free DNA (cfDNA) represents a relatively non-invasive method of assessing genomic alterations using peripheral blood. We compared the concordance of genomic alterations between cfDNA and tissue biopsies in this retrospective study. Twenty-eight patients with advanced solid tumors with paired next-generation sequencing tissue and cfDNA biopsies were identified. Sixty-five genes were common to both assays. Concordance was defined as the presence or absence of the identical genomic alteration(s) in a single gene on both molecular platforms. Including all aberrations, the average number of alterations per patient for tissue and cfDNA analysis was 4.82 and 2.96, respectively. When eliminating alterations not detectable in the cfDNA assay, mean number of alterations for tissue and cfDNA was 3.21 and 2.96, respectively. Overall, concordance was 91.9–93.9%. However, the concordance rate decreased to 11.8–17.1% when considering only genes with reported genomic alterations in either assay. Over 50% of mutations detected in either technique were not detected using the other biopsy technique, indicating a potential complementary role of each assay. Across 5 genes ( TP53, EGFR, KRAS, APC, CDKN2A ), sensitivity and specificity were 59.1% and 94.8%, respectively. Potential explanations for the lack of concordance include differences in assay platform, spatial and temporal factors, tumor heterogeneity, interval treatment, subclones, and potential germline DNA contamination. These results highlight the importance of prospective studies to evaluate concordance of genomic findings between distinct platforms that ultimately may inform treatment decisions.