Concordance of Genomic Alterations between Circulating Tumor DNA and Matched Tumor Tissue in Chinese Patients with Breast Cancer

Abstract

Purpose: Circulating tumor DNA (ctDNA) served as a noninvasive method with less side effects using peripheral blood. Given the studies on concordance rate between liquid and solid biopsies in Chinese breast cancer (BC) patients were limited, we sought to examine the concordance rate of different kinds of genomic alterations between paired tissue biopsies and ctDNA samples in Chinese BC cohorts.

Materials and methods: In this study, we analyzed the genomic alteration profiles of 81 solid BC samples and 41 liquid BC samples. The concordance across 136 genes was evaluated.

Results: The median mutation counts per sample in 41 ctDNA samples was higher than the median in 81 tissue samples (p=0.0254; Wilcoxon rank sum test). For mutation at the protein-coding level, 39.0% (16/41) samples had at least one concordant mutation in two biopsies. 20.0% tissue-derived mutations could be detected via ctDNA-based sequencing, whereas 11.7% ctDNA-derived mutations could be found in paired tissues. At gene amplification level, the overall concordant rate was 68.3% (28/41). The concordant rate at gene level for each patient ranged from 83.8% (114/136) to 99.3% (135/136). And, the mean level of variant allele frequency (VAF) for concordant mutations in ctDNA was statistically higher than that for the discordant ones (p < 0.001; Wilcoxon rank sum test). Across five representative genes, the overall sensitivity and specificity were 49.0% and 85.9%, respectively.

Conclusion: Our results indicated that ctDNA could provide complementary information on genetic characterizations in detecting single nucleotide variants (SNVs) and insertions and deletions (InDels).

Figure 1

Comparison of the mutation number in different biopsies. (a) Mutation counts in 41 ctDNA samples and 81 tissue samples. One dot in the figure represented as the mutation counts of one sample. (b) Mutation counts and density of the top 10 genes in two biopsies. Green and blue bars represented the mutation counts or density in ctDNAs and tissues, respectively.

Figure 2

Concordant and discordant alterations detected in ctDNAs and tissues. (a) Venn diagrams representing the counting number of alterations, SNVs, InDels, and detected amplifications (AMPs) detected only in tissues (blue), detected only in ctDNAs (green), and detected in both biopsies (overlap). (b) Oncoprint chart for 17 genes which had at least one concordant protein-coding mutation site or concordant gene amplification across all 41 patients. One vertical bar represents one patient. Green bar: mutations in plasma; blue bar: mutations in tissue; red bar: concordant mutation in two biopsies; orange bar: mutations in the same gene, but discordant in ctDNA and tissue.

Figure 3

Comparison of VAF between concordant and discordant ctDNA mutations. Boxplot displayed the minimum, maximum, median, and interquartile range of VAF of ctDNA. Concordant ctDNA mutations had higher frequency than discordant ctDNA mutations (p < 0.001, Wilcoxon rank sum test).