Abstract
Tumor heterogeneity, especially intratumoral heterogeneity, is a primary reason for treatment failure. A single biopsy may not reflect the complete genomic architecture of the tumor needed to make therapeutic decisions. Circulating tumor DNA (ctDNA) is believed to overcome these limitations. We analyzed concordance between ctDNA and whole-exome sequencing/whole-genome sequencing (WES/WGS) of tumor samples from patients with breast (n = 12), gastrointestinal (n = 20), lung (n = 19), and other tumor types (n = 13). Correlation in the driver, hotspot, and actionable alterations was studied. Three cases in which more-in-depth genomic analysis was required have been presented. A total 58% (37/64) of patients had at least one concordant mutation. Patients who had received systemic therapy before tissue next-generation sequencing (NGS) and ctDNA analysis showed high concordance (78% (21/27) vs. 43% (12/28) p = 0.01, respectively). Obtaining both NGS and ctDNA increased actionable alterations from 28% (18/64) to 52% (33/64) in our patients. Twenty-one patients had mutually exclusive actionable alterations seen only in either tissue NGS or ctDNA samples. Somatic hotspot mutation analysis showed significant discordance between tissue NGS and ctDNA analysis, denoting significant tumor heterogeneity in these malignancies. Increased tissue tumor mutation burden (TMB) positively correlated with the number of ctDNA mutations in patients who had received systemic therapy, but not in treatment-naïve patients. Prior systemic therapy and TMB may affect concordance and should be taken into consideration in future studies. Incorporating driver, actionable, and hotspot analysis may help to further refine the correlation between these two platforms. Tissue NGS and ctDNA are complimentary, and if done in conjunction, may increase the detection rate of actionable alterations and potentially therapeutic targets.
Highlights
The increasing availability of next-generation sequencing (NGS) coupled with the identification and targeting of individual oncogenic drivers has generated great interest in genomic-driven therapies.Several genomic markers are routinely used to guide therapeutic decisions in multiple solid tumors.Examples include epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib in advanced lung adenocarcinoma, and cetuximab and panitumumab in metastatic colorectal cancers
Given that all breast cancer patients in this study were given treatment prior to tissue NGS and Circulating tumor DNA (ctDNA) analysis, we looked at the gene-level concordance of the remaining cohort excluding breast cancers
When we looked at correlation based on tumor type, we found a significant correlation between tissue tumor mutation burden (TMB) and the number of ctDNA mutations among breast cancer patients, but not in lung or GI cancer patients (Supplementary Figure S1, Supplementary Table S4)
Summary
The increasing availability of next-generation sequencing (NGS) coupled with the identification and targeting of individual oncogenic drivers has generated great interest in genomic-driven therapies.Several genomic markers are routinely used to guide therapeutic decisions in multiple solid tumors.Examples include epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib in advanced lung adenocarcinoma, and cetuximab and panitumumab in metastatic colorectal cancers. The increasing availability of next-generation sequencing (NGS) coupled with the identification and targeting of individual oncogenic drivers has generated great interest in genomic-driven therapies. Several genomic markers are routinely used to guide therapeutic decisions in multiple solid tumors. Recent prospective studies have shown improved survival when patients are treated with genomic-driven therapies [1,2]. Genomic-driven therapeutic decisions have been based primarily on tissue NGS. Tissue heterogeneity, intra-tumoral heterogeneity (heterogeneity among the tumor cells), inter-metastatic heterogeneity (heterogeneity among different metastatic lesions in the same patient), and temporal heterogeneity (heterogeneity during tumor evolution) often exist and, if not taken into consideration, may lead to missed opportunities for targeted therapies or inappropriate therapeutic interventions. While obtaining multiple biopsies from tumor sites seems like an attractive solution, logistical and safety limitations make it impractical in a clinical setting
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