Concurrent Tissue and Circulating Tumor DNA Molecular Profiling to Detect Guideline-Based Targeted Mutations in a Multicancer Cohort
Related Experiment Video
Updated: Jul 5, 2025
Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids
Published on: June 8, 2019
Wade T Iams1, Matthew Mackay2, Rotem Ben-Shachar2
1Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Importance:
Tissue-based next-generation sequencing (NGS) of solid tumors is the criterion standard for identifying somatic mutations that can be treated with National Comprehensive Cancer Network guideline-recommended targeted therapies. Sequencing of circulating tumor DNA (ctDNA) can also identify tumor-derived mutations, and there is increasing clinical evidence supporting ctDNA testing as a diagnostic tool. The clinical value of concurrent tissue and ctDNA profiling has not been formally assessed in a large, multicancer cohort from heterogeneous clinical settings.
Objective:
To evaluate whether patients concurrently tested with both tissue and ctDNA NGS testing have a higher rate of detection of guideline-based targeted mutations compared with tissue testing alone.
Design, Setting, And Participants:
This cohort study comprised 3209 patients who underwent sequencing between May 2020, and December 2022, within the deidentified, Tempus multimodal database, consisting of linked molecular and clinical data. Included patients had stage IV disease (non-small cell lung cancer, breast cancer, prostate cancer, or colorectal cancer) with sufficient tissue and blood sample quantities for analysis.
Exposures:
Received results from tissue and plasma ctDNA genomic profiling, with biopsies and blood draws occurring within 30 days of one another.
Main Outcomes And Measures:
Detection rates of guideline-based variants found uniquely by ctDNA and tissue profiling.
Results:
The cohort of 3209 patients (median age at diagnosis of stage IV disease, 65.3 years [2.5%-97.5% range, 43.3-83.3 years]) who underwent concurrent tissue and ctDNA testing included 1693 women (52.8%). Overall, 1448 patients (45.1%) had a guideline-based variant detected. Of these patients, 9.3% (135 of 1448) had variants uniquely detected by ctDNA profiling, and 24.2% (351 of 1448) had variants uniquely detected by solid-tissue testing. Although largely concordant with one another, differences in the identification of actionable variants by either assay varied according to cancer type, gene, variant, and ctDNA burden. Of 352 patients with breast cancer, 20.2% (71 of 352) with actionable variants had unique findings in ctDNA profiling results. Most of these unique, actionable variants (55.0% [55 of 100]) were found in ESR1, resulting in a 24.7% increase (23 of 93) in the identification of patients harboring an ESR1 mutation relative to tissue testing alone.
Conclusions And Relevance:
This study suggests that unique actionable biomarkers are detected by both concurrent tissue and ctDNA testing, with higher ctDNA identification among patients with breast cancer. Integration of concurrent NGS testing into the routine management of advanced solid cancers may expand the delivery of molecularly guided therapy and improve patient outcomes.
Insights
Concurrent tissue and circulating tumor DNA (ctDNA) next-generation sequencing (NGS) identifies unique actionable mutations, particularly in breast cancer. Combining both methods improves detection of guideline-based targeted therapies for advanced solid tumors.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Tissue-based next-generation sequencing (NGS) is standard for identifying targetable tumor mutations.
- Circulating tumor DNA (ctDNA) sequencing also detects tumor mutations, with growing clinical support.
- The combined clinical value of tissue and ctDNA profiling in diverse cancer types is not well-established.
Purpose of the Study:
- To determine if concurrent tissue and ctDNA NGS testing increases the detection rate of guideline-based mutations compared to tissue testing alone.
- To assess the concordance and discordance of actionable variant detection between tissue and ctDNA profiling across various cancers.
Main Methods:
- A cohort of 3209 patients with stage IV non-small cell lung, breast, prostate, or colorectal cancer was analyzed.
- Patients underwent concurrent tissue and plasma ctDNA genomic profiling, with samples collected within 30 days.
- Detection rates of guideline-based variants uniquely identified by each method were compared.
Main Results:
- Of 1448 patients with detected guideline-based variants, 9.3% were uniquely identified by ctDNA and 24.2% by tissue testing.
- Variant detection differences varied by cancer type, gene, and ctDNA levels.
- In breast cancer, ctDNA uniquely identified actionable variants in 20.2% of cases, notably increasing ESR1 mutation detection by 24.7%.
Conclusions:
- Concurrent tissue and ctDNA testing detects unique actionable biomarkers, with higher ctDNA yield in breast cancer.
- Integrating both testing modalities may enhance molecularly guided therapy delivery for advanced solid cancers.
- This approach has the potential to improve patient outcomes through expanded therapeutic options.
