Dataset Information

Patient specific circulating tumor DNA fingerprints to monitor treatment response across multiple tumors.

ABSTRACT:

Background

Circulating tumor DNA (ctDNA) offers a convenient way to monitor tumor progression and treatment response. Because tumor mutational profiles are highly variable from person to person, a fixed content panel may be insufficient to track treatment response in all patients.

Methods

We design ctDNA fingerprint panels specific to individual patients which are based on whole exome sequencing and target to high frequency clonal population clusters in patients. We test the fingerprint panels in 313 patients who together have eight tumor types (colorectal, hepatocellular, gastric, breast, pancreatic, and esophageal carcinomas and lung cancer and cholangiocarcinoma) and exposed to multiple treatment methods (surgery, chemotherapy, radiotherapy, targeted-drug therapy, immunotherapy, and combinations of them). We also monitor drug-related mutations in the patients using a pre-designed panel with eight hotspot genes.

Results

291 (93.0%) designed fingerprint panels harbor less than ten previously known tumor genes. We detected 7475 ctDNA mutations in 238 (76%) patients and 6196 (96.0%) of the mutations are detected in only one test. Both the level of ctDNA content fraction (CCF) and fold change of CCF (between the definitive and proceeding tests) are highly correlated with clinical outcomes (p-values 1.36e-6 for level and 5.64e-10 for fold change, Kruskal-Wallis test). The CCFs of PD patients are an order of magnitude higher than the CCFs of SD and OR patients (median/mean 2.22%/8.96% for SD, 0.18/0.21% for PD, and 0.31/0.54% for OR; pairwise p-values 7.8e-6 for SD?~?PD, 2.7e-4 for OR?~?PD, and 7.0e-3 for SD?~?OR, Wilcoxon rank sum test). The fold change of CCF distinguishes the patient groups even better, which increases for PD, remains stable for SD, and decreases for OR patients (p-values 0.002,?~?1, and 0.0001 respectively, Wilcoxon signed-rank test). Eleven drug-related mutations are identified from nine out of the 313 patients.

Conclusions

The ctDNA fingerprint method improves both specificity and sensitivity of monitoring treatment response across several tumor types. It can identify tumor relapse/recurrence potentially earlier than imaging-based diagnosis. When augmented with tumor hotspot genes, it can track acquired drug-related mutations in patients.

SUBMITTER: Li J

PROVIDER: S-EPMC7395971 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

Patient specific circulating tumor DNA fingerprints to monitor treatment response across multiple tumors.

Li Jiaping J Jiang Wei W Wei Jinwang J Zhang Jianwei J Cai Linbo L Luo Minjie M Wang Zhan Z Sun Wending W Wang Shengzhou S Wang Chen C Dai Chun C Liu Jun J Wang Guan G Wang Jiping J Xu Qiang Q Deng Yanhong Y

Journal of translational medicine 20200801 1

<h4>Background</h4>Circulating tumor DNA (ctDNA) offers a convenient way to monitor tumor progression and treatment response. Because tumor mutational profiles are highly variable from person to person, a fixed content panel may be insufficient to track treatment response in all patients.<h4>Methods</h4>We design ctDNA fingerprint panels specific to individual patients which are based on whole exome sequencing and target to high frequency clonal population clusters in patients. We test the finge ...[more]

PMID: 32738923

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Project description:Background: Colorectal cancer is one of the most common cancers worldwide and has a high mortality rate following disease recurrence. Treatment efficacy is maximized by providing tailored cancer treatment, ideally involving surgical resection and personalized neoadjuvant and adjuvant therapies, including chemotherapy, radiotherapy and increasingly, targeted therapy. Early detection of recurrence or disease progression results in more treatable disease and is essential to improving survival outcomes. Recent advances in the understanding of tumor genetics have resulted in the discovery of circulating tumor DNA (ctDNA). A growing body of evidence supports the use of these sensitive biomarkers in detecting residual disease and diagnosing recurrence as well as enabling targeted and tumor-specific adjuvant therapies. Methods: A literature search in Pubmed was performed to identify all original articles preceding April 2019 that utilize ctDNA for the purpose of monitoring response to colorectal cancer treatment. Results: Ninety-two clinical studies were included. These studies demonstrate that ctDNA is a reliable measure of tumor burden. Studies show the utility of ctDNA in assessing the adequacy of surgical tumor clearance and changes in ctDNA levels reflect response to systemic treatments. ctDNA can be used in the selection of targeted treatments. The reappearance or increase in ctDNA, as well as the emergence of new mutations, correlates with disease recurrence, progression, and resistance to therapy, with ctDNA measurement allowing more sensitive monitoring than currently used clinical tools. Conclusions: ctDNA shows enormous promise as a sensitive biomarker for monitoring response to many treatment modalities and for targeting therapy. Thus, it is emerging as a new way for guiding treatment decisions-initiating, altering, and ceasing treatments, or prompting investigation into the potential for residual disease. However, many potentially useful ctDNA markers are available and more work is needed to determine which are best suited for specific purposes and for improving specific outcomes.

Project description:BackgroundMonitoring circulating tumor cells (CTC) has been shown to be prognostic in most solid malignancies. There is no CTC assay in clinical use for lung cancer therapy monitoring due to inconclusive clinical utility data. Limited data has been published outside of the standard CTC enumerations, regarding clinical significance of phenotypic heterogeneity of CTCs in late stage NSCLC and its ability to correlate with treatment outcomes.MethodsIn 81 patients with stage IV NSCLC, multiple timepoints for CTC analysis were collected after initiation of treatment across 139 lines of therapy using single cell high definition diagnostic pathology imaging of all nucleated cells from 362 peripheral blood samples as a liquid biopsy.ResultsWe analyzed the subset of 25 patients with complete time series data, totaling 117 blood samples, to determine the significance of HD-CTC kinetics during the initiation of treatment. These kinetics follow three distinct patterns: an increase in HD-CTCs with therapy (mean + 118.40 HD-CTCs/mL), unchanged HD-CTCs numbers (stable; mean 0.54 HD-CTCs/mL), and a decrease in HD-CTCs numbers (mean - 81.40 HD-CTCs/mL). Patients with an increasing CTC count during the first 3 months post initiation of new treatment had a better PFS and OS compared to the other groups. There was weak correlation between the absolute number of HD-CTCs at a single time point of therapy and patient outcomes (OS p value = 0.0754). In the whole cohort of 81 patients, HD-CTCs were detected in 51 (63%) patients at initiation of therapy with a median of 2.20 (range 0-509.20) and a mean of 26.21 HD-CTCs/mL (± 15.64).ConclusionsCTCs are identifiable in most patients with stage IV NSCLC. While absolute HD-CTC counts do not correlate with prognosis, the changes in CTC counts were predictive of survival in patients with metastatic lung cancer receiving chemotherapy. The level and dynamics of CTCs indicate very different biological and pharmacological phenomena at different stages of disease and timepoints of treatment, highlighting the complex role of CTCs in cancer research and clinical management.

Dataset Information

Patient specific circulating tumor DNA fingerprints to monitor treatment response across multiple tumors.

Background

Methods

Results

Conclusions

Publications

Patient specific circulating tumor DNA fingerprints to monitor treatment response across multiple tumors.

Similar Datasets

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