Development of a highly sensitive liquid biopsy platform to detect clinically-relevant cancer mutations at low allele fractions in cell-free DNA

Gale, Davina; Lawson, Andrew; Howarth, Karen; Madi, Mikidache; Durham, Bradley; Smalley, Sarah; Calaway, John D.; Blais, Shannon; Jones, Greg; Clark, James J.; Dimitrov, Peter; Pugh, Michelle; Woodhouse, Samuel; Epstein, Michael; Fernández-González, Ana; Whale, Alexandra S.; Huggett, Jim F.; Foy, Carole A.; Jones, Gerwyn M.; Raveh-Amit, Hadas; Schmitt, Karin; Devonshire, Alison S.; Green, Emma; Forshew, Tim; Plagnol, Vincent; Rosenfeld, Nitzan

doi:10.1371/journal.pone.0194630

Cited by 133 publications

(87 citation statements)

References 38 publications

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“…It has been found that overall sensitivity of alterations in plasma cfDNA can achieve 94% by using a NGS panel of 35 cancer-related genes. 45 In addition to being consistent with tumor biopsy, some of the results discovered by ctDNA but not in tumor tissue were also likely to be demonstrated as meaningful in some cases. For example, drug resistant mutation T790M can be found in plasma but not in tumor, and the outcome of following therapy reflected the accuracy of this result provided by plasma ctDNA only.…”

Section: Effective Detection Of Genotype To Select Proper Patients Fomentioning

confidence: 79%

<p>Update on liquid biopsy in clinical management of non-small cell lung cancer</p>

Wu¹,

Yang²,

Dai³

et al. 2019

OTT

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Lung cancer, a leading cause of cancer-related mortality, has a low rate of early diagnosis and a poor prognosis for advanced stages. Recent advances in further mastery of the biology of tumors promote the diagnosis and therapy, especially for non-small cell lung cancer (NSCLC). However, tumor tissue-based information is often not available in most cases due to the invasive and high risk nature of the tumor biopsy procedures. Liquid biopsy, based on the multiple liquid samples including circulating tumor cells (CTC), circulating tumor DNA (ctDNA), and tumor-derived exosome obtained from blood or urine as well as other body fluids, can also provide valuable tumor-related information, playing an important role in management of NSCLC in clinical practice. It is widely believed that concordance of detection for tumor by liquid samples in comparison with tissue biopsy for both early and advanced stage NSCLC patients is optimistic. We herein review the current and future clinical application of liquid biopsy, including early diagnosis and management of precise personalized treatment in lung cancer. The future directions of development for liquid biopsy are also discussed in this review.

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Section: Effective Detection Of Genotype To Select Proper Patients Fomentioning

confidence: 79%

<p>Update on liquid biopsy in clinical management of non-small cell lung cancer</p>

Wu¹,

Yang²,

Dai³

et al. 2019

OTT

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“…Analysis of circulating tumor DNA (ctDNA), commonly referred to as "liquid biopsy," is a noninvasive way to detect and measure cancerspecific molecular alterations in the blood (1)(2)(3)(4)(5). The use of ctDNA is emerging as a useful tool in several settings, including detection of postsurgical residual disease and identifying mechanisms of drug resistance (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Recent data suggest that ctDNA levels within an individual patient correlate with tumor burden over time and that serial assessment of ctDNA may represent a promising approach for monitoring treatment response, with early decreases in ctDNA serving as a predictor of response (17)(18)(19)(20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers

Parikh

Mojtahed

Schneider

et al. 2020

Clinical Cancer Research

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Purpose: ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer. Experimental Design: A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response. Results: A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR, P < 0.0001) and clinical benefit [CB: PR and stable disease (SD), P < 0.0001]. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (P < 0.0001). Four-week change in tumor markers also predicted response (P ¼ 0.0026) and CB (P ¼ 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (P ¼ 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00; P < 0.0001). Conclusions: Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.

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“…This technique is adapted to sequence, detect, and quantify tumor mutations across a gene panel including both tumor hotspots, as well as entire coding regions of selected genes [ 73 ]. The precision of this methods could be shown by the detection limit of 0.02% with 99.9997% specificity for point mutations in EGFR in circulating DNA [ 89 ]. The development of a bioinformatic method is a clear advantage that has helped to design more efficient gene panels, improve the detection sensitivity of mutant alleles, and reduce the detection of false positives.…”

Section: Ctdna Detection Technologiesmentioning

confidence: 99%

Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management

Elazezy

Joosse

2018

Computational and Structural Biotechnology Journal

281

223

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Precision medicine in the clinical management of cancer may be achieved through the diagnostic platform called “liquid biopsy”. This method utilizes the detection of biomarkers in blood for prognostic and predictive purposes. One of the latest blood born markers under investigation in the field of liquid biopsy in cancer patients is circulating tumor DNA (ctDNA). ctDNA is released by tumor cells through different mechanisms and can therefore provide information about the genomic make-up of the tumor currently present in the patient. Through longitudinal ctDNA-based liquid biopsies, tumor dynamics may be monitored to predict and assess drug response and/or resistance. However, because ctDNA is highly fragmented and because its concentration can be extremely low in a high background of normal circulating DNA, screening for clinical relevant mutations is challenging. Although significant progress has been made in advancing the detection and analysis of ctDNA in the last few years, the current challenges include standardization and increasing current techniques to single molecule sensitivity in combination with perfect specificity. This review focuses on the potential role of ctDNA in the clinical management of cancer patients, the current technologies that are being employed, and the hurdles that still need to be taken to achieve ctDNA-based liquid biopsy towards precision medicine.

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Development of a highly sensitive liquid biopsy platform to detect clinically-relevant cancer mutations at low allele fractions in cell-free DNA

Cited by 133 publications

References 38 publications

<p>Update on liquid biopsy in clinical management of non-small cell lung cancer</p>

<p>Update on liquid biopsy in clinical management of non-small cell lung cancer</p>

Serial ctDNA Monitoring to Predict Response to Systemic Therapy in Metastatic Gastrointestinal Cancers

Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management

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