Detection of Circulating Tumor Dna in Early and Late Stage Human Malignancies

Bettegowda, Chetan; Sausen, Mark; Leary, Rebecca J.; Kinde, Isaac; Agrawal, Nishant; Bartlett, Bjarne R.; Wang, Hao; Luber, Brandon; Kinzler, Kenneth W.; Vogelstein, Bert; Papadopoulos, Nickolas

doi:10.1093/neuonc/nou206.24

Cited by 1,167 publications

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“…As illustrated by recent reviews, [19][20][21] the majority of publications have presented hypothesis generating data, although with great potential, not comparable, and not ready for translation into clinical practice. As opposed to the present study, the majority of studies have investigated biological aspects of circulating tumor DNA (ctDNA), as recently published by Bettegowda et al 22 This comprehensive work on several tumor types showed increasing levels of ctDNA with more advanced stages and longer survival with lower baseline levels, in line with our data.…”

Section: Discussionsupporting

confidence: 90%

Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer

et al. 2014

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The purpose was to investigate total cell-free DNA (cfDNA) in colorectal cancer (CRC) patients during treatment with secondline chemotherapy and in healthy controls and patients with different comorbidities. Patient treated with second-line irinotecan for metastatic CRC (n 5 100), a cohort of healthy controls with and without comorbidity (n 5 70 and 100, respectively) were included. cfDNA was quantified by an in-house developed quantitative polymerase chain reaction from plasma samples drawn prior to the first cycle of chemotherapy and at time of progression. cfDNA levels were significantly higher in CRC compared to controls, with a clear capability for discriminating between the groups (receiver operation curve analysis; area under the curve 0.82, p < 0.0001). Patients with high levels had a shorter survival from irinotecan compared to those with lover levels. The cohort independent upper normal limit divided patients into high and low risk groups. The progression-free survival (PFS) was 2.1 months [95% confidence interval (CI) 2.0-3.4] and 6.5 (95% CI 4.2-7.2) months [hazard ratio (HR) 2.53; 95% CI 1.57-4.06, p < 0.0001] and overall survival (OS) 7.4 months (95% CI 4.3-8.7) and 13.8 months (95% CI 11.9-18.9; HR 2.52; 95% CI 1.54-4.13, p < 0.0000), respectively. Cox regression multivariate analysis showed a PFS HR of 1.4 (95% CI 1.1-1.7) for each increase in cfDNA quartile, p 5 0.03 and 1.6 (1.3-2.0) for OS, p < 0.0001, respectively. A combined marker analysis with plasma KRAS mutations added further prognostic impact, which was consistent when performed on the samples drawn at time of progression. In conclusion, cfDNA measurement holds important clinical information and could become a useful tool for prediction of outcome from chemotherapy in mCRC.Despite the availability of several effective cytotoxic drugs and new biological agents the prognosis of metastatic colorectal cancer (mCRC) is still poor and the curative options are limited to a subgroup of patients with resectable metastasis. Consequently, the majority of patients will be offered several lines of palliative chemotherapy, which imply a high level of side effects and careful selection of patients and monitoring during therapy is therefore essential. Irinotecan (a semisynthetic analog of camptothecin) is widely used in combination with flouropyrimidines or as monotherapy for mCRC. 1 The major dose limitating toxicities include diarrhea and myelosupression. 2,3 Better selection criteria in terms of predictive and prognostic markers to optimize treatment are needed.The presence of circulating nucleic acids in peripheral circulation was discovered more than 60 years ago by Mandel and Metais 4 followed by Leon et al. 5 in 1971 who later described the importance of circulating tumor DNA in cancer development. A substantial proportion of the circulating cell-free DNA (cfDNA) in cancer patients is believed to originate from tumor cells. 6,7 Recent studies have consequently focused on the multipurpose utility of cfDNA for molecular characterization to aid in...

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Section: Discussionsupporting

confidence: 90%

Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer

et al. 2014

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“…early recognition of NPC (17)(18)(19). However, the presence of these antibodies among moderate numbers of non-NPC individuals has caused difficulties in the use of EBV specific IgA antibodies to differentiate populations at high risk for NPC.…”

Section: Discussionmentioning

confidence: 99%

Circulating Epstein–Barr virus microRNAs miR‐BART7 and miR‐BART13 as biomarkers for nasopharyngeal carcinoma diagnosis and treatment

Zhang

Zong

Shen

et al. 2014

Intl Journal of Cancer

102

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More than 75% of nasopharyngeal carcinoma (NPC) patients have already developed local or regional spread at diagnosis, which hampers effective treatment and results in a poor prognosis. It is essential to characterize more sensitive and specific biomarkers for screening of high risk individuals and assessment of NPC treatment effectiveness. NPC is an Epstein-Barr virus (EBV) associated tumor in which only a few viral proteins but more than 20 BamHI A rightward transcripts (BART) microRNAs are detected, at abundant levels. We hypothesized that these BART microRNAs may be novel biomarkers for NPC. Systematic analysis of EBV BART microRNA expression profiles in EBV latently infected Mutu I and Mutu III cell lines, EBV-harboring NPC and noncancerous NP cells found that miR-BART3, miR-BART7 and miR-BART13 microRNAs are highly expressed and regularly secreted into the extracellular environment of NPC cells. These BART microRNAs were evaluated for used as potential NPC biomarkers. Analysis of plasma specimens obtained from NPC patients (n 5 89), and healthy (n 5 28) and non-NPC tumor patient controls (n 5 18) found levels of both miR-BART7 and miR-BART13, but not miR-BART3, to be distinctly presence among NPC patients, with elevated levels being particularly apparent among patients with advanced disease. Receiver operating characteristic curve analysis combining miR-BART7 and miR-BART13 levels produces a 90% predictive value for the presence of NPC. Analysis of 41 NPC patients before and after radiotherapy showed that miR-BART7 and miR-BART13, but not miR-BART3, were diminished after treatment. These results indicate that EBV microRNAs, miR-BART7 and miR-BART13, may constitute useful new serological biomarkers for diagnosis of NPC and prediction of treatment efficacy.

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“…Although not formally proven, this potential advantage of cfDNA is particularly important in the setting of secondary clinical resistance, 236 to enable broad sampling of different tumor subclones. 232,240,241 Analytical methods for cfDNA have high analytical specificity, with very low (<5%e20%) false-positive rates, 232,234,235,242,243 such that demonstration of a mutation, in the proper clinical context, can be used to guide treatment with a targeted inhibitor. However, sensitivity of cfDNA analysis is lower (60%e70%), 232,234,235,242,243 such that the absence of mutation finding does not exclude the possibility of a mutation.…”

Section: No Recommendationmentioning

confidence: 99%

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

Aung

Donald

Ellison

et al. 2014

The Journal of Molecular Diagnostics

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Context: In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. Objective: To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. Design: The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. Results: Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. Conclusions: The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of

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Detection of Circulating Tumor Dna in Early and Late Stage Human Malignancies

Cited by 1,167 publications

References 35 publications

Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer

Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer

Circulating Epstein–Barr virus microRNAs miR‐BART7 and miR‐BART13 as biomarkers for nasopharyngeal carcinoma diagnosis and treatment

Analytical Validation of BRAF Mutation Testing from Circulating Free DNA Using the Amplification Refractory Mutation Testing System

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