Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling

Chaudhuri, Aadel A.; Chabon, Jacob J.; Lovejoy, Alexander F.; Newman, Aaron M.; Stehr, Henning; Azad, Tej D.; Khodadoust, Michael S.; Esfahani, Mohammad Shahrokh; Liu, Chih Long; Zhou, Li; Scherer, Florian; Kurtz, David M.; Say, Carmen; Carter, Justin N.; Merriott, David J.; Dudley, Jonathan C.; Binkley, Michael S.; Modlin, L.A.; Padda, Sukhmani K.; Gensheimer, Michael F.; West, Robert B.; Shrager, Joseph B.; Neal, Joel W.; Wakelee, Heather A.; Loo, Billy W.; Alizadeh, Ash A.; Diehn, Maximilian

doi:10.1158/2159-8290.cd-17-0716

Cited by 706 publications

(617 citation statements)

References 33 publications

Supporting

Mentioning

583

Contrasting

Unclassified

Order By: Relevance

“…Quarterly ctDNA testing yielded a similar lead time of 150 days because of our assumption that imaging is performed at the same frequency. These predicted lead times for early stage lung cancer are similar to the reported median of ~160 days by Chaudhuri et al (Chaudhuri et al 2017) and slightly longer than the reported median of 70 days (range, 10 -346 days) by Abbosh et al (2017), likely due to less frequent relapse testing and a lower average number of clonal mutations covered by the sequencing panel (range 3-26).…”

Section: Tumor Relapse Detection If Mutations Are Known a Priorisupporting

confidence: 86%

A mathematical model of ctDNA shedding predicts tumor detection size

Avanzini

Kurtz

Chabon

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Early cancer detection aims to find tumors before they progress to an uncurable stage. Prospective studies with tens of thousands of healthy participants are ongoing to determine whether asymptomatic cancers can be accurately detected by analyzing circulating tumor DNA (ctDNA) from blood samples. We developed a stochastic mathematical model of tumor evolution and ctDNA shedding to investigate the potential and the limitations of ctDNA-based cancer early detection tests. We inferred ctDNA shedding rates of early stage lung cancers and calculated that a 15 mL blood sample contains on average only 1.5 genome equivalents of ctDNA for lung tumors with 1 billion cells (size of ~1 cm 3 ). We considered two clinically different scenarios: cancer screening and cancer relapse detection. For monthly relapse testing with a sequencing panel covering 20 tumor-specific mutations, we found a median detection size of 0.24 cm 3 corresponding to a lead time of 160 days compared to imaging-based relapse detection. For annual screening, we found a median detection size of 2.8-4.8 cm 3 depending on the sequencing panel size and on the mutation frequency. The expected detection sizes correspond to lead times of 390-520 days compared to current median lung tumor sizes at diagnosis. This quantitative framework provides a mechanistic interpretation of ctDNA-based cancer detection approaches and helps to optimize cancer early detection strategies.

show abstract

Section: Tumor Relapse Detection If Mutations Are Known a Priorisupporting

confidence: 86%

A mathematical model of ctDNA shedding predicts tumor detection size

Avanzini

Kurtz

Chabon

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Conventional PCR amplification is useful to confirm the presence of the fusion sequence and corresponding tumor cells, without the need for an allele‐specific or mutation‐specific amplification system mainly used in earlier studies; however, strict precautions are necessary to avoid any contaminations, which may result in false‐positive results. As reported previously, an assay using cfDNA has been proven to be useful for the early detection of tumor progression/recurrence. In the nested PCR analysis for the PAX3‐FOXO1 fusion using plasma cfDNA samples, the fusion sequence turned out to be detectable at the “remission stage,” when imaging analyses such as FDG‐PET scanning could not detect any recurrence of the tumor (Figures and B).…”

Section: Discussionmentioning

confidence: 86%

Early detection of the PAX3‐FOXO1 fusion gene in circulating tumor‐derived DNA in a case of alveolar rhabdomyosarcoma

Eguchi‐Ishimae

Tezuka

Kokeguchi

et al. 2019

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Cell‐free DNA (cfDNA), which are small DNA fragments in blood derived from dead cells including tumor cells, could serve as useful biomarkers and provide valuable genetic information about the tumors. cfDNA is now used for the genetic analysis of several types of cancers, as a surrogate for tumor biopsy, designated as “liquid biopsy.” Rhabdomyosarcoma (RMS), the most frequent soft tissue tumor in childhood, can arise in any part of the body, and radiological imaging is the only available method for estimating the tumor burden, because no useful specific biological markers are present in the blood. Because tumor volume is one of the determinants of treatment response and outcome, early detection at diagnosis as well as relapse is essential for improving the treatment outcome. A 15‐year‐old male patient was diagnosed with alveolar RMS of prostate origin with bone marrow invasion. The PAX3‐FOXO1 fusion was identified in the tumor cells in the bone marrow. After the diagnosis, cfDNA was serially collected to detect the PAX3‐FOXO1 fusion sequence as a tumor marker. cfDNA could be an appropriate source for detecting the fusion gene; assays using cfDNA have proved to be useful for the early detection of tumor progression/recurrence. Additionally, the fusion gene dosage estimated by quantitative polymerase chain reaction reflected the tumor volume during the course of the treatment. We suggest that for fusion gene‐positive RMSs, and other soft tissue tumors, the fusion sequence should be used for monitoring the tumor burden in the body to determine the diagnosis and treatment options for the patients.

show abstract

“…Molecular characterization of circulating tumor DNA (ctDNA) is finding wide applications in cancer diagnostics and clinical decision-making including, but not limited to, early cancer detection (Phallen et al, 2017), tissue of origin classification (Kang et al, 2017), cancer genome characterization (Parikh et al, 2019), epigenetic profiling (Snyder et al, 2016), and cancer monitoring after treatment (Chaudhuri et al, 2017). Although analyzing cfDNA sequencing data do not conceptually differ from the 1 analysis of biopsy-based DNA sequencing, there are several details that require specialized bioinformatics tools.…”

Section: Introductionmentioning

confidence: 99%

ctDNAtools: An R package to work with sequencing data of circulating tumor DNA

Alkodsi

Meriranta

Pasanen³

et al. 2020

Preprint

View full text Add to dashboard Cite

Sequencing of cell-free DNA (cfDNA) including circulating tumor DNA (ctDNA) in minimally-invasive liquid biopsies is rapidly maturing towards clinical utility for cancer diagnostics. However, the publicly available bioinformatics tools for the specialized analysis of ctDNA sequencing data are still scarce.Here, we present the ctDNAtools R package, which provides functionalities for testing minimal residual disease (MRD) and analyzing cfDNA fragmentation. MRD detection in ctDNAtools utilizes a Monte Carlo sampling approach to test ctDNA positivity through tracking a set of pre-detected reporter mutations in follow-up samples. Additionally, ctDNAtools includes various functionalities to study cfDNA fragment size histograms, profiles and fragment ends patterns. AvailabilityThe ctDNAtools package is freely available under MIT license at https://github.com/alkodsi/ctDNAtools.

show abstract

Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling

Cited by 706 publications

References 33 publications

A mathematical model of ctDNA shedding predicts tumor detection size

A mathematical model of ctDNA shedding predicts tumor detection size

Early detection of the PAX3‐FOXO1 fusion gene in circulating tumor‐derived DNA in a case of alveolar rhabdomyosarcoma

ctDNAtools: An R package to work with sequencing data of circulating tumor DNA

Contact Info

Product

Resources

About