The potential of liquid biopsies in cancer research2016

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Tumors shed both intact cells (resulting in circulating tumor cells) as well as cellular components, such as nucleic acids (resulting in cell-free DNA or RNA).

Liquid biopsy: circulating biomarkers for cancer

Diaz, Jr., L.A. and Bardelli, A. (2014) “Liquid biopsies: genotyping circulating tumor DNA.” Am. Soc. Clin. Oncol. 32, 579.

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Circulating cell-free DNA can be found under physiological as well as pathophysiological conditionsderives from necrotic and apoptotic tissue/cells is highly fragmentedctDNA is only a minor fraction of cfDNA

Origin of circulating cell-free DNA

Crowley et al., 2013

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Applications for liquid biopsy

Non-invasive prenatal diagnosticsChromosomal aberrationsSub-chromosomal aberrations

Pathogen detectionVirusBacteria

Detection of rejection after transplantation

Cancer diagnostics Early detectionTreatment selectionTherapy monitoring

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Early detection of cancer is crucial!

Tumour growth and metastasis

Source: American Cancer Society

stage 5-year survival CRC 5-year survival breast cancer

0 100% 100%I 92% 100%II 63-89% 93%III 53-89% 72%IV 11% 22%

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Limitations of tissue biopsy

Biopsy is invasiveMay not be feasible based on patient condition or tumour accessibilityImpractical for periodic monitoring for progression recurrence

Cancer is a heterogeneous diseaseMolecular properties differ within tumoursPrimary tumour biopsy may not reflect current disease condition (clonal evolution)

Surgery is costlyGreater demand due to molecular profiling

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Liquid biopsy for cancer detection

Bettegowda et al 2014.

The opportunityCirculating tumour DNA (ctDNA) is easy accessible and can be detected in most metastatic cancers

The challengectDNA is often only present at low levels

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cfDNA is highly fragmentedDNA content differs largely (1-100 ng / mL plasma)

Characteristics of cell-free DNA

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Challenges of ctDNA

Crowley et al., 2013

How to discriminate between ctDNA and ‘normal’ cfDNA?

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Alterations of ctDNA

Crowley et al., 2013

Point mutationsInsertions / DeletionsCopy number variationsStructural changes or rearrangements (gene fusions)Hypo- and/or hypermethylation

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Challenges of ctDNA

Crowley et al., 2013

How to discriminate between ctDNA and ‘normal’ cfDNA?

How to detect very low levels of ctDNA?

How to quantify the number of mutant DNAs in a sample?

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- services for cancer research

Unbiased discoveryExome sequencing of matched samples from tumour tissue, cell-free DNA and blood

ONCOEXOME

Targeted screeningPanel sequencing of clinically actionable mutations, including low frequency mutations

ONCOPANEL

MonitoringFrequent detection of single driver mutations after treatment, such as surgery or therapy

ONCOTARGET

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- services placed on the cancer treatment timeline

Screening Diagnosis Follow-upTreatment

STAGING SURGERY | CHEMO | RADIATION RECUPERATIONBiopsyImagingTumour sizeMolecular stratification

Tumour removalIrradianceMedication

Monitoring

Diagnosis

Adjuvant treatment decisionCompanion diagnosticsMeasurement of therapeutic response Follow-up

ONCOEXOMEONCOPANEL

ONCOTARGET

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Thank you very much for your attention