#AGBTPH – AmirAli Talasaz, NGS analysis of circulating tumour DNA from 20,000 advanced cancer patients demonstrates similarity to tissue alteration patterns

AmirAli Talasaz, Guardant Health

Spatial and Temporal heterogeneity is becoming more important.  Resistance clones are a major challenge.

Risk and cost of lung biopsies:  19.3% patients experience adverse events.  Mostly pneumothorax.  By pass this by doing liquid biopsies.  Tumours release cell free DNA – active tumours actively shed.  We can get this via simple blood tests.  cDNA can be used to study tumour heterogeneity.

Tumour cell free signals are very dilute.  Standard NGS would limit what you can see.  Take  two samples: biobank one, process one.  digital sequencing library, involves non-random tagging.  target capture 70 genes followed by error correction and bioinformatics.  After 10’s of thousands, the performance has improved very well.

Call CNV, SNV, SV, epigenetics. Variant calling an interpretation.

Half of reported variants occur below 0.4% MAF.  Reported Somatic variants are highly variable, up to 97% MAF, but median is 0.4%.

Accuracy of Low VAF is excellent using this method – correlates perfectly.

High detection rate across most cancers – better for stuff like liver 92%, brain is in 50’s% because of the blood brain barrier [57%?].

Typical driver mutations are frequently found, ranging from 100% for an EGFR variant, down to 13% –  27% for a different EGFR variant.

TCGA and ctDNA have similar mutation patterns. (some exceptions where ctDNA reflects generally the heterogeneity of cancer)

Fusion calls are similar.

When you have access to treatment data at time of blood draw, you can see actionable resistance variants.  27% of resistance mutations found in ctDNA are potentially actionable.

Example with NSCLC – biomarkers were only complete for 37%.

Example with clinical trial – using ctDNA was able to make excellent predictions in large fraction of cases, with favourable outcomes in majority of cases.

[Wasn’t a real summary so here’s mine: – ctDNA is a thing, and their protocol seems to be working.  Very cool.]

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