AGBT 2010 - Ian Bosdet - BC Gancer Agency

Mutational Profiling of Pre and Post-Treatement Lung Tumors Using Whole-Transcriptome Sequencing and Targeted Sequence Capture

EGF receptor is often mutated (non-small cell)

* some tyrosine kinase inhibitors exist, but response is variable.

* clinical characteristics known to be associated with response was used as primary criterial for recruitment

Identifying patients that are likely to bbenefit from TKI therapy can have a significant impact on overall survival.

* cells become addicted to the rampant signalling from TK. Cutting it off can kill them

* often a mutation that can dampen or negate result of drug.

All cancers used were first line.

* non-smoker

* female & asian

* stage IIIb

* NSCLC 1st line.

Majority of patients have now progressed - and encouraged to donate 2nd biopsy.

65 patients over 2 years,

goal: non progression over 8 weeks.

80% did not progress in 8 weeks.

* 23 partial response,

* 24 stable disease

30 tumours selected for RNA sequencing

* 13 responders, 14 non-responders

* 3 progression tumours

* gene expression analysis and mutation discovery

* some correlation to clinical characteristics.

One gene correlated with EGFR sensitivity mutations.

Another seemed to correlated to smokers who did not respond: IER5L

Excess unaligned reads were aligned to virus transcripts - Highly enriched for Epistein-Barr Virus. Tumour ended up being re-classified.

3 patients then sequenced with Capture:

* Used Agilent (47,558 baits)

* Normal, pre-treatment and post-treatment tumour samples

* can be used to identify small deletions

* Putative somatic mutations resulting in significant amino-acid alterations were identified using SNVMix

* Mutations similar between patients were not observed, but pre-treatment tumour pairs show significant overlap.

[Talking about putative somatic mutations.... I got ripped into for doing the exact same analysis and calling the same mutations "most likely" somatic 2 weeks ago... DOH.]

Sumary:

* clinical selection of patients can greatly enhance incidence of EGFR and mutations and response to erlotnib at 8-weeks

* EGFR mutation status is a good but imperfect predictor of patient response

* mutation discovery in treatment naive lung tumours has identified a relatively small number of mutations (need validation(

* more progressions will be analyzed.