Next-Gen DNA Sequencing as a Tool for Clinical Decision-Making in Cancer Patient Management

1. Next-Gen DNA Sequencing as a Tool for Clinical Decision-Making in Cancer Patient Management May 3-4, 2012 Bethesda, MD

2. Clinical, Ethics, and Regulatory Aspects Breakout • Assigning treatment based on NGS results in clinical trials • Sensitivity/specificity • Nothing that was specific to NGS – ie rules for current molecular tests still apply • Reports should state tumor cellularity and % allele frequency • Need to follow pts with low and high allele frequencies • Dose of gene mutation vs drug response should be followed in studies • Need for tumor registry with public/private partnership • What evidence is needed to act on an NGS result from a patient? • Secondary evaluation was controversial because it’s not clear if the secondary evaluation would be as sensitive and it’s not feasible to have a secondary pre-validated CAP/CLIA-certified test for every mutation that will be found • Also, no way a private company would perform a secondary evaluation on everything • What is the device or assay? • According to the FDA – the whole thing including pre-analytics to bioinformatics

3. Clinical, Ethics, and Regulatory Aspects Breakout • How do we assess comparability of different assays etc? Is a profiency panel approach adequate? • Two initiatives • CDC – 12878 and 19240 hapmap cell lines being deep sequenced by multiple groups and data will be pooled; will be able to be purchased by Coriel. • FDA/NIST – generating reference material for genome sequencing • Neither has a minimal proficiency standard yet defined • Some concern about whether every facility that wants to should offer NGS, esp. given the high level of complexity

4. Clinical, Ethics, and Regulatory Aspects Breakout • When does NGS become the assay of choice? • Clinical utility • Economics – inflection point is when it’s cheaper and more efficient to do NGS vs multiple other tests (ie. multiple genes, FISH, etc) • Sample volume • Turnaround • How badly is the info needed? • Should every patient that goes on trial have NGS done? • Context dependent • Most likely for early phase trials after MTD of drug is determined • What should a complete molecular work-up of patient tumors include? • Context dependent

5. Clinical, Ethics, and Regulatory Aspects Breakout • Translation issues • What types of databases are needed? • Need for tumor registry – “COSMIC for Clinicians” • Need to collect data on one-offs to move forward as a group • Example is Clinvar (already for germline genetics) • What about a patient who had his/her tumor sequenced 2 years prior? • Who stored their data? • How do you pay for storage of the data? • Who has access to it? • If a previously discovered mutation is found to be newly actionable, whose responsibility is it to notify the patient and who pays for that and the personnel to keep looking at the data? • Also, what happens if a pt gets treated on two different trials and two different institutions?

6. Clinical, Ethics, and Regulatory Aspects Breakout • What types of education are needed for clinicians and for patients? • Team approach – everyone has to be involved • YouTube videos • AMP/CAP/IASLC and other organizations are already promoting practice guidelines • What concerns are there about privacy? • Same as always – genomic information is no different from other medical information • One cannot identify someone by their DNA without having a second sample of DNA genotyped