Session 5: Germline Testing

Top Tier Recommendations

What are the top 3 recommendations that would significantly accelerate progress and what must be done to achieve them? Please be as specific as possible.

Recommendations from the presentations and notes from the discussion can be found beginning on page 2.

3. Key Questions, Panelist Recommendations, and Discussion Notes

Key Questions

 Do oncologists underestimate the power of germline genetics? Predictive testing can prevent disease – in our patients and their family members It is important and valuable in its own right Germline findings can have therapeutic implications on their own Many of our patients should have already had germline testing before they developed cancer

 There are several ways to do tumor testing: do patients and providers understand germline implications of each method? Paired germline/somatic vs somatic with germline subtracted vs somatic only Understand strengths and weaknesses Develop strategies so that data can be used Appropriate consent

 Reporting: Differential level of variant review and annotation for germline and somatic Testing is done for different reasons – and may have different thresholds Not everything needs to be further evaluated in the germline (VUS/benign in ClinVar) Clarification of reporting Founder mutations Allelic frequency? Beyond cancer related genes?

 Somatic only – the de facto standard in the community at this time What results should trigger rapid and low barrier referral for germline testing? Why does this matter? Extending beyond the traditional model - cancer community has create new models

Recommendations

Domchek Considerations • Embrace the germline: risk prediction and prevention for patients and family members – as well as targeted therapy • Consent, disclosure, and data usage • Clarity of testing and reporting for providers and patients • Novel models for consent and information dissemination

Recommendations  Encourage analysis of the germline  Improve annotation and reporting  Evolve paradigms for consent and return of results  Provide guidance for community oncologist for inferences of germline in somatic testing Robson  Develop approaches that reduce barriers to efficient testing of appropriate patients  Underutilization is as much an issue as overutilization  Educate providers (and patients) about potential for germline findings from tumor profiling

Pellini  Tremendous confusion in the ‘communities”: “I’m going to order genetic testing.” o Genetic vs Genomic o Germline vs Somatic o Base sub vs InDel vs CNA vs Translocation/Fusion  Physician and patient education essential  Patient privacy protection / data protection issues  Clinical and analytic validation standards for NGS tests needed  Health economic and outcomes data necessary for sustainable reimbursement  Cannot overcome these challenges in a timely way without general alignment from clinicians, industry, regulators, payers, and patients

Chanock  Encourage the analysis of germline in tumor sequencing- either derived or in tandem o Improve interpretation  Improve knowledge base for interpretation and re-interpretation of germline data o Annotation resources for information & ’counseling’  Transform paradigms for returning information & making concrete counseling o Beyond the ACMG model…......  Guidance for comprehensive interpretation of variants

Garber

Discussion Notes Domchek: Payments and reimbursements in the filed gets more complicated over time. BRCA panel tests – lots of options and lots of labs and depends on payment options and family history, deductibles, etc. Some labs have inexpensive tests but not covered by insurance. Overall we are able to get coverage to patients.

Kate: Very occasionally someone cannot get covered because of their insurance situation but usually not the case.

Mark: The interpretation part is equally important.

Staudt: Difficulty in understanding certain terms like penetrance. What is the model to ensure people interpret properly – videos?

Domchek: Online education that’s interactive. We are working on this. Because the demand for genetic testing is going up. Chanock: need to think outside academic box.

Conley: NCI Match will have additional trials into the education issue. Somatic testing and figure out what that means to them. 2. Somatic test with potential germline implication – a small pilot trial. Patients are limited as to whether the can go to academic med centers.

Garber: People in all these wstudies have learned ewhat they needed to know. The companies have been very good at detailing. We all qagree that there are more acceeible ways to provide genetic education and we have to do more.

XX: When the data come back primarily as pdfs they become useless.

Domchek: We are also sensitive to the issue of getting the results to patients quickly.

Demetri: The data sharing experience – as we propose bigger collaborative porjects the IRBS have been fear mongering about genetic tests. How do we go about data sharing in this environment?

Domcheck: “In our IRBs its always about consent.

Chanock: Its an operative problem.

Eric: The burdens are much greater if it is more than minimal risk.

Galbraith: in context of clinical trials – anything we can do better in pharma?

Chanock: pharmacogenomics could be important for modifying response. What is it about the germline that can help identify those individuals that can most benefit from drug.

Domcheck: IRB dependent. At Penn, we separate out genetic testing from the trial. We view it as Standard of Care.

Garber: How do you prepare a patient for the information that comes from their tests?

Chanock: Clinical trials are a remarkable opportunity. We need to understand that it is about the germline that is predictive?

Putcha: Working with IRBs and consent – silicon valley meeting experience. 2. How comparable are the cheaper and more expensive tests in terms or results and interpretation. 3. Reimbursement – Silliness in coding and reimbursement. A code that is more comprehensive of sequencing more expensive that a smaller test for sequencing.

Robson: Are the tests comparable – its hard to know if the inexpensive tests are comparable to the expensive tests.

Garber: We have to be certain about communicating negative results and be aware of the possibility of misunderstanding/misinterpretation. Kate: Bundling of costs – the first thing you would cut is germline testing if you don’t think that would help patient.

Abrams: Consent – if it’s a standard of care test we don’t need to talk about it to the patient. But if you’re going to do research and just going to bank it you have to tell the patient. The place where you need to tell more is when you do investigational studies on the actual treatment. That puts boundaries on what researchers can do.

Domchek: Issue of research test results is a whole diff issue. An approach is to have it in the consent form that we may find something and will have the opportunity to receive the result.

Robson: Patients don’t want to come offline and get a very complicated explanation of their results. Design educational intervention that helps patients know that they need to know.

Domchek: : You’re picking things out that will help family (CASCADE testing). Different counseling for someone with metastatic cancer vs. unaffected young patients.