1. New Approaches to Cancer Susceptibility Testing
Mark Robson, MD
Clinical Genetics and Breast Medicine
@MarkRobsonMD

2. Historical parallels In 1996:
Actionable germline mutations considered rare
Limited evidence base to guide intervention
Uncertainty about test interpretation (penetrance, VUS)
Concerns about downstream impact of testing
Cost:benefit ratio of risk reduction interventions
Concerns about psychological impact

3. Clinical utility of germline testing
Assessment and management of second primary risk
Family risk assessment/guidance
Treatment determination

4. We have a problem… Many patients who should be getting tested…aren’t
Quite a few patients are getting tested when they “shouldn’t be” (low mutation risk)
Lack of consensus about the optimal “NNT”
Utilization review vs. population screening

5. Traditional approach to germline testing
MDs may not identify patients for referral
Carriers may not meet criteria for referral
Referral is a (big) barrier
Patient selection
Referral for pretest counseling
Post-test counseling
Intervention
Desgined to maximize autonomy and personal utility in situtions where testing had limited clinical utility

6. Germline analysis as part of tumor profiling
Tearing down the wall
“Mainstreaming”
Test ordering by primary oncologist
Video pre-test education and e-consent
Result communication in tandem with genetics
Germline analysis as part of tumor profiling

7. Sources of germ line findings in tumor mutation profiling
Indirect: germ line DNA sequence reflected in DNA of tumor
Direct: germ line DNA sequence determined for comparison to tumor sequence

8. Tumor sequencing without matched normal
ACCGGTTT
Tumor
Compare to reference sequence
Read-out
ACCGGTTT
Variant could be germline or somatic
Variant may or may not be pathogenic
Variant may or may not be related to diagnosis

9. Isolating somatic variants
ACCCGTTT
ACCGGTTT
Normal
Tumor
Normal BAM
Tumor BAM
Informatic subtraction
Read-out
---G----
May or may not be functional

10. Problem: Subtraction masks significant germline variants
ACCGGTTT
ACCGGTTT
Normal
Tumor
Normal BAM
Tumor BAM
Informatic subtraction
Machine
Human
Read-out

11. Prevalence of pathogenic variants
15.7%
12.6%
6.4% (5.0% excl. MUTYHm)
Schrader et al, JAMA Oncol Jan;2(1):104-11

12. Direct generation of germline information during tumor profiling
ACCGGTTT
ACCGGTTT
Normal
Tumor
Normal BAM
Tumor BAM
Subtracted
analysis
Active comparison to reference sequence
---G----
Tumor read-out

13. Secondary Germline Analysis at MSK
Consented to tumor profiling
Tumor and normal samples sequenced
Offered germline analysis (76 genes)
Video pre-test education and separate consent
Germline sequence curated
Pathogenic/Likely pathogenic variants reported
Patient informed by MD
Follow-up by genetic counselor

14. Outcomes (7/6/16) Genes 1113 results reported
APC
MITF
ATM
MLH1
BAP1
MSH2
BARD1
MSH6
BRCA1
MUTYH
BRCA2
NBN
BRIP1
PALB2
CDH1
PMS2
CDKN2A
RAD50
CHEK2
RAD51D
FAM175A
REQL4 FH
SDHA
FLCN
SDHB
MEN1
VHL
Outcomes (7/6/16)
1113 results reported
216 (19.4%) P/LP variants

15. Advantages Disadvantages Uncertainties
Efficient
Low barrier to testing
Not constrained by personal/FH
Incremental resources for curation
Class 3 variants (VUS) not reported
Knowledge gaps among treating MDs
Uncertainties
Test sensitivity
Psychological outcomes
Family communication
Effectiveness of follow-up

16. Summary Germline susceptibility variants are not rare
Sensitivity of traditional referral criteria variable (depends on cancer site)
Failing to recognize germline susceptibility is a missed opportunity (and medico-legal risk)
Mainstreaming and routine secondary analysis with limited pretest education are feasible

17. Recommendations
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