New Approaches to Cancer Susceptibility Testing 2016-07-13 Mark Robson, MD Clinical Genetics and Breast Medicine @MarkRobsonMD robsonm@mskcc.org

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

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

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

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

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

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

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

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

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

Prevalence of pathogenic variants 15.7% 12.6% 6.4% (5.0% excl. MUTYHm) Schrader et al, JAMA Oncol. 2016 Jan;2(1):104-11

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

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

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

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

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

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