CAP Cancer BioMarker Reporting Committee Biomarker - Problem, ROI and Scope

1. CAP Cancer BioMarker Reporting CommitteeBiomarker - Problem, ROI and Scope College of American Pathologists’ Biomarker Reporting Committee Problem • Clinicians think of biomarkers (e.g. : EGFR Exon 19 deletions) and need to understand non-standardized results • Bioinformaticists think of specific nucleotide changes • Cancer Registrars also need to understand non-standardized results, largely dependant on testing platform • From Report: How can clinicians connect nucleotide change with clinical guidelines, which are often expressed in terms of biomarkers? • From Lab: How can a molecular pathologist map from the nucleotide change to the biomarker? ROI • Eliminate bottleneck in reporting, by enabling algorithms to map from identified mutations to biomarkers. • Increase efficiency of Molecular Pathologists (a very limited resource). Scope • College of American Pathologists – Cancer BioMarker Reporting Templates • somatic, nucleotide biomarkers for clinical reporting

2. Mapping from Machine Generated Sequence Variation to Cancer BioMarker Reporting Template Lung Cancer BioMarker Reporting Template Machine Readable to BioMarker Mapping Machine readable version from NGS: Chr: 7 Seq: NC_000007.13 genomic start: 55249071 Ref: C Allele: T HGVS Clinical Genetics Representation: NM_005228.3: c.2369C>T NP_005219.2:p.Thr790Met Human Understandable Biomarker: EGFR Exon 20 Thr790Met Machine (platform NGS) + EGFR Mutational Analysis (Note B) + ___ No mutation detected (wild-type EGFR allele) + ___ Mutation identified (select all that apply) + ___ Exon 18 Gly719# + ___ Exon 19 deletion# + ___ Exon 20 insertion## + ___ Exon 20 Thr790Met### + ___ Exon 21 Leu858Arg# + ___ Other (specify)####: ______________________ + ___ Cannot be determined (explain): __________ # This EGFR activation mutation is associated with response to EGFR tyrosine kinase inhibitors. ## This form of EGFR activating mutation is generally associated with resistance to EGFR tyrosine kinase inhibitors although insertions at or before position 768 can be associated with sensitivity. ### This mutation is typically secondary to other EGFR activating mutations and is associated with acquired resistance to tyrosine kinase inhibitor therapy. If seen in untreated/pretreated patients, may be present in the germline and indicate a hereditary cancer syndrome, in which case genetic counseling is suggested. #### There is limited data on response to EGFR tyrosine kinase inhibitors for many of the uncommon EGFR activating mutations. Molecular Pathologist (platform ABI Seq) Oncologist (platform kit)

3. Multiple Transcript Reference Sequences Which is the canonical Transcript Reference Sequence & associated Exon placement???

4. Recommendations from HL7 Clinical Genomics & Anatomic Pathology Workgroups, NCBI, and LOINC/Lister Hill Center at NLM • For each Gene: provide a canonical reference sequence • For each Exon: derived from the canonical reference sequence • For each term ‘deletion’, ‘insertion’, ‘mutation’: define what is meant (e.g. mutation = DNA change type is ‘missense’, etc… OR if ‘Exon 20 deletion’ is it all deletions in Exon 20 or a specific list of Exon 20 deletions)?