Genomic/Genetic Testing Germline v Somatic testing and the importance of Molecular Tumor - PowerPoint Presentation

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Genomic/Genetic TestingGermline v Somatic testing and the importance of Molecular Tumor Boards

Ben Ho Park MD PhD

Johns Hopkins UniversitySlide2

Financial Disclosures

I have financial relationships with commercial entities that are relevant to the content of this presentation.

Royalties from Horizon Discovery, LTD

Scientific Advisory Board Member for Loxo OncologyOwnership interest in Loxo OncologyConsultant for Foundation Medicine, Inc.Consultant for H3 BiomedicineConsultant for Casdin CapitalConsultant for Jackson Labs

This presentation is the intellectual property of the author/presenter. Contact bpark2@jhmi.edu for permission to reprint and/or distribute.Slide3

Germline testingClassic examples include Myriad’s testing for BRCA1 and BRCA2

Testing has evolved over time

“Panel” gene testing is now becoming routine

Typically still a very small number of genesTesting has been done in the past with aid of genetic counselors, testing only patients deemed high riskGuidelines developed and modified over yearsImportantly, requires consentSlide4

Tumor Only TestingIn the past involved only hotspot mutations, then larger cancer gene panels with several hundred genes. Whole Exome Sequencing (WES) is on the horizon

With bigger panels of genes, distinguishing true somatic alterations can be problematic

Generally, no consent is required from patient

Although there is utility for some mutations with approved therapies, no definitive proof testing all cancers affords general benefitMostly performed in metastatic diseaseSlide5

Germline Filtering of Tumor SequencingSequencing of both normal germline DNA along with tumor tissue allows for filtering out of germline variants

Advantages: Can “see” only tumor somatic mutations

Disadvantages: Potentially filters out meaningful germline variants (e.g. BRCA1, 2, MLH1, MSH2, etc.)

Because these patients are not consented for germline testing, heritable mutations are not seen nor reportedSome tumor only tests now state the possibility of germline variantsSome germline filtering tests, selectively “unfilter” germline variants and report thisSlide6

One needs to understand what is being tested and what is NOT being testedSlide7

CAVEATS (there are always caveats…)

Blood cells that have mutations may be reported as a tumor mutation if there are contaminating blood cells

The source of germline DNA therefore has to be considered (saliva has many blood cells)Slide8

Genetic Alterations In Tumors With Actionable Yields (GAITWAY) – Tumor BoardSlide9

PurposeAs part of the Cancer Center’s Personalized Medicine effort, there is a need to have a “molecular profiling tumor board” to interpret genetic alterations found in a patient’s tumor sample.

The GAITWAY tumor board was formed in response to this need.Slide10

Mission Statement

To review a patient’s molecular tumor profile including but not limited to mutations, copy number changes of potentially “actionable” genes from commercial and in house assays.

To review the relevant literature on the evidence that such genetic alterations are of functional consequence and therefore could be actionable.

To review the current state of FDA approved therapies and clinical trials evaluating therapies for the individual genetic alterations.To evaluate the weight of evidence for current standard of care therapies versus pursuing “actionable” alterations and the likelihood of best responses for each patient.To discuss and prioritize recommendations based upon the genetic assays and convey the GAITWAY tumor board’s suggestions back to the referring physician and patient.Slide11

Definition of “actionable”

A genetic alteration that has an FDA approved therapy for the given tumor type (highest priority) e.g. HER2 directed therapy for HER2 amplified metastatic breast cancer.

A genetic alteration that has an FDA approved therapy for a different tumor type; e.g. HER2 directed therapy for HER2 amplification found in esophageal cancer

A genetic alteration that may provide rationale for participation in a clinical trial of a targeted therapy. A genetic alteration that may lead to recommendations for genetic counseling and germline mutation testing.Slide12

Additional Considerations

Ethical considerations for pursuing “nth” line standard of care therapies versus targeted therapies with unproven value.

Discovering and interpreting potential germline variants and need for genetic counseling/testing.

Legal implications for reporting or not reporting incidental findings; e.g. finding proviral HIV DNA in cancers using whole genome sequencing.Slide13

And now “Liquid Biopsies” with cfDNA

Most tests display allelic frequencies

Germline variants and clonal

hematopoesis are usually easy to spot based upon gene mutations and allelic frequencyBut there can be confusionSlide14

Case Report

73 y/o with met. Breast cancer originally diagnosed in 1998; strong family history of breast cancer.

Never received germline testing. No easily

biopsiable lesion (mostly lung and bone mets). Liquid biopsy with cfDNA obtained.Slide15

Case Report (cont.)Given the truncating BRCA1 mutation and her family history it was plausible that this was a somatic mutation, though likely in a

subclonal

population

However, germline testing was recommended and was negative for any BRCA1 variantsThus, it would be very unlikely that initiating a PARPi now would have meaningful benefit. A PI3Kinase inhibitor trial was recommended.Slide16

ConclusionsTumor testing and Germline testing can yield actionable variants

Great care must be used when interpreting these tests

Knowing what is being tested, filtered, reported is of paramount importance

Recognizing caveats (CH, concurrent blood disorders/mutations, etc.)Keeping up to date with the literature and clinical trials is difficult but necessaryEstablishing molecular tumor boards can aid in decision making when interpreting genetic/genomic test results