Lecture:  Primary Care Providers –  Future Heralds and Interpreters  

of Gene c Tes ng  

Alisdair Philp, PH D 

2/23/2015

1

Primary Care Providers –

the future Gatekeepers, Heralds and

Interpreters of Genetic Testing

Alisdair Philp, PhD

Declaration of financial interests:

Shares:

Sequenom 10 shares

Nanostring technonogies 18 shares

Total value < $ 400.00

2/23/2015

2

Imperial College

USUHS

Affiliate Scientist

Associate Scientist

? ?

Objectives:

1- The changing role of the PCP

2- New testing options

3- Incidental findings

4- Physician judgment

2/23/2015

3

Gatekeepers-

access/referrals to testing

Heralds-

informed consent

Interpreters-

explaining the results

Gatekeepers-

access/referrals to testing

Personalized medicine

Direct to consumer testing

2/23/2015

4

Personalized medicine –

Pharmacogenetics

CYP2C19

Enzyme is associated

with conversion of

Clopidogrel to active

form

Clopidogrel

- Rx vs atherothrombotic

events.

- Drug is not metabolically

active

2/23/2015

5

CYP2C19 Enzyme is associated with conversion of Clopidogrel to active form

Clopidogrel - Rx vs atherothrombotic events. - Drug is not metabolically active

Examples of Polymorphisms in Genes That Alter Cardiovascular Function and Responses to Drugs.

. N Engl J Med 2003;349:60-72. As more studies are carried out and the costs of screening is reduced, it is not unreasonable to expect that in the near future patients prescreening for responses to drugs will be routine.

2/23/2015

6

Consultation with PCP

DNA

extracted and

interpreted Selection of

drug/dosage

for individual

patient

Personalized medicine

https://cpt.uchicago.edu/

Incorporating genetic information

into the decision making process

when prescribing medications as a

way to individualize therapies.

2/23/2015

7

Direct to Consumer Testing

Be careful what you ask for … because you

might just get it …

..

..

… and then some….

Case study 1

2/23/2015

8

15

Bloom’s Syndrome

Gaucher Disease

Phenylketonuria

Asthma

Floxacillin Toxicity

Height

Memory

Kidney Disease

Stomach Cancer

Type 2 Diabetes

Earwax Type

2/23/2015

9

Ermmmm .. … yeah… I’ll have one of everything thanks.

An equivalent would be taking samples from a patient and ordering every test the hospital offers… you are going to find something odd … testing is usually diagnosis driven…

The DTC companies state that they ‘do not provide medical advice based on their test results’. The family were unable to interpret the results they received from 23andme . A medical professional interpreted the results and indicated that the patient likely carries a pathogenic mutation. “The genotyping services of 23andMe are performed in LabCorp's CLIA-certified laboratory. The tests have not been cleared or approved by the FDA but have been analytically validated according to CLIA standards. The information on this page is intended for research and educational purposes only, and is not for diagnostic use.”

2/23/2015

10

This article was designed to survey how primary care physicians feel about DTCs…

Some of the data: 38% of Primary care physicians were aware of DTC testing 85% of PCPs did not feel prepared to answer questions about DTC tests.

20

“Last year in the US, only 135 medical geneticists and 331 genetic counselors were certified, and there are cumulatively <3000 of these professionals for a country of over 300 million people.”

“… 90% of consumers (of Direct to Consumer Tests) regard their physicians as the best resource for guidance about their genomic data but, at the same time, over 90% of physicians surveyed have indicated that they do not feel confident in using genetic information to guide their practice of medicine.”

Am J Med. 2012 Jan;125(1):5-6.

2/23/2015

11

… but the FDA are on the

case … so has it gone away?

Personalized Medicine Coalition

2/23/2015

12

Sales team directly contact PCPs and other providers – but patients can contact Counsyl directly ….

Family prep screen - carrier screening - over 100 conditions

Informed pregnancy screen - Non-invasive prenatal screen

Inherited cancer screen - BRCA1/2

“.. You have to sell that to the provider..”

Heralds-

informed consent

NIPS – Non-invasive Prenatal Screening

2/23/2015

13

NIPS – Non-invasive Prenatal Screening

NIPS – Non-invasive Prenatal Screening

2/23/2015

14

Higher detection rate

Clearer results –

Typically combined results

reported as a risk e.g. 1/25

2/23/2015

15

…”should not be part of routine prenatal laboratory assessment, but should be an informed patient choice after pretest counseling”.. … “practitioners inform the patients of the risk of false positives as well as false negatives”… Patients …“should be referred for genetic counseling and offered invasive prenatal diagnosis for confirmation of test results”… … “should only be offered to ‘high risk’ women as it has not sufficiently been evaluated in other groups”…

Already some companies have expanded the test and there is a high likelihood that in the future it will be able to extend past aneuploidies and evaluate other genetic disorders… Patients are informed and are demanding this type of testing.

Informed consent – Providers must become familiar with the advantages and disadvantages … …physicians can provide pretest and posttest counseling… If a test is positive it should be followed up by diagnostic testing… either an amniocentesis or CVS

2/23/2015

16

Interpreters-

explaining the results

DNA sequencing … finding a change in the gene

CAG T TCGA

GTC A AGCT

CAG G TCGA

GTC C AGCT

Normal sequence

Pathogenic sequence

2/23/2015

17

Exome sequencing

Human genome – 3164 million bases of DNA

It may be sufficient to examine the coding sequence of genes (exome) to find most

pathogenic changes.

Only 1.5% are coding

introns exons

If we examine only the exons we will only need to look at around 50 million bases of

DNA.

The method used is called exome sequencing.

This is coupled with ‘massively parallel sequencing’ which examines all of the

coding sequences at the same time.

All of the coding part of all of the genes in the

genome are amplified at the same time but in short

fragments, they are then ‘read’ by a sequencer and

aligned … multiple alignments eventually produce

a ‘true read’.

2/23/2015

18

There are two caveats………

Caveat 1- What do you do with results you did not expect?

Incidental findings ----

In a similar manner – if a patient has a chest

x-ray following a positive TB skin test, and a

‘shadow’ is observed on the lungs – should

you report that or not?...

2/23/2015

19

ACMG original recommendations were that results should be reported and that

patients could NOT opt-out of having incidental findings reported.

But they could opt-out of testing.

What disorders are we talking

about?

What about age of onset?

What about testing in children?

What about patient ‘opt out’?

Who should explain these

things to the patient?

2/23/2015

20

“Primary care providers are likely gatekeepers

to referrals for this technology.

Clinical sequencing has proven successful in

the diagnosis of rare genetic disorders; is

finding a place in cancer care; and will soon be

available in the direct to consumer (DTC)

genetic testing marketplace.”

But the results are available in three flavours.

Positive – known pathogenic mutations…

Negative – no known pathogenic mutations found…

VUS – Variant of Unknown Significance….

Caveat 2- What do the results look like?

2/23/2015

21

Case study 2

28 year old female, family history of breast cancer

Presented for genetic testing –

elected to have a panel….

Case study 2 Patient was positive for a VUS in the promoter in PTEN….

PTEN Cowden syndrome …

Mucocutaneous lesions

Trichilemmomas (facial)

Acral keratoses

Papillomatous lesions

Musocal lesions

Breast cancer

Thyroid cancer

Macrocephaly

Endometrial cancer

Surveillance

Breast exams

Thyroid ultrasound

Endometrial biopsies

Issues:

Diagnostic testing / personalized medicine –

Pre-test counseling,

Post test counseling…

… what about her family members … ?

2/23/2015

22

Why should we care?

There was a lot of fuss over the Human Genome

Project, the practice of medicine didn’t change ..

…. It will continue pretty much as it was won’t it?

…………….. Probably NOT………..

The number of diseases that can be tested for is increasing exponentially. Advances in technology make the majority of single gene sequencing test redundant. For the larger genetic panels, it is estimated that there is a 30% chance of finding a VUS.

2/23/2015

23

Implications

…. Many new single gene disorders will be identified, especially congenital

diseases.

Pre and perinatal genetic testing will become routine.

Complex Diseases such as Heart Disease, T2D will have ‘risk factor’

calculations available.

DTC will increase (non-diagnosis directed testing)

Greater availability of WES testing, lower cost and DTC applications

More drug response testing will be available.

More genetic counseling will be needed

Legal issues need to be considered – ownership of samples, retrospective

testing, discrimination.

46

“Last year in the US, only 135 medical geneticists and 331 genetic counselors were certified, and there are cumulatively <3000 of these professionals for a country of over 300 million people.”

“… 90% of consumers (of Direct to Consumer Tests) regard their physicians as the best resource for guidance about their genomic data but, at the same time, over 90% of physicians surveyed have indicated that they do not feel confident in using genetic information to guide their practice of medicine.”

Am J Med. 2012 Jan;125(1):5-6.

2/23/2015

24

Practice Recommendations

PCPs become/remain aware of developments in genetic testing trends –

NIPS/Panels/WES

Awareness of changes in industry – specifically DTC companies and other

providers who may be primary point of contact with patients.

Familiarization of the implications of testing – types of results, counseling,

informed consent

Increase/improve the amount of genetics in education especially for PCPs.

Physicians PAs

Healthcare Providers

Associates & Affiliates: ACMG NSGC NCHPEG APHMG etc

Questions

Interaction with physicians

Questions…

FAQ…

CMEs…

Testing organization

Pharm tests

NCBI

Genetests.org

Links

CF Foundation

Eye diseases

Interest/support groups

ACOFP

Regional or national Organization

Web-resource page

… I would like to suggest a web base resource…..