PGx implementation (hematology+oncology)

Question 1

PGx program interventions

Answer 1

1. offer PGx education to clinicians
2. establish clinically valid PGx testing platforms
3. establish PGx referral clinical and consult service
4. Develop effective clinical decision support modalities (allow alerts for pt with actionable genotype-predicted phenotypes)
5. Engage pt in PGx-guided care
6. utilize genomic seq data to extract PGx genotypes (identify pt for confirmatory PGx)
7. Track and advocate for third-party reimnbursement of PGx testing
8. establish genomnic med clinical council,PGx subcommittee
9. Preform PGx implementation research to establish efficacy of interventions and best implementation practices

Question 2

CYP2C19

Answer 2

-critical for clopidogrel bioactivation (ACS+PCI tx)
-loss of function reduces clopidogrel efficacy

Question 3

Evidence supporting CYP2C19 testing for clopidogrel

Answer 3

1. clinical validity
2. Clinical utility (change dose or meds due to test)
3. cost effectiveness? (testing endorsed by AHA): covered by CMS and most private payers POST-PCI only (not stroke or anything

Question 4

IGNITE steps to PGx implementation

Answer 4

1. Gather institutional support for genetic testing
2. Develop genetic testing ordering and interpretation process
3. Establish reimbursement process for genetic testing
4. Integrate genetic data into EHR
5. Develop provider education for testing
6. Develop patient education for testing
7. Establish workflow for clinical PGx implementation of testing

Question 5

CYP2C19 best practice alerts

Answer 5

-genotype results go into EHR
-alerts recommend other P2Y12 inhibitors upon clopidogrel orders
-most practicioners prescribe clopidogrel
-32-33 graphs?
-overrides for clinical judgement, pt stable on clopidogrel, doctor selected clopidogrel
-need to emphasize that interventional cardiologist who started clopidogrel did so before CYP2C19 genotype results were available

Question 6

Opportunities for PGx in clinical oncology

Answer 6

-DPYD-guided fluropyrimidine dosing
-tyrosine kinase inhibitors (docetaxal (cytotoxic))

Question 7

Clinical services to support PGx in oncology

Answer 7

1. precision med recommendations
2. genomic analysis od cancer tx pt e bad drug toxicities
3. PGx consult service
   4.collaboration w IU to build and maintain PGx panel

Question 8

Clinical interventions to support PGx in oncology for clinicians

Answer 8

1. embed PGx results in EHR
2. implement EHR practice alerts that recommend tx options for genotypes

Question 9

IU genomics clinic

Answer 9

-somatic variants guide targeted tx
-GERMLINE data contain all (WGS or most (WES) PGx variatnts
-provide recommendations at tumor board for precision med

Question 10

Validation of PGx genotype extraction methods from next-gen seq data

Answer 10

-diplotype call overall accuracy rate of 99.7% in whole genome seq cohort and 99.9% in whole exome seq cohort

Question 11

current limitations

Answer 11

-valid genotype tests need CLIA validation
-cant validate PGx genotype if done at external lab
-IU developing seq core, then CLIA validates
-in the meantime, PGx results identify pt for confimaroty testing by CLIA preformed at IU!!

Question 12

IU PGx genotyping panel

Answer 12

-CLIA validated
-4-5 days
-46 variants in 13 major genes
-gene subsets available

Question 13

DPYD best practice alerts

Answer 13

-intermediate and poor metabolizer have inc toxicity risk w capecitabine tx

Question 14

PT case 1

Answer 14

-started capecitabine
-toxicity sx = hospital
-collect whole blood cample
-IU germline testing
-DPYD1/1 = normal metabolizer
-pt is HETEROZYGOUS (2/9)
-idk slide 14

Question 15

PT case 2: grade 4 pneumonitis during docetaxel

Answer 15

-inc concentrations, lots of toxicities
-CYP3A4 diplotype (22/22) but + 3 idk man
-CYP3A422/*37 predict CYP3A5 3/3 = predicted CYP3A4/CYP3A5 poor metabolizer phenotypes

Question 16

pt case 3

Question 17

pt case 4

Question 18

Seq vs genotyping

Answer 18

genotyping < WES < WGS in terms of providing comprehensive PGx information
-phasing can change genotype predicted phenotypes

Question 19

Phasing

Answer 19

-wheter variants occur on sam or separate gene copies (mom vs dad chromos)
-relevant ONLY for heterozygous variants
-can change genotype predicted phenotypes

Question 20

Evaluation of prescriber use of DPYD genotyping

Answer 20

DYPD results not available at first time of first fluropyrimidine order for 71% pt
-ordering test at time of first cancer diagnosis would allow 25+/- 28 days of return for return of results before firts fluropryrimidine order
-alerts on EHR

Question 21

Implementation evaluation

Answer 21

1. implement
2. evaluate
3. Revise
4. Re-evaluate
5. Revise as needed