Pharmacogenomics Implementation for Oncology

Peter H. O’Donnell, M.D.

Department of Medicine

Committee on Clinical Pharmacology and Pharmacogenomics

Center for Personalized Therapeutics

The University of Chicago

http://www.mychances.net/images/college/1416-crest-250-200-69f66bc4e09bf96305a6c6516f183c63.pnghttp://www.mychances.net/images/college/1416-crest-250-200-69f66bc4e09bf96305a6c6516f183c63.png

Hertz and McLeod, Clin Pharm Ther (2016)

Precision Medicine for Cancer Treatment

Pharmacogenomics (PGx)

• Study of the effect of genetic variation on drug response or toxicity

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Germline Pharmacogenomics Are We Ready?

• Survey of >10,000 U.S. physicians:

– 98% believe genetic profiles may influence drug therapy

– 13% had ordered a pharmacogenomic (PGx) test

– 10% feel adequately informed about PGx testing

Stanek et al., CPT (2012)

Oncologists are Primed for PGx Use

Bonter et al., BMJ Open (2011)

Mercaptopurine Pharmacogenetics (II)

• Intermediate Activity Patients: dose at 30-80% of normal

• Deficient Patients: drastically reduce dose and frequency

Relling et al., CPT (2011)

Genotype-Directed Dosing of Irinotecan

A Very Recent Example - Abiraterone

Hahn et al. Mol Cancer Ther (2019)

SLCO2B1 encodes a

transporter for

steroids including

abiraterone into cells

(AG = 18.5% of

population)

5-Fluorouracil and DPD Deficiency

Cancer Prospective Testing

Deenen et al. JCO (2016)

Genotype-Directed Dosing

Deenen et al. JCO (2016)

*Net savings to the institution with preemptive screening

($3,767/patient; $3,828/pt for nonscreening)

8% of patients carried one of these variantsLancet Oncology (2018)

“Since fluoropyrimidines are among the most

commonly used anticancer agents, these findings

suggest that implementation of DPYD genotype-

guided individualized dosing should be a new

standard of care.”

Barriers to Realizing Pharmacogenomic Implementation

• PGx test availability

• Delay in obtaining results

• Lack of provider knowledge

• Evolving PGx evidence base

• Provider concerns regarding interpretation

• Who Pays?

Hypothesis

Providing preemptively-obtained pharmacogenomic results at the time of

prescribing will improve prescribing decisions, and patient outcomes

“Genomic

Prescribing

System” (GPS)

from Ratain CPT 2007

Model

BROAD CUSTOM TEST PANEL

(all relevant genotypes assayed)

PREEMPTIVE TESTING

(not reactive)

BUNDLED, “LIFETIME” TEST

(reduces marginal cost)

PATIENT and PROVIDER

ENGAGEMENT

Current GPS Content• Reportable information for:

70

Medications

>100

Germline

Variants

>50

Genes

• Oncology Drugs with Germline PGx:

capecitabine/fluorouracil, doxorubicin, irinotecan,

mercaptopurine, tamoxifen, vincristine, cisplatin,

ondansetron, codeine, tramadol, oxycodone

Pharmacogenomics Alters Drug Prescribing

No pharmacogenomically high-risk medications were prescribed during the entire

study when physicians consulted the GPS toolO’Donnell et al., Clin Pharm Ther (2017)

Patient Perceptions of Personalized Care

Physician Accessed GPS: OR 1.8 [95% CI 1.2-2.9], P

*p=0.001

Borden et al., Pharmacogenomics J, 2019

Could Pharmacogenomic-Guided Prescribing Improve Medication Adherence?

Conclusions

• Successfully implemented an individualized health care model of preemptive pharmacogenomic testing

• Patient interest robust; physician adoption high

• Pharmacogenomic information improved prescribing in a pattern aimed at reducing patient risk

Future Directions

Acknowledgements

NIH 1R01HG009938-01A1

NIH 1U54MD010723-01

Bucksbaum Institute Associate Faculty Scholar Pilot Grant

Chicago Innovation Exchange - Innovation Fund Award

The University of Chicago Cancer Research Foundation Auxiliary

The William F. O’Connor Foundation

Central Society for Clinical and Translational Research