pharmacogenomics in oncology

Question 1

what is pharmacogenomics

Answer 1

the study of the effects of variations in DNA on drug response through changes in drug processing enzymes (pharmacokinetics) or drug targets (pharmacodynamics)

Question 2

what are possible variations in DNA and variations in protein?

Answer 2

DNA: single nucleotide polymorphisms (SNPs), insertions/deletions, copy number variants
Protein: drug metabolizing enzymes, drug transporter, drug targets

Question 3

what are two sources of PGx info in oncology?

Answer 3

1. somatic (cancer) data: targetable mutations, chemoresistance mutations
2. germline (patient) data: drug metabolizing enzymes, transporters

Question 4

chemotherapy agents have a _____ therapeutic index

Answer 4

narrow

Question 5

what is CPIC?

Answer 5

clinical pharmacogenomic implementation consortium
translates genetic lab test results into actionable prescribing decisions. provides implementation resources, practice guidelines, systematic grading of evidence

Question 6

what are some possible deficiencies that can cause thiopurine cytotoxicity (mercaptopurine)

Answer 6

TPMT
NUDT15

Question 7

what are the recommendations for mercaptopurine in TPMT or NUDT15 intermediate metabolizers (IM)?

Answer 7

initiate at 30-80% of normal dose
(this is a large range, aim for higher dose for leukemia and lower dose for nonmalignant indications)

Question 8

what are the recommendations for mercaptopurine in TPMT poor metabolizers (PM)?

Answer 8

nonmalignant: alternative
malignant: initiate at 10% of the normal dose, administer only 3 times weekly

Question 9

what are the recommendations for mercaptopurine in NUDT15 poor metabolizers (PM)?

Answer 9

nonmalignant: alternative
malignant: initiate at 10 mg/m2 daily

Question 10

what is a deficiency that can affect fluoropyrimidines cytotoxicity (5FU)

Answer 10

DPD deficiency

Question 11

_____ have higher rates of 5FU myelotoxicity due to which unique decreased function variants

Answer 11

African-American
DPD deficiency: variants c.557A>6 or Y186C

Question 12

what are the challenges with DPYD guidelines implementation?

Answer 12

concern for efficacy
lack of alternatives (5FU is the backbone of colon cancer regimens)
topical 5FU?

Question 13

recommendations for DPYD normal metabolizer (activity score 2)

Answer 13

use label-recommended dose, no indication to change

Question 14

recommendations for DPYD intermediate metabolizer (activity score 1-1.5)

Answer 14

initiate 5FU or capecitabine at 50% of the recommended dose

Question 15

recommendations for DPYD poor metabolizer (activity score 0.5)

Answer 15

avoid use of 5FU drugs or initiate at <25% of the recommended dose if alternative drugs are unacceptable

Question 16

considerations for PGx testing in tamoxifen?

Answer 16

tamoxifen is metabolized by CYP2D6 to a more potent active metabolite (Endoxifen) so CYP3D6 intermediate and poor metabolizers lead to decreased efficacy. Consider an aromatase inhibitor instead, or if tamoxifen is preferred you can consider a higher dose of 40 mg

Question 17

considerations for PGx testing in irinotecan?

Answer 17

irinotecan active metabolite SN-38 is metabolized by UGTIA1. poor metabolizers lead to increased toxicity. decrease the starting dose by 30% and titrate based on neutrophil count

Question 18

what is the mechanism by which TPMT and NUDT15 deficiency causes cytotoxicity

Answer 18

more triphosphate thioguanine is formed which causes cytotoxicity