Pharmacogenomics Lecture 4: Oncology

dihydropyrimidine dehydrogenase (DPYD)

genotyping for fluoropyrimidine [5-fluorouracil, Capecitabine (Xeloda)]

UDP glucuronosylstransferase (UGT1A1)

genotyping for Irinotecan

Thiopurine S-methyltransferase (TPMT) and NUDT15

genotyping for thiopurine drugs: Azathioprine (Imuran), Mercaptopurine (Purinethol)

CYP2D6

genotype testing for Tamoxifen

inherited: germline

acquired: somatic, cancer cell‐specific

In cancer patients, we deal with inherited genetic characteristics (_____) and acquired genetic characteristics (______)

germline

For a _____ genotype, DNA can come from normal tissue (whole blood)

somatic

For a _____ genotype, DNA can come from tumor tissue

✶3A, ✶3C, ✶2

which alleles of TPMT cause increased toxicity with 6-Mercaptopurine

✶2A

which allele of DPYD causes increased toxicity with 5-FU?

✶28

which allele of UGT1A1 causes increased toxicity with Irinotecan?

✶4

which allele of CYP2D6 causes decreased efficacy of Tamoxifen?

myelosuppression

The potential benefit of testing TPMT activity to adjust the dose of 6­MP was demonstrated in a 6­ year ­old acute lymphoblastic leukemia (ALL) patient. After receiving a standard dose of 6­MP for post remission therapy, the patient developed severe _____ requiring a discontinuation of her treatment regimen. Interestingly, she was found to have 7× the population median value of 6­TG in her RBCs. Subsequent therapy with 6% of the standard 6­MP dosage allowed her to complete the potentially curative regimen without further toxicity.

myelosuppression and increased risk of secondary cancer

TMPT Mut/Mut with Mercaptopurine is associated with ______ and ______

decreased toxicity and increased risk or relapse

TMPT Wt/Wt with Mercaptopurine is associated with _____ and _____

✶1, ✶24

Genetic variations in the TPMT gene leads to changes in metabolic activity of the TPMT enzyme. which alleles are functional,/normal/activity/wild-type?

✶2, ✶3, ✶4

Genetic variations in the TPMT gene leads to changes in metabolic activity of the TPMT enzyme. which alleles are non-functional/variant/no activity?

normal starting doses

if a patient has normal or high TPMT activity, what dose do you start Mercaptopurine or Azathioprine at?

2 weeks

if a patient has normal or high TPMT activity, start Mercaptopurine or Azathioprine at the normal starting dose and allow ____ weeks to reach steady state after each dose adjustment

30-70% dose

if a patient has intermediate TPMT activity (heterozygote), start Mercaptopurine or Azathioprine at _____% of full dose

2-4 weeks

if a patient has intermediate TPMT activity (heterozygote), start Mercaptopurine or Azathioprine at 30-70% of full dose. Adjust the dose based on myelosuppression and disease specific guidelines. Allow ____ weeks to reach steady state after each dose adjustment

90%; 3 times per week

if a patient has low or absent TPMT activity, for non-malignant conditions, consider alternative non-thiopurine immunosuppressants. For malignancy, reduce the daily dose of Mercaptopurine or Azathioprine by ____% and reduce the frequency to _____x per week instead of daily

4-6 weeks

if a patient has low or absent TPMT activity, for non-malignant conditions, consider alternative non-thiopurine immunosuppressants. For malignancy, reduce the daily dose of Mercaptopurine or Azathioprine by 90% and reduce the frequency to 3x per week instead of daily. Allow _____ weeks to reach steady state after each dose adjustments.

TPMT or NUDT15

Consider an alternate agent or extreme dose reduction of Mercaptopurine/Azathioprine for patients who are _____ or _____ poor metabolizers.

30-80%

Start at ___-____% of target dose of Mercaptopurine/Azathioprine for patients who are intermediate metabolizers of either TPMT or NUDT15

20-50%

Start at ___-____% of target dose of Mercaptopurine/Azathioprine for patients who are intermediate metabolizers of both TPMT and NUDT15

2nd tumors

Some regimens have so many myelosuppressive agents early in therapy, that profound myelosuppression early may delay subsequent therapy‐‐‐so 6MP dose "titration" less feasible. Some long‐term adverse effects such as ______ have been associated with defective TPMT activity—so acute myelosuppression is not the only problem

DPYD

- genetic variations in the DPYD gene can alter the DPYD enzyme function

metabolizes fluoropyrimidines like fluorouracil (5‐FU) and capecitabine to an inactive metabolite: DHFU

5-7%

Population studies demonstrate that ____% of US population exhibit 5-FU dose limiting toxicity.

increased in AA and females

complete DPYD enzyme deficiency is rare but is increased in which race and which gender?

12.3%

____% of AA women had partial activity of DPYD

4.0%

____% of AA men had partial activity of DPYD

3.5%

_____% of white women had partial activity of DPYD

1.9%

___% of white men had partial activity of DPYD

use label-recommended dose

If a patient is homozygous wild-type or normal, high DPD activity (two or more functional ✶1 alleles), what dose of 5-FU and Capecitabine be used?

start with at least 50% reduction in starting dose followed by titration of dose based on toxicity or PK test (if available)

If a patient is heterozygous or intermediate activity (3-5% of patients), they may have partial DPD deficiency and are at risk for toxicity with exposure to 5-FU and Capecitabine. Which dose of these drugs should be used?

select an alternative drug

If a patient is homozygous variant or DPD deficient (0.2% of patients), they are at risk for toxicity with drug exposure (2 nonfunctional alleles). What dose of 5-FU and Capecitabine are recommended in these patients?

HER2

which gene is targeted by Trastuzumab?

Cetuximab

which MAb targets Epidermal Growth Factor?

Rituximab

which MAb targets CD20?

CYP2D6

which enzyme is responsible for metabolizing 5HT3 antagonists?

Granisetron

what 5HT3 antagonist does not interact with CYP2D6?

CYP2C19

which enzyme shows up as a "fire" alert in an EHR for Citalopram, Escitalopram, and Clopidogrel?

CYP2D6

which enzyme shows up as a "fire" alert in an EHR for Codeine, Fluoxetine, Fluvoxamine, Paroxetine, Tamoxifen, Tramadol, and Venlafaxine?

CYP3A5

which enzyme shows up as a "fire" alert in an EHR for Tacrolimus?

HLA-B5701

which HLA gene shows up as a "fire" alert in an EHR for Abacavir?

HLA-B5801

which HLA gene shows up as a "fire" alert in an EHR for Allopurinol?

HLA-B1502 and HLA-A 3101

which HLA genes shows up as a "fire" alert in an EHR for Carbamazepine?