Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Clinical Applications of Pharmacogenomics in Cancer Therapy
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poor metabolizer (PM), and ultrarapid metabolizer (UM). Because CYP2D6 exhibits
genetic and phenotypic polymorphisms, it plays an essential role in the metabolism of
tamoxifen, a selective estrogen receptor modulator, widely used for estrogen receptorpositive
premenopausal breast cancer. Tamoxifen is a substrate of CYP3A, CYP2C19,
and CYP2D6, and an inhibitor of P-glycoprotein (P-gp). CYP2D6 is the predominant
enzyme producing the active metabolite endotoxifen, whose binding affinity for
estrogen receptors is 100 times stronger than tamoxifen.
Although studies show genetic polymorphisms of CYP2D6 are associated with
decreased plasma concentrations of endotoxifen, their clinical impact on breast cancer
patients is still inconclusive. 33,34
Several studies have determined whether different variant alleles of CYP2D6
could be associated with both the side effects and clinical efficacy of the relevant
chemotherapy (measured with disease-free survival). Goetz et al. reported that the
CY2PD6*4 variant allele was associated with a higher risk of relapse and a lower
incidence of hot flashes. 59 The NCCTG 89-30-52 trial reported that the PM of
CYP2D6 was associated with a higher risk of relapse of breast cancer. 60 In the study
conducted by Schroth et al, patients with two CYP2D6 null alleles or presumed
CYP2D6-reduced activity showed reduced OS compared to other individuals with
the wild-type alleles, 61 and patients lacking CYP2D6 activity (PM) had a twofold
increased risk of breast cancer recurrence compared with those with two functional
CYP2D6 alleles. 61
Currently, most PGx studies suggest that the number of CYP2D6 allele variants
could affect the plasma concentrations of tamoxifen metabolites. The decrease in
metabolites in turn may negatively affect tamoxifen efficacy and its treatment outcome.
56 The relationship between CYP2D6 polymorphisms and the treatment outcome
of tamoxifen points to a possible benefit from detecting CYP2D6 genotype
prior to making a decision on an adjuvant endocrine therapy. At present, there is no
enough data to justify the routine testing of CYP2D6 to incorporate it to the guideline
of clinical decision making. 62,63
PATIENT CASE 4
GC is a patient who was diagnosed with acute myeloid leukemia (AML), and she
was to be started on the 7+3 regimen. GC’s uric acid after 1 treatment cycle of the
7+3 regimen has increased from 7.5 to 11.5 (unit). Her white blood cell count has
decreased from 14.9 to 4.8 (unit). Her K+ increased from 3.5 to 6.7 (unit).
Question: What genetic test should be considered for this patient at this time before
therapy is started?
Answer: G6PD testing should be considered. Patients with AML and a high tumor
burden, like GC, are most likely to experience tumor lysis syndrome, which can
increase uric acid, potassium, and phosphorus levels in these patients. When patients
have a high uric acid level, rasburicase can be used. Rasburicase is contraindicated
with the patients with G6PD deficiency as it might cause hemolytic anemia and methemoglobinemia.
Thus, a G6PD test should be considered prior to the start of the
treatment for AML patients.