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

148 Applying Pharmacogenomics in Therapeutics
severe cancer treatment toxicities. 8 The PGx instructions in the drug package insert
of these drugs have clearly explained the potential clinical impact of these gene
variants on toxicities associated with cancer treatments or potential drug interactions.
There are over 120 FDA-approved drugs with recommended PGx information
linked to over 50 genes in the drug package insert. About 30 of these PGx drugs are
commonly indicated for cancer patients. 7
Although over 2 million single nucleotide polymorphisms (SNP, resulting from
the deletion, insertion, or exchange of a single nucleotide) have been discovered in
the human genome, the majority of these SNPs have no clinical significance. Some
of these SNPs (TPMT, UGT1A1, CYP2D6, and G6PD) contribute to clinically significant
changes in the pharmacokinetics and/or pharmacodynamics of cancer drugs.
Most of these SNPs are identified for the DMEs. Based on their catalytic activity levels,
patients with SNPs can be classified as: (1) extensive metabolizers (EM); (2) poor
metabolizers (PMs); (3) intermediate metabolizers (IM); and (4) ultrarapid metabolizers
(UMs). 4 Standard doses of drugs with a steep dose–response curve or a narrow
therapeutic window are more likely to produce ADRs in PMs who are taking that
drug, or have decreased efficacy when taking a prodrug. In contrast, when taken by
UMs, that standard dose may be inadequate to exert the desired therapeutic effect.
PGx plays an important role in the pharmacotherapy of cancer due to the presence
of narrow therapeutic windows and low ORRs for cancer drugs. Therefore, acute and
severe systemic toxicity along with unpredictable efficacy are all hallmarks of cancer
therapies. Approximately 10% of Caucasians have partial deficiency in TPMT enzyme
activity, while 0.3% of the patients have a complete deficiency in the enzyme activity.
However, these 0.3% TPMT PMs account for over 25% of those life-threatening
toxicities associated with 6-MP treatment. Therefore, PM of TPMT is at significant
risk for severe drug toxicity associated with the use of 6-MP. The FDA recommends
a dosage reduction for patients with heterozygous or homozygous mutations in TPMT,
but the FDA does not provide the exact scale of dose reduction. The NCCN Acute
Lymphoblastic Leukemia Guidelines require a 10- to 15-fold reduction in 6-MP dosage
for patients homozygous for TPMT loss-of-function variant alleles to alleviate
hematopoietic toxicity. Heterozygosity at the TPMT gene locus occurs in 5–10% of
the population and has been shown to have intermediate enzyme activity; therefore,
a 10–15% reduction in 6-MP dose is recommended in these patients to minimize the
risk of drug toxicity. Determination of patient TPMT genotype using genomic DNA is
recommended to optimize 6-MP dosing, especially in patients who have experienced
myelosuppression at standard doses. 3,4
On the other hand, CYP2D6 is an important DME to activate the prodrug tamoxifen
(Table 6.2). Although CYP2D6 genetic testing is not recommended by the US FDA
and NCCN and ASCO guidelines for breast cancer patients treated with tamoxifen
due to limited clinical evidence, it is recommended to avoid strong CYP2D6 inhibitors,
such as most selective serotonin reuptake inhibitor antidepressants, such as fluoxetine,
paroxetine, and sertraline. 4,20 Moreover, clinical evidence indicates that the
risk of morphine overdose is higher for patients who were UMs of CYP2D6 taking
codeine, since CYP2D6 is essential to activate codeine, the prodrug of morphine. For
patients with UMs of CYP2D6, it is recommended to select an alternative analgesic
or to closely monitor for ADRs due to morphine overdose. It is recommended to either