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

144 Applying Pharmacogenomics in Therapeutics
KEY CONCEPTS
• Better management of cancer patients is a big challenge clinicians have
to face in patient care as many cancer chemotherapies are associated with
severe drug toxicities. For these patients, these toxicities may affect their
quality of life and also impair their adherence to subsequent therapy.
• Factors that could affect drug efficacy and toxicities include demographic,
physiological, pathophysiological, and pharmacogenomic (PGx) factors.
• PGx factors that include genetic polymorphisms have been associated with
interindividual differences in toxicity of many chemotherapy agents. With
modern-day research, biomarkers for these genetic polymorphisms have
been identified.
• There are three different types of biomarkers that have been associated with
drug toxicities: drug-metabolizing enzymes, drug transporters, and drug
targets. The majority of the biomarkers that have been identified are drugmetabolizing
enzymes.
• Genetic polymorphisms of drug-metabolizing enzymes may have important
effects on both drug efficacy and toxicities. Based on these genetic
polymorphisms, various dosing recommendations have been published.
• Genetic polymorphisms of drug transporters can lead to decreased efficacy
of therapeutic medication and unpredictable toxicities with drug therapy.
• Drug target-related biomarkers may lead to drug toxicities for drug therapies:
for example, patients with EGFR intron 1 short allele polymorphisms
can have a higher risk of skin toxicities.
• Various polymorphisms or biomarkers related to repair and detoxifying
mechanisms can lead to reduced response, poor progression-free survival
(PFS), and increased toxicities from chemotherapy. An example of this
includes lower levels of glutathione S-transferase leading to increased toxicities
from cyclophosphamide.
• Integration of PGx in cancer therapy can offer the ability to maximize therapy
while decreasing chances of adverse drug reactions (ADRs) in patients.
INTRODUCTION
Although cancer and heart disease remain the top two causes of death (representing
nearly 25% of all deaths in the United States alone), the total mortality of cancer has
already fallen more than 20% in the past two decades. Evidence credits this steady
decline mainly due to a reduction in the smoking population, improved cancer treatments
with more specific targets, increased drug efficacies and minimized toxicities,
and earlier diagnosis of cancer. 1 When a patient is recommended to undergo cancer
chemotherapies, narrow therapeutic indices, low overall response rates (ORRs), rapid
and severe systemic toxicity, and unpredictable clinical outcomes are all hallmarks
of these cancer therapies. In addition, missed early diagnosis and staging, rapid progress
and wild metastasis, considerable heterogeneity across the cancers, and frequent
drug resistance are some of the reasons to indicate why many malignancies, especially
advanced ones, are extremely difficult to treat. 2–4 For example, most of the standard