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

Clinical Applications of Pharmacogenomics in Cancer Therapy
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chemotherapy, radiotherapy, surgical therapy, and even biological therapies (such as
interleukin and interferon) have failed to significantly improve the overall survival
(OS) for patients with advanced melanoma. 5 The new strategy is to target the specific
mutations at the molecular level to slow down or block the process of tumor growth
and metastasis. Since the genetic mutations in melanoma tumors are heterogeneous,
it is important to stratify the patient population based on their genetic profiles and to
further individualize the treatment. 5 Pharmacogenomics (PGx) plays an important role
in targeted therapy through genetic subgrouping to define who would respond well
to the specific treatment. Therefore, nowhere is PGx research needed more than in
cancer treatment to guide clinicians to better predict the differences in drug response,
resistance, efficacy, and toxicity among patients treated with chemotherapy or targeted
therapy, and to further optimize the treatment regimens based on these differences. 2–4
The application of PGx in oncology is in the discovery of biomarkers that guide
selective therapy, predict drug toxicities, screen and detect high-risk patients, and
target the mechanisms of drug resistance. Because adverse drug reactions (ADRs) to
prescribed drugs are one of the leading causes of death in the United States, according
to the National Council on Patient Information and Education, applying PGx
in therapeutics has the potential to save lives and increase the quality of life for
patients. 6 One of the most significant challenges in cancer therapy is to manage the
severe or fatal toxicities associated with cancer treatments. Many of these severe
toxicities, such as myelosuppression, chronic renal insufficiency, acute renal failure,
elevated transaminases, acute left ventricular failure, heart failure, diarrhea, constipation,
pneumonitis, thrombosis, pulmonary fibrosis, and seizures, can be dose limiting
and even life-threatening. These toxicities can compromise both the patients’
quality of life and the carefully designed curative therapy plan for the patients. 4 The
most important example of a biomarker associated with cancer therapy is thiopurine
methyltransferase (TPMT), which is a drug-metabolizing enzyme (DME) responsible
for the inactivation of 6-mercaptoputine (6-MP) in the liver. Clinical evidence
indicates that the steady-state levels of 6-MP in acute lymphocytic leukemia (ALL)
patients vary up to 10-fold or higher among cancer patients treated with the same
dose because of the highly variable and polymorphic TPMT activity levels. Patients
with low or absent TPMT activity have an increased risk for developing severe, lifethreatening
myelotoxicitiy. In contrast, the error margin for dose calculation of the
affected drugs in oncology practice is less than 3%. Thus, it is critical for clinicians
to identify those patients with TPMT polymorphisms and then adjust their dose of
6-MP accordingly. 3,4 The ultimate goal of application of PGx in oncology is to focus
therapy on specific biomarkers to identify interracial, interethnic, and interindividual
genetic polymorphisms related to tumor molecular targets/signal transduction
pathways, DMEs, transporters, and drug resistance, in order to reduce ADRs
and improve therapeutic outcomes in cancer patients. 4 The factors that could affect
drug efficacy and toxicities are summarized in Figure 6.1, including demographic,
physiological, morphometric, pathophysiological, pharmacological, and PGx factors.
4 Clinicians should personalize cancer treatment by evaluating the impact of
these essential factors on the pharmacokinetics and pharmacodynamics of the pharmacotherapy,
and adjust the treatment based on the scientific evidence and clinical
recommendations. 4