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

Clinical Applications of Pharmacogenomics in Cancer Therapy
153
TABLE 6.3 (Continued)
Clinical Recommendations for Biomarkers Related to
Drug-Metabolizing Enzymes
PGx Biomarkers/
Affected Cancer
Drugs
G6PD/
rasburicase
dabrafenib
Clinical
Significant
Polymorphisms Genetic Testing Clinical Recommendations
G6PD
deficiency
G6PD activity
assay
FDA recommends not to
administer rasburicase to patient
with G6PD deficiency, which
may trigger acute hemolysis.
FDA recommends a close
monitoring for patients with
G6PD deficiency that is started
with Dabrafenib.
Sources: References 24–38, FDA-approved drug package inserts, and Lexi-Comp drug monographs.
Adapted from Feng X, et al., US Pharmacist, 37(1), 2–7, 2012. With permission.
Note: MTHFR, methylenetetrahydrofolate reductase.
PATIENT CASE 1
AC is a 46-year-old man who is undergoing treatment of FOLFIRI + bevacizumab
for Stage 4 colon cancer. AC has undergone 1 cycle treatment of FOLFIRI +
bevacizumab. Today is AC’s cycle 2 day 1 treatment. He has reported complaints
of severe bloody diarrhea (grade 3), and thus his physician has reduced his dose of
irinotecan from 180 to 140 mg/m 2 . On AC’s cycle 3 treatment, he still reports complaints
of severe bloody diarrhea (grade 3).
Question: What should have been considered for the patient at the beginning of
therapy?
Answer: UGT1A1 genetic testing can determine the presence of the UGT1A1*28
variant allele that is associated with an increased toxicity for irinotecan, which may
lead to an increase in cholinergic symptoms, diarrhea, and hematological toxicities,
such as anemia, thrombocytopenia, and neutropenia.
UGT1A1 and Irinotecan
Irinotecan, a topoisomerase I inhibitor, is approved by the US FDA for the treatment of
advanced colorectal cancer and other various solid tumors. Irinotecan is a prodrug that
requires activation by carboxylesterase to its active metabolite, SN-38. Furthermore,
SN-38 is converted to inactive metabolite SN-38G by glucuronidation via UGT1A1
isoform. Diarrhea and neutropenia are the result of dose-limiting toxicities of irinotecan,
which are associated with increased levels of SN-38. 46–48 The UGT1A1*28
polymorphism may occur in 35% of white and black Americans. UGT1A1*28 allele
is associated with reduced UGT1A1 gene expression, which leads to reduced SN-38