Personalized Health Care (PHC) in Cancer - Genomic Biomarkers for Pharmaceutical Development - page 33

substrates [75] . When the *28 allele is present on one chromosome, a 25% decrease in enzyme
activity can be observed, and when the allele is homozygous, the activity is reduced by 70%
[77] . In 2005, the FDA recommended that the package insert of irinotecan be amended to
warn of the elevated risk of neutropenia for patients with specific UGT1A1 genotypes [76] .
Additional studies are warranted to further understand the precise relationship between
UGT1A1 genotype and dose of irinotecan, but an example of how this information could be
used in clinical decision making for CRC is shown in Fig. 2.3 (reprinted from [75] ).

TPMT AND CHEMOTHERAPY IN ALL
About 80% of children with acute lymphoblastic leukemia (ALL) can be cured with combi-
nation chemotherapy [78] . Treatment-related toxicity can be life-threatening and is the num-
ber one reason for discontinuing chemotherapy. Mercaptopurine interferes with the activity
of DNA-processing enzymes due to structural changes in DNA after incorporation of thio-
guanine nucleotides (TGNs) [78,79] . Mercaptopurine metabolic conversion is in competition
with methylation by thiopurine methyltransferase (TPMT), such that variant alleles of TPMT
lead to increases in TGN concentration and a higher risk of hematopoietic toxicity after mer-
captopurine treatment [78-81] . Lowering doses of mercaptopurine in TPMT heterozygotes
and in TPMT-deficient patients allows the administration of the full doses of other chemo-
therapies while maintaining TGN concentrations that are comparable to patients treated with
high doses of mercaptopurine [80,81] . Although patients with non-functional TPMT alleles
have reduced tolerance to mercaptopurine, they can be safely treated with lower doses, illus-
trating a clear rationale for assessing TPMT genotype before initiating therapy. Currently,
ALL protocols are being adjusted for TPMT genotype, permitting all patients to receive treat-
ment without high toxicity and without losing efficacy [78-81] .

Colorectal Cancer

FOLFIRI regimen Single-agent regimen

Irinotecan treatment
Dose < 150 mg/m 2

Irinotecan treatment
Dose < 150 mg/m 2

No UGT1A1*28 genotyping UGT1A1*28 genotyping

No severe adverse
reactions

*28/*28

Neutropenia *1/*1

*1/*28

Reduce irinotecan
dose and study tumor
responsiveness

Administer
regular dose

FIGURE 2.3

Algorithm for the use of UGT1A1 genotyping in clinical decision making for colon cancer.