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

Clinical Applications of Pharmacogenomics in Cancer Therapy
159
TPMT (rs12201199) and COMT (rs9332377) are associated with higher incidences
of ototoxicity. Cisplatin ototoxicity is associated with the PGx because the decreased
TPMT enzyme activity causes an increase in cisplatin cross-linking efficiency, thus
increasing cisplatin toxicity. 54,55
Although there is currently no recommendation from the US FDA, with the result
of the cohort study, it may be possible to identify individuals at a higher risk of
ototoxicity with the use of cisplatin. 54,55 Therefore, treatment alternatives, such as
lower doses of cisplatin or treatment with other agents such as carboplatin, may be
warranted for patients who could face this higher risk.
PATIENT CASE 3
AR is a 68-year-old African American man with Stage 4 colon cancer metastatic to
the liver and lungs. He is treated with the CAPEOX regimen. AR has been tested for
DPD deficiency through DPYD*2A.
Question: What does this mean for AR’s therapy?
Answer: As AR’s therapy includes capecitabine, which is an oral prodrug for 5-FU,
the reduced expression of DPD will result in severe or even life-threatening toxicity,
such as diarrhea, neutropenia, and hand–foot syndrome. Careful monitoring and
dose reduction of capecitabine may be warranted for AR.
Dihydropyrimidine and 5-FU
5-FU is an injectable antimetabolite pyrimidine analog drug used in the treatment
of colorectal cancer, breast cancer, ovarian cancer, gastrointestinal cancers, and head
and neck cancers. The enzyme responsible for the catabolism of 5-FU is DPD, which
is the rate-limiting step involved in the nucleotide metabolism of pyrimidines uracil
and thymine. DPD is the first of the three enzymes in the fluoropyrimidine metabolic
pathway, and its activity varies widely due to genetic polymorphisms.
DPD deficiency is an autosomal recessive metabolic disorder in which DPD
activity is absent or significantly diminished in cells. Patients with partial or complete
DPD deficiency may have increased toxicity from 5-FU. Individuals with DPD
deficiency may develop life-threatening toxicity following exposure to 5-FU or
the widely prescribed oral prodrug fluoropyrimidine capecitabine. Such toxicities
include severe diarrhea, mucositis, and pancytopenia. More than 40 SNPs have been
identified in the DPD gene.
DPD deficiency may be detected with the assay of TheraGuide 5-FU. This assay
analyzes DNA samples taken from peripheral blood cells. The cost of the test is
approximately $1000 with a turnaround time of seven days. The results will classify
patients as high, moderate, low risk, less or no risk. 56
The most common variant, DPYD*2A, has been reported in approximately 45%
of people with partial or complete DPD deficiency. 16 Complete DPD deficiency
is relatively uncommon, occurring in less than 5% of white populations. Black
Americans, especially black women, have a markedly reduced mean DPD activity
and a higher partial DPD deficiency when compared with their white counterparts.