Table 2.
Drug | Germline markers | Single Nucleotide Polymorphisms | Tests | Toxicity | Risk of Developing Toxicity |
---|---|---|---|---|---|
5-Flurouracil (5-FU), capecitabine | DPYD | More than 40 different polymorphisms of DYPD reported, of which 17 mutations are found in patients with severe 5-FU toxicity.(112) Approximately 3–5% of the population is heterozygous and0.1% is homozygous for alleles with impaired DPYD function.(113) DPYD*2A most common polymorphism associated with decreased activity, ~1.8% in Caucasians and <1% in Asians(75,76) | Commercially available assays, including TheraGuide 5-FU | Severe diarrhea, Neutropenia Neurotoxicity | Up to two-thirds of patients who experienced treatment toxicity do not have a molecular basis for DPYD deficiency.(77) The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5% with a positive predictive value of only 46%. Inclusion of additional DPYD variants improved prediction only marginally.(79) |
6-Mercaptopurine (6-MP), thioguanine | TPMT | TPMT*2 (0.4%), TPMT*3A, (4.4%) TPMT*3C (0.2%) account for95% of low activity phenotype in Caucasians.(114) TPMT*3C most common in Asians (1–2.4%)(115) |
Commercially available, including Prometheus | Increased risk for myelotoxicity, Higher incidence of etoposide-induced myeloid leukaemia.(116) Higher incidence of radiation-induced brain metastases.(117) |
1 in 300 are homozygous variant, at risk of severe toxicity(114) 1 in 10 increased risk of toxicity due to heterozygous genotypes(114) |
Irinotecan | UGT1A1 | UGT1A1*28, most common variant in Caucasians, (~10%)(81) UGT1A1*6 most common variant in Asians (~15%)(82) |
Commercially available Invader Assay FDA approved for the detection of UGT1A1*28 | Neutropenia is the most common toxicity with Severe diarrhea is also associated but less so compared to neutropenia (117) | Homozygotes, as well as double heterozygotes (*6/*28) are associated with an increased risk of toxicity due to decreased clearance of SN-38.(82) Up to 35% of patients experience dose limiting toxicities.(82) Association for doses greater than 150mg/m2 in patients homozygous for UGT1A1*28.(118) No association was seen at lower doses (100–125mg/m2), which is the dose often used for weekly dosing.(118) |
Nilotinib | UGT1A1 | As above | As above | Hyperbilirubinemia | Not known to be glucuronidated by UGT1A1 Inherent low UGT1A1 activity and further inhibition by nilotinib increases rate of hyperbilirubinemia, though elevation is benign.(119) |
Pazopanib | UGT1A1 | As above | As above | Hyperbilirubinemia | Similar to nilotinib, elevation of bilirubin through competitive inhibition of UGT1A1 is benign.(120) |