Table 2.

Examples of FDA approved predictive markers for toxicity in oncology. (Nonstandard abbreviations: DPYD=Dihydropyrimidine dehydrogenase, TPMT=Thiopurine methyltransferase, UGT=UDP-glucuronasyltransferase)

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)