Evidence behind clinical practice guidelines
We will consider the evidence behind clinical practice guidelines described on the PharmGKB pharmacogenomics knowledge resource website
Cancer chemotherapy has the potential for prolonging lives, and regimes that include the fluoropyrimidines lead to responses and improved overall survival for patients with many solid tumours including colorectal cancer.
However, the associated adverse effects can result in serious morbidity, or even mortality. Approximately one fifth of patients suffer from severe adverse events including gastrointestinal symptoms, mucositis/stomatitis, palmar-plantar syndrome, paraesthesia, cardiac toxicity, neutropenia, anaemia, thrombocytopenia and abnormal liver function tests.
If individuals with high susceptibility for adverse effects could be picked up early with predictive tests (biomarkers) appropriate risk mitigation strategies could be put in place, with the option of dose modification and/or the application of supportive therapeutics.
In ideal circumstances, any biomarker would reliably separate out two contrasting groups of patients; those likely to derive considerable benefit from chemotherapy (good tumour response with low risk of adverse effects) as opposed those with poor benefit: harm ratio (limited tumour response with high likelihood of serious harm).
In practice, patients usually have different patterns of clinical response; substantial beneficial tumour response linked to high levels of adverse effects, and vice versa, leading to uncertain clinical utility.
Dihydydropyrimidine dehydrogenase (DPD)
This is a key metabolic enzyme that affects the pharmacokinetics of and toxicity of fluoropyrimidines including 5-fluorouracil (5-FU) and its oral prodrugs. Over 80% of 5-FU is catabolised by DPD into non-cytotoxic metabolites. The activity of DPD varies widely between patients. Treatment of patients with fluoropyrimidines is not recommended if they have complete DPD deficiency.
This is a fluoropyrimidine that has been used as a chemotherapeutic agent for more than five decades.
This is a pro-drug that is preferentially converted to 5-FU in tumour cells, it was designed for oral administration.
DPYD is the gene that encodes DPD. It is highly polymorphic between individuals, with several functionally important and even catalytically inactive alleles described.
Positive predictive value (PPV)
If we consider the performance of a biomarker for a given phenotype; the PPV is the probability that a positive test means that the individual truly has the phenotype.
Negative predictive value (NPV)
If we consider the performance of a biomarker for a given phenotype; the NPV is the probability that a negative test means that the individual does not show the phenotype.
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