Page 33 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Prospective DPYD genotyping: ready for prime time
be that such a recommendation is drug-specific and not tumour-type specific while oncology guidelines are traditionally tumour-type specific (e.g. KRAS mutation, human epidermal growth factor receptor 2 (HER2) expression).
The Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association provide evidence-based guidelines and recommendations what dose adjustments to apply in DPYD variant allele carriers.37,68,69 Recommendations depend on the DPYD allele and carrier status (heterozygous, homozygous), and are guided by the gene activity score. After initial reduction dosages can be further titrated based on clinical tolerance. Dose reductions are 75, 50 or 25% for gene activity scores of 0.5, 1 and 1.5, respectively. The gene activity score varies from 0 (no DPD activity) to 2 (normal DPD activity).38,69
Barriers for clinical implementation
Potential barriers hampering the clinical implementation of prospective DPYD testing are: ‘Perceived lack of scientific evidence’;
The evidence for the association of DPYD variants and severe fluoropyrimidine-induced toxicity has been discussed and is considered convincing. Furthermore, an RCT is considered unethical and unnecessary.
‘There is a lack of laboratory facilities and there is no reimbursement’;
The number of laboratories that offer genetic testing for DPYD is continuously increasing, techniques are easier to operate and prices for genetic testing will continue to decrease.37 The cost of a DPYD genetic test is currently in the range of €50 to €100. These amounts are negligible compared to the costs of treatment that could easily reach €10,000 or more.70 This genetic test (which is a once-in-a-lifetime test when no additional SNPs are added) should be as normal as testing for other contraindications for drugs such as liver enzymes, renal function or physical condition. Laboratories usually offer the test with a turnaround time of 2–3 days which is acceptable and does not result in treatment delay, which is a serious concern of clinicians and patients.
‘There is not enough guidance on how to use the test’;
Peer reviewed guidance on how to use the outcomes of the genetic test is well covered.37,38,68,69
‘There is a risk of underdosing patients’;
Guidelines advise to reduce the dose of fluoropyrimidines in the first cycle in patients carrying DPYD variants associated with decreased DPD activity to create similar systemic drug levels compared to wild-type patients. In the following cycles tolerance-guided dose titration is used to create the most optimal treatment. This strategy minimises the risk for underdosing. In addition, 5-FU and capecitabine are often used in combination with other anti-cancer drugs, so only a fraction of the total therapy is reduced.
‘Phenotyping tests are more specific’;
Phenotyping tests measuring DPD enzyme activity directly are more closely predicting DPD deficiency as compared to DPYD genotyping. However, DPD enzyme measurements are also more expensive, more time consuming, have dreadful logistics (can be time-dependent), high turnaround-times (>1 week) and only a very limited number of laboratories provide the tests. For these reasons DPD enzyme activity measurements are less likely to be
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