Page 332 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 13
weighing factor, depending on the severity of the risk.
In addition to analysing DPYD genetics, baseline characteristics of patients and therapy-
related factors to develop dosing algorithms, ethnicity should also be taken into account. The current four DPYD variants associated to the onset of severe fluoropyrimidine-induced toxicity are mainly identified in Caucasian patients. DPYD*2A and c.2846A>T have been identified in ~0.1% in African-Americans, compared to a frequency of ~1% in Caucasians.76-78 Novel deleterious DPYD variants can be identified in different ethnic populations, as was recently shown for an East African population.79 Dosing algorithms might not predict DPD activity correctly in patients who are not Caucasian, depending on the variants included in the algorithm.
Current genotyping techniques are mostly single SNP-based assays or chip-based assays. In the near future extensive sequencing techniques will become less expensive and more available for daily practice in the laboratories of hospitals, or hospitals can outsource genotyping to special genotyping facilities. An increasing amount of genotyping data of patients will be known in a shorter period of time, and should be linked to clinical patient data in order to first translate the genotype into a prediction for toxicity, and second, the data can be used to complement and perfect the algorithm. The question that remains is, can we build an algorithm which can predict the majority of severe fluoropyrimidine- induced toxicity? When all previously reported risk factors for toxicity are validated and included, and when the complete genotype of patients is taken into account, what risk factors will remain to be discovered?
The future of fluoropyrimidines
5-FU has been used to treat cancer for decades and the first studies on DPD deficiency were published in the eighties.1-3 Now, capecitabine is the preferred drug of use over 5-FU in various tumour types in several countries, including the Netherlands. To improve efficacy of cancer therapy, fluoropyrimidines are combined with several other anticancer drugs, yet they remain the backbone of therapy for a substantial number of tumour types.
To conclude with the following quote by Hamzic et al.: “While additional genetic factors or phenotyping approaches may complement pharmacogenetic testing in the future, DPYD genotyping provides an important tool that is available today to identify patients at increased risk of severe adverse effects from fluoropyrimidine-based therapies”.80
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