Three years on from NHS Wales becoming the first nation within the NHS to recommend DPYD screening to predict a negative response to treatment for all cancer patients prescribed fluoropyrimidine therapy, the All Wales Medical Genomics Service has highlighted some key clinical findings, as well as providing valuable recommendations for institutions or authorities who could benefit from establishing their own service.
Cancer is a global health crisis. The current burden stands at 19 million new cases and 9.9 million cancer-related deaths per year,1 the second most common cause of illness-related death in the world. Many compounding factors mean that these figures are expected to rise by an estimated 40% by 2040. Despite this, the overall risk of death due to cancer has dropped steadily in the last thirty years; when adjusted for age and population, the cancer death rate has fallen by 15% since 1990.2 Whilst there are complex dynamics at play, it is becoming increasingly clear that our greatest gains in the fight against cancer can be attributed to three key strategies:
The critical nature of all three of these strategies are highlighted in the way in which precision medicine is being deployed with great effect; none more so than in the case of DPYD genotyping. Precision medicine is the branch of genetics concerned with the way in which an individual’s genetic attributes affect their likely response to therapeutic drugs. In the case of HERCEPTIN (trastuzumab) treatment for HER2-positive breast cancer,3 GLEEVEC (imatinib) for Philadelphia (Ph)-chromosome-positive leukaemias,4 and VESANOID (all-trans retinoic acid [ATRA]) for acute promyelocytic leukaemia (APML),5 those underlying genetic events indicate a positive predictive outcome to individuals’ response to these targeted therapies. Conversely, DPYD is an example of pharmacogenetic testing where a negative response to therapy can be predicted, allowing for safe alternatives to be prescribed prior to a severe adverse toxicity event (SATE) occurring.
The metabolism of a class of drugs called fluoropyrimidines (eg 5-fluorouracil/5-FU, capecitabine, tegafur) is performed by the dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by the DPYD gene. Treatment is generally well tolerated, but variants in the DPYD gene cause reduced efficiency in 5-FU breakdown. Identifying patients with DPD deficiency prior to commencing chemotherapy treatment with 5-FU therapy is critical to avoid adverse reactions, as patients with these variants are at an increased risk of severe or fatal 5-FU toxicity. An estimated 3–8% of the global population has a mutation which places them in an ‘at risk’ category, and vulnerable to experiencing an SATE. Symptoms of an adverse event include diarrhoea, stomatitis, neutropenia, hyperbilirubinemia, and hand-foot syndrome. Effects of 5-FU toxicity are so severe as to be fatal in approximately 1% of patients treated with 5-FU.6 Since around two million 5-FU prescriptions are written globally each year for a variety of cancers, including colorectal, head and neck, breast, pancreatic and stomach cancer, an estimated 60,000–160,000 individuals are at risk of being killed by the very therapy which is intended to fight their disease.7
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