A recent UK study has revealed that a significant proportion of cancer patients could benefit from pharmacogenetic (PGx) testing to minimize adverse drug reactions. The analysis of whole genome sequencing (WGS) data, encompassing over 76,000 participants, indicates that nearly 63% of cancer patients possess genetic variations that elevate their risk of experiencing adverse effects from at least one of five commonly used oncology drugs. This finding, published in the Journal of Clinical Oncology, underscores the potential for personalized medicine to improve cancer treatment outcomes.
The study, led by Ivone U.S. Leong, PhD, of Genomics England, examined germline WGS data from participants in the 100,000 Genomes Project. Researchers focused on pharmacogenetic variants in four genes (DPYD, NUDT15, TPMT, UGT1A1) linked to toxicity induced by five drugs: capecitabine, fluorouracil, mercaptopurine, thioguanine, and irinotecan. By linking genomic data with prescribing and hospital records, the team identified correlations between specific genetic variants and adverse drug reactions (ADRs).
The results showed that a substantial number of patients could benefit from either a reduced dose or an alternative medication. According to the researchers, 6-10% of patients on each of the five drugs could potentially avoid adverse reactions through personalized treatment strategies. Extrapolating these findings to the broader population, the researchers estimate that over 14,500 patients in England alone could benefit annually from optimized drug selection and dosing.
"Identifying key patient groups that would benefit most and designing testing strategies that fit within current health care pathways could help address key implementation challenges and questions, such as cost-effectiveness, how and when to test, ethics, and education," the authors stated. They emphasized that PGx implementation could be particularly beneficial in cancer treatment, where timely and effective intervention is crucial, but drug-induced toxicity can often delay or prevent treatment.
One well-established example is genetic variation in the DPYD gene, which encodes dihydropyrimidine dehydrogenase. Deficiencies in this enzyme can lead to severe, even fatal, fluoropyrimidine-induced toxicity. Approximately 10–30% of patients receiving fluorouracil (FU) experience grade 3–4 toxicity, with a mortality rate of 0.5%. Studies have shown that 19% of severe toxicity cases can be attributed to underlying DPYD variants. A 50% dose reduction in patients with DPYD variants conferring no enzyme function can significantly reduce the risk of severe toxicity.
This study highlights the growing importance of pharmacogenomics in oncology. As genetic testing becomes more accessible and affordable, preemptive screening for pharmacogenetic variants could become a standard practice, leading to more effective and safer cancer treatments.
