Evaluation of pharmacogenomics in relapsed/refractory pediatric cancer patients
Pharmacogenomics (PGx) is an emerging field of study that offers an additional approach to precision medicine through the genotyping of important genes related to drug metabolism. By understanding an individual’s PGx profile, drug choice and dosage can be tailored to the individual to reduce risks of ineffective medicine or toxic side effects. We evaluated PGx profiles in a cohort of 184 pediatric patients with relapsed or treatment-refractory cancer enrolled in clinical trials conducted by the Beat Childhood Cancer Consortium. A majority of these patients had previously received chemotherapy as part of standard-of-care treatment. PGx analysis was performed using PharmCat, publicly available software that assigns genotypes along with relevant CPIC prescribing recommendations based on individual input variant call files. 7.6% (14/184) of pediatric patients were found to have thiopurine methyltransferase (TPMT) genotypes associated with intermediate metabolism of the chemotherapy cisplatin and therefore had increased risk of ototoxicity. Five of these intermediate metabolizers received cisplatin during their treatment course, with at least one patient experiencing hearing loss related to cisplatin exposure. We next investigated single nucleotide polymorphisms (SNPs) in PGx genes, focusing on genes linked to metabolism of chemotherapeutic agents commonly used in pediatric oncology. An RARG SNP (rs2229774) linked to increased risk of cardiotoxicity from the chemotherapeutic agent doxorubicin was identified in twenty-two patients, ten of whom received doxorubicin during their treatment course. These results indicate that 19% (35/184) of relapsed/refractory pediatric cancer patients had a PGx informative variant. Fifteen of these patients received a chemotherapeutic agent for which their PGx profile indicated higher risk of toxicity. This outcome, considering the limited scope of the PGx analysis, suggests pharmacogenomics should receive increased attention in pediatric oncology.
