Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

Abstract

In the past decades, new cancer treatments have been introduced in pediatric oncology leading to improvement in clinical outcomes and survival rates. However, due to inter-individual differences, some children experience severe chemotherapy-induced toxicities or a poor clinical outcome. An explanation for the diversity in response to chemotherapy is genetic variation, leading to differences in expression and activity of metabolizing and transport enzymes as well as drug targets. Pharmacogenetic testing has emerged as a promising tool to predict and limit acute and long-term adverse effects in patients. However, in pediatric oncology, limited number of patients and a considerable diversity in study results complicate the interpretation of test results and its clinical relevance. With this review, we provide an overview of new developments over the past four years regarding relevant polymorphisms related to toxicity in pediatric oncology. The following chemotherapeutics and associated toxicities are discussed: alkylating agents, anthracyclines, asparaginase, methotrexate, platinum compounds, steroids, thiopurines, topoisomerase inhibitors, and vinca alkaloids. Our review identifies several questions regarding the role of genetic variants in chemotherapy-induced toxicities. Ambiguities in the literature stem from small population sizes, differences in (statistical) interpretation and variations in sequencing technologies as well as different clinical outcome definitions. Standardization of clinical outcome data and toxicity definitions within electronic health records combined with the increased availability of genomic sequence techniques in clinical practice will help to validate these models in upcoming years.

Keywords: adverse effects; chemotherapeutic agents; drug toxicity; pediatric oncology; pharmacogenomics.

Figure 1

Figure used with permission of PharmGKB (Thorn et al., 2011; Doxorubicin Pathway (Cardiomyocyte Cell) P, 2020). This is an example of genes involved in doxorubicin-induced cardiotoxicity. The presented genes (e.g. CBR, NOS, and AKR) are involved in the metabolizing and transport pathways of anthracyclines. The formation of ROS during the metabolism of anthracyclines is thought to play an important role in anthracycline-induced cardiotoxicity.

Figure 2

Figure used with permission of PharmGKB (Thorn et al., 2011; Doxorubicin Pathway, 2020). This is an example of genes involved in doxorubicin pharmacokinetic pathway. These include metabolizing genes such as CBR, AKR, and NOS as well as SLC and ABC transporters.

Figure 3

Figure used with permission of PharmGKB (Mikkelsen et al., 2011; Methotrexate Pathway, 2020) Genes involved in transport of methotrexate (Mikkelsen et al., 2011; Methotrexate Pathway, 2020).