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.
Highlights
Over the past decades, the 5‐year survival rate for childhood cancer improved from 58% for children diagnosed during 1975 to 1977 to 83% for those diagnosed during 2005 to 2015 (O’Leary et al, 2008; Pui et al, 2011; Siegel et al, 2019)
To address the recent developments, we reviewed recent publications using terms related to pediatric oncology, pharmacogenomics and pharmacogenetics, and toxicities of cancer drugs
Variants in methylenetetrahydrofolate reductase (MTHFR) activity have been described and the role of MTHFR polymorphism in relation to toxicity has been studied by several groups (Campbell et al, 2016; Ramıŕ ez-Pacheco et al, 2016; 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)
Summary
The 5‐year survival rate for childhood cancer improved from 58% for children diagnosed during 1975 to 1977 to 83% for those diagnosed during 2005 to 2015 (O’Leary et al, 2008; Pui et al, 2011; Siegel et al, 2019). In the Netherlands, The Dutch Pharmacogenetics Working Group (DPWG) has reviewed 97 gene-drug interactions, leading to multiple recommendations for clinical practice (KNMP apothekersorganisatie; van der Wouden et al, 2019). These guidelines are predominantly based on research in adults and exclude some pediatric cancer treatment drugs (e.g. asparaginase). In this literature review we provide an overview of developments and new insights over the last years regarding relevant genes and polymorphisms as well as their role in acute and long-term adverse effects of drugs in pediatric oncology. While a wide variety of supportive care drugs (e.g. anti-infective drugs, analgesics drugs, and antiemetic drugs) and immunotherapy are used in pediatric oncology, we focus exclusively on the association between genetic variants and chemotherapy-induced toxicities
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