Pharmacogenomics in Pediatric Oncology: Mitigating Adverse Drug Reactions While Preserving Efficacy

Abstract

Cancer is the leading cause of death in American children older than 1 year of age. Major developments in drugs such as thiopurines and optimization in clinical trial protocols for treating cancer in children have led to a remarkable improvement in survival, from approximately 30% in the 1960s to more than 80% today. Short-term and long-term adverse effects of chemotherapy still affect most survivors of childhood cancer. Pharmacogenetics plays a major role in predicting the safety of cancer chemotherapy and, in the future, its effectiveness. Treatment failure in childhood cancer—due to either serious adverse effects that limit therapy or the failure of conventional dosing to induce remission—warrants development of new strategies for treatment. Here, we summarize the current knowledge of the pharmacogenomics of cancer drug treatment in children and of statistically and clinically relevant drug–gene associations and the mechanistic understandings that underscore their therapeutic value in the treatment of childhood cancer. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 7, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Retracted Article: Treatment Failure in Children with Cancer

“…Advances in medical research technologies have led to a rapid increase in the understanding of the genetics of childhood cancer in the last decade, facilitating the identification of molecular targets that can potentially be exploited for therapeutic benefits. 2 Nonetheless, despite remarkable developments in drug therapy, pharmacogenomics, and pharmacogenetics research, 1 we could not explain the cause of treatment failure in some children with cancer. Based on the Islamic teachings, we believe that everything cannot be explained by positivism.…”

“…Currently, due to major drug developments and optimization in treatment protocols, 80% of pediatric cancer patients respond to therapy; however, a significant number of cases of childhood cancer have shown treatment failure. 1 Treatment failure can be seen due to either serious adverse effects that limit therapy or the failure of conventional dosing to induce remission in childhood cancer. 1 Herein, we evaluated the treatment failure in children with cancer from a spiritual perspective to attract attention to the spiritual dimension of treatment.…”

“…1 Treatment failure can be seen due to either serious adverse effects that limit therapy or the failure of conventional dosing to induce remission in childhood cancer. 1 Herein, we evaluated the treatment failure in children with cancer from a spiritual perspective to attract attention to the spiritual dimension of treatment.…”

Landscape of germline cancer predisposition mutations testing and management in pediatrics: Implications for research and clinical care

“…Pharmacogenomics is another exploratory space that is growing in parallel with the field of germline cancer genetics. It is established that polymorphisms and/or mutations in genes involved in drug metabolism can impact the pharmacokinetics of various medicines, including chemotherapies, immunosuppressants, and supportive care medications in pediatrics ( 98 ). While people who have germline predisposition to therapy intolerance are not more likely to develop a primary malignancy, they are more likely to have adverse events from the management of a cancer diagnoses and may be at increased risk of developing a secondary malignancy, such as increased risk of brain tumors and AML among survivors of childhood ALL who are treated with mercaptopurine and have low-activity TMPT genetic polymorphisms ( 98 , 99 ).…”

Model Based Evaluation of Hypersensitivity Adverse Drug Reactions to Antimicrobial Agents in Children

“…Dose calculation for pediatric patients based on weight and body surface area (BSA) can be both inaccurate and prone to errors. Children are not merely little adults; they have their own unique pharmacokinetics and pharmacodynamics and these parameters change dramatically especially during the first few years of life (Elzagallaai et al, 2021). Dose estimation from adult studies can be extrapolated with allometric scaling but this may not always result in an optimal or safe dose due to the variability imposed by ontogeny.…”