Cardiovascular health status and genetic risk in survivors of childhood neuroblastoma and nephroblastoma treated with doxorubicin: protocol of the pharmacogenetic part of the LESS-Anthra cross-sectional cohort study (Preprint)

Abstract

Cardiac toxicity is the most common non-malignant cause of death in childhood cancer survivors attributed to treatment-related consequences. Identifying patients at risk of developing late cardiac toxicity is therefore crucial to improving treatment outcomes. Genetic markers have been proposed to be used together with clinical risk factors to predict the individual risk of cardiac toxicity from cancer therapies such as doxorubicin.

The primary aim is to replicate the previously described associations of doxorubicin-induced cardiotoxicity with RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants and to evaluate the predictive value of the multimarker genetic test. The secondary aim is to evaluate the prevalence of cardiovascular dysfunction in childhood cancer survivors and to replicate the association of doxorubicin-related cardiotoxicity with other candidate genes.

This is the pharmacogenetic sub-study of the research project Structural Optimization for Children with Cancer after Anthracycline Therapy (LESS-Anthra). We invited 2158 survivors of childhood neuroblasoma or nephroblastoma who were treated with doxorubicin according to the trial protocols of SIOP 9/GPOH, SIOP 93-01/GPOH, SIOP 2001/GPOH, NB 90, NB 97, or NB 2004 to participate in this prospective cross-sectional cohort study. The study participants underwent a cardiological examination and were asked to provide a blood or saliva sample for genotyping. The health status and cardiovascular diagnoses of the study participants were recorded using a questionnaire completed by the cardiologist. Digital echocardographic data were centrally evaluated to determine the contractile function parameters. Medical data on tumor diagnosis and treatment protocol were taken from the study documentation. Survivors were screened for variants in several candidate genes by TaqMan genotyping.

This study included 657 survivors treated with doxorubicin for childhood cancer, resulting in the largest German cohort assembled for investigation of cardiovascular late effects to date. Data analyses are yet to be completed.

The study will define the genetic risk related to three marker genes proposed for risk assessment in a pharmacogenetic guideline. Moreover, the results of this study will show the prevalence of cardiovascular dysfunction in survivors of pediatric neuroblastoma or nephroblastoma treated with doxorubicin. The results will help to improve primary treatment and follow-up care to reduce cardiovascular late effects in the growing population of childhood cancer survivors.

German clinical trials register ID: DRKS00015084