Personalized Medicine in Infant Population with Cancer: Pharmacogenetic Pilot Study of Polymorphisms Related to Toxicity and Response to Chemotherapy

Abstract

[EN] Simple Summary Cancer is still the leading cause of disease-related death in pediatric populations and an important source of morbidity. These can be due to the neoplasm itself but also to the treatment administered; infants are patients of special vulnerability. The aim of this work was to identify genetic variants that correlate with significant impacts on treatments' safety and efficacy. 64 oncologic infant patients (under 18 months of age) were genotyped, calling for SNPs (single nucleotide polymorphisms) in genes related to the efficacy and/or toxicity of the chemotherapeutic drugs employed. The relationship of these genetic variants with 37 clinical parameters during 578 chemotherapy cycles was analyzed. Associations were found between 46 SNPs (in genes involved in drug transport and metabolism, gene repair, tumor suppression, and other biological functions) and survival and hematological toxicity. Following studies that confirm these findings, personalized medicine could be offered to improve response and tolerance to chemotherapeutic schemes. Background: Pharmacogenetics is a personalized medicine tool that aims to optimize treatments by adapting them to each individual's genetics, maximizing their efficacy while minimizing their toxicity. Infants with cancer are especially vulnerable, and their co-morbidities have vital repercussions. The study of their pharmacogenetics is new in this clinical field. Methods: A unicentric, ambispective study of a cohort of infants receiving chemotherapy (from January 2007 to August 2019). The genotypes of 64 patients under 18 months of age were correlated with severe drug toxicities and survival. A pharmacogenetics panel was configured based on PharmGKB, drug labels, and international experts' consortiums. Results: Associations between SNPs and hematological toxicity were found. Most meaningful were: MTHFR rs1801131 GT increasing the anemia risk (OR 1.73); rs1517114 GC, XPC rs2228001 GT, increasing neutropenia risk (OR 1.50 and 4.63); ABCB1 rs1045642 AG, TNFRSF11B rs2073618 GG, CYP2B6 rs4802101 TC and SOD2 rs4880 GG increasing thrombocytopenia risk (OR 1.70, 1.77, 1.70, 1.73, respectively). Regarding survival, MTHFR rs1801133 GG, TNFRSF11B rs2073618 GG, XPC rs2228001 GT, CYP3A4 rs2740574 CT, CDA rs3215400 del.del, and SLC01B1 rs4149015 GA were associated with lower overall survival probabilities (HR 3.12, 1.84, 1.68, 2.92, 1.90, and 3.96, respectively). Lastly, for event-free survival, SLC19A1 rs1051266 TT and CDA rs3215400 del.del increased the relapse probability (HR 1.61 and 2.19, respectively). Conclusions: This pharmacogenetic study is a pioneer in dealing with infants under 18 months of age. Further studies are needed to confirm the utility of the findings in this work to be used as predictive genetic biomarkers of toxicity and therapeutic efficacy in the infant population. If confirmed, their use in therapeutic decisions could improve the quality of life and prognosis of these patients.