SNPs in predicting clinical efficacy and toxicity of chemotherapy: walking through the quicksand

Abstract

In the “precision medicine” era, chemotherapy still remains the backbone for the treatment of many cancers, but no affordable predictors of response to the chemodrugs are available in clinical practice. Single nucleotide polymorphisms (SNPs) are gene sequence variations occurring in more than 1% of the full population, and account for approximately 80% of inter-individual genomic heterogeneity. A number of studies have investigated the predictive role of SNPs of genes enrolled in both pharmacodynamics and pharmacokinetics of chemotherapeutics, but the clinical implementation of related results has been modest so far. Among the examined germline polymorphic variants, several SNPs of dihydropyrimidine dehydrogenase (DPYD) and uridine diphosphate glucuronosyltransferases (UGT) have shown a robust role as predictors of toxicity following fluoropyrimidine- and/or irinotecan-based treatments respectively, and a few guidelines are mandatory in their detection before therapy initiation. Contrasting results, however, have been reported on the capability of variants of other genes as MTHFR, TYMS, ERCC1, XRCC1, GSTP1, CYP3A4/3A5 and ABCB1, in predicting either therapy efficacy or toxicity in patients undergoing treatment with pyrimidine antimetabolites, platinum derivatives, irinotecan and taxanes. While formal recommendations for routine testing of these SNPs cannot be drawn at this moment, therapeutic decisions may indeed benefit of germline genomic information, when available. Here, we summarize the clinical impact of germline genomic variants on the efficacy and toxicity of major chemodrugs, with the aim to facilitate the therapeutic expectance of clinicians in the odiern quicksand field of complex molecular biology concepts and controversial trial data interpretation.

Nutrition and Female Fertility: An Interdependent Correlation

“…Nelen and coworkers proved that two months of daily supplementation of 0.5 mg folic acid in females with a history of unexplained frequent miscarriages and homozygous for the MTHFR-gene 677C> T mutation reduced their Hcy concentrations (61). Therefore, these studies demonstrate the importance of the nutritional supplementation with folate, especially in infertile patients with MTHFR polymorphisms related to the folate metabolism (61, 62).…”

Genetic Variations of VEGFA Gene Are Associated With Infiltration of Adjacent Tissues and the Clinical Outcome of Patients With Nasopharyngeal Carcinoma

“…Over the years, various technologies have been developed for efficient SNP genotyping, including arraybased hybridization, discrete PCR-based SNP assays as well as targeted Sanger sequencing, while recently the advent of next-generation sequencing technology (NGS) has allowed high-throughput but also flexible SNP genotypic analysis, proving advantage in terms of cost-effectiveness, number of SNPs and samples processed at once (41). This technological explosion has also helped the study of SNPs in the context of pharmacogenomics, contributing to the individualized management of cancer patients (42).…”

Drug–Drug Interactions and Pharmacogenomic Evaluation in Colorectal Cancer Patients: The New Drug-PIN® System Comprehensive Approach

“…Thus, testing DPD activity is strongly recommended before starting fluoropyrimidine treatment [ 11 , 12 ]. However, as extensively described by Palmirotta et al, many other SNPs, such as those affecting genes involved in irinotecan, oxaliplatin, or glutathione metabolism, could determine different responses and toxicities related to chemotherapy in gastrointestinal (GI) cancer patients [ 13 ].…”