Is a pharmacogenomic panel useful to estimate the risk of oxaliplatin-related neurotoxicity in colorectal cancer patients?

Federico Nichetti, Felicia Stefania Falvella, Rosalba Miceli, Stefania Cheli, Raffaella Gaetano, Giovanni Fucà, Gabriele Infante, Antonia Martinetti, Carlotta Antoniotti, Alfredo Falcone, Maria Di Bartolomeo, Chiara Cremolini, Filippo de Braud, Filippo Pietrantonio

Research output: Contribution to journalArticle

Abstract

Oxaliplatin-induced peripheral neurotoxicity (OXPN) is a dose-limiting toxicity in colorectal cancer (CRC) patients. Single nucleotide polymorphisms (SNPs) in genes involved in drug transport may lead to higher intracellular oxaliplatin accumulation in the dorsal root ganglia and thus increased risk of OXPN. In this study, a panel of 5 SNPs, namely ABCC2 (−24C > T/rs717620 and c.4544 G > A/rs8187710), ABCG2 (c.421 C > A/rs2231142), ABCB1 (c.3435 C > T/rs1045642) and SLC31A1 (c.−36 + 2451 T > G/rs10981694), was evaluated to assess their association with grade 2–3 OXPN in metastatic CRC patients. SNPs were considered according to a dominant model (heterozygous + homozygous). Germline DNA was available from 120 patients who received oxaliplatin between 2010 and 2016. An external cohort of 80 patients was used to validate our results. At the univariable logistic analyses, there were no significant associations between SNPs and incidence of OXPN. Taking into account the strength of observed association between OXPN and the SNPs, a clinical risk score was developed as linear predictor from a multivariable logistic model including all the SNPs together. This score was significantly associated with grade 2–3 OXPN (p = 0.036), but the external calibration was not satisfactory due to relevant discrepancies between the two series. Our data suggest that the concomitant evaluation of multiple SNPs in oxaliplatin transporters is an exploratory strategy that may deserve further investigation for treatment customization in CRC patients.

Original languageEnglish
Pages (from-to)465-472
Number of pages8
JournalPharmacogenomics Journal
Volume19
Issue number5
DOIs
Publication statusPublished - Oct 1 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Fingerprint Dive into the research topics of 'Is a pharmacogenomic panel useful to estimate the risk of oxaliplatin-related neurotoxicity in colorectal cancer patients?'. Together they form a unique fingerprint.

  • Cite this