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

The Pharmacogenomics Journal volume 19, pages 465–472 (2019)Cite this article

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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.

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Acknowledgements

The authors gratefully thank Alessandro Bonfante for his graphical assistance.

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Authors and Affiliations

  1. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Federico Nichetti, Giovanni Fucà, Antonia Martinetti, Maria Di Bartolomeo, Filippo de Braud & Filippo Pietrantonio

  2. Unit of Clinical Pharmacology, Department of Laboratory Medicine, ASST Fatebenefratelli-Sacco, Milan, Italy

    Felicia Stefania Falvella, Stefania Cheli & Raffaella Gaetano

  3. Unit of Medical Statistics, Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

    Rosalba Miceli & Gabriele Infante

  4. Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

    Carlotta Antoniotti, Alfredo Falcone & Chiara Cremolini

  5. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Filippo de Braud & Filippo Pietrantonio

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  1. Federico Nichetti
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Correspondence to Filippo Pietrantonio.

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Nichetti, F., Falvella, F.S., Miceli, R. et al. Is a pharmacogenomic panel useful to estimate the risk of oxaliplatin-related neurotoxicity in colorectal cancer patients?. Pharmacogenomics J 19, 465–472 (2019). https://doi.org/10.1038/s41397-019-0078-0

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