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A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen

The Pharmacogenomics Journal volume 13, pages 403–409 (2013)Cite this article

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Abstract

The discovery of pharmacogenomic markers in colorectal cancer (CRC) could be setting-specific. FOLFOX4 is employed in the adjuvant and metastatic setting in CRC. This prospective study is aimed to validate in the adjuvant setting the pharmacogenomic markers of toxicity reported in the metastatic setting (that is, GSTP1-rs947894, and -rs1138272; GSTM1-null genotype; AGXT-rs4426527, -rs34116584 and del-74 bp), and to discover additional markers. CRC patients (n=144) treated with adjuvant FOLFOX4 were genotyped for 57 polymorphisms in 29 genes. Grade ⩾2 neurotoxicity was associated (false discovery rate-adjusted q-value <0.1) with single-nucleotide polymorphisms in ABCC1 (rs2074087: odds ratio=0.43(0.22–0.86)), and ABCC2 (rs3740066: 2.99(1.16–7.70); rs1885301: 3.06(1.35–6.92); rs4148396: 4.69(1.60–13.74); rs717620: 14.39(1.63–127.02)). hMSH6-rs3136228 was associated with grade 3–4 neutropenia (3.23(1.38–7.57), q-value=0.0937). XRCC3-rs1799794 was associated with grade 3–4 non-hematological toxicity (8.90(2.48–31.97), q-value=0.0150). The markers previously identified in metastatic CRC were not validated. We have identified new markers of toxicity in genes of transport and DNA repair. If validated in other studies, they could help to identify patients at risk of toxicity.

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Authors and Affiliations

  1. Experimental and Clinical Pharmacology Unit, ‘Centro di Riferimento Oncologico’- National Cancer Institute, Aviano, Italy

    E Cecchin, C Zanusso, E De Mattia & G Toffoli

  2. Medical Oncology Unit, ‘San Filippo Neri Hospital’, Rome, Italy

    M D'Andrea

  3. Medical Oncology Unit 1, Istituto Oncologico Veneto-IRCCS, Padova, Italy

    S Lonardi

  4. Medical Oncology Unit, University Hospital, Udine, Italy

    N Pella

  5. Medical Oncology Unit, Ospedale Civile di Vittorio Veneto, Treviso, Italy

    D Errante

  6. Epidemiology and Biostatistics Unit, ‘Centro di Riferimento Oncologico’- National Cancer Institute, Aviano, Italy

    J Polesel

  7. Eshelman School of Pharmacy, Institute for Pharmacogenomics and Individualized Therapy, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    F Innocenti

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Cecchin, E., D'Andrea, M., Lonardi, S. et al. A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen. Pharmacogenomics J 13, 403–409 (2013). https://doi.org/10.1038/tpj.2012.31

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