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Comprehensive pharmacogenetic analysis of DPYD, UGT, CDA, and ABCB1 polymorphisms in pancreatic cancer patients receiving mFOLFIRINOX or gemcitabine plus nab-paclitaxel

The Pharmacogenomics Journal volume 21, pages 233–242 (2021)Cite this article

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Abstract

Modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine + nab-paclitaxel (GemNab) regimens represent a standard treatment in advanced pancreatic cancer (aPC). DPYD and UGT1A1 variants are relevant predictors of fluoropyrimidine and irinotecan-associated adverse events (AEs). Furthermore, data about the associations between polymorphisms in ABCB and CDA genes and GemNab-related toxicities are still controversial. The present study analyzes the association between DPYD, UGT, ABCB1, CDA variants, and AEs in aPC patients (pts) treated with mFOLFIRINOX or GemNab. Blood samples collected from 104 aPC pts treated with mFOLFIRINOX and 63 with GemNab were tested for DPYD c.1679T>G, IVS14+1G>A, c.2194G>A, c.2846A>T, UGT1A1*28, CDA c.79A>C, and ABCB1 c.1236C>T, c.2677G>T/A, c.3435C>T by real-time PCR and automatic sequencing. In mFOLFIRINOX cohort, DPYD IVS14+1GA genotype was associated with G4 hematological AEs, while the UGT1A1*28 significantly correlated with the risk of thrombocytopenia (p = 0.006). In the GemNab cohort, a significant association between CDA c.79CC and high-grade nausea was observed (p = 0.002). Moreover, the presence of at least a mutant allele in ABCB1 increased the risk of overall hematological AEs (p = 0.01), both further strengthened by the presence of CDA c.79CC (p = 0.0002). DPYD IVS14+1A allele is confirmed to be associated with fluoropyrimidine life-threatening toxicities, and UGT1A1*28 is related with a higher risk of hematologic AEs following irinotecan treatment. CDA c.79C and ABCB1 c.1236T, c.2677T/A, and c.3435T mutant alleles are predictive biomarkers of GemNab-related AEs. All these variants should be considered in aPC pts candidate to mFOLFIRINOX or GemNab treatments.

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Fig. 1: Involvement of UGT1A1*28 in clinical outcome of patients.

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Data availability

Data and results are available at the Unit of Clinical Pharmacology and Pharmacogenetics, University Hospital of Pisa.

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Funding

This work was supported by a grant of the University of Pisa (Italy) to RD.

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  1. These authors contributed equally: Caterina Vivaldi, Stefania Crucitta

Authors and Affiliations

  1. Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

    Caterina Vivaldi, Silvia Catanese, Irene Pecora, Lorenzo Fornaro, Francesca Salani, Valentina Massa & Enrico Vasile

  2. Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Stefania Crucitta, Federico Cucchiara, Elena Arrigoni, Eleonora Rofi, Romano Danesi & Marzia Del Re

  3. Departmental Section of Statistical Support for Clinical Trials, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

    Riccardo Morganti

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  1. Caterina Vivaldi
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Contributions

Conception and design: MDR, CV. Development of methodology: MDR, SC, ER, and EA. Clinical protocols/amendments: MDR, RD. Acquisition of data: MDR, SC, ER, EA, and CV. Analysis and interpretation of data: MDR, CV, SC, FC. RM, and RD. Writing, review, and/or revision of the paper: all authors. Administrative, technical, or material support: MDR, SC, ER, and RD. Study supervision: MDR, RD.

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Correspondence to Romano Danesi.

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The study was approved by the Ethics Committee of Pisa University Hospital. Written informed consent was obtained from each patient included, and this study was performed in accordance with the Declaration of Helsinki.

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Vivaldi, C., Crucitta, S., Catanese, S. et al. Comprehensive pharmacogenetic analysis of DPYD, UGT, CDA, and ABCB1 polymorphisms in pancreatic cancer patients receiving mFOLFIRINOX or gemcitabine plus nab-paclitaxel. Pharmacogenomics J 21, 233–242 (2021). https://doi.org/10.1038/s41397-020-00203-7

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