PMID- 33462346 OWN - NLM STAT- MEDLINE DCOM- 20220112 LR - 20221207 IS - 1473-1150 (Electronic) IS - 1470-269X (Linking) VI - 21 IP - 2 DP - 2021 Apr TI - Comprehensive pharmacogenetic analysis of DPYD, UGT, CDA, and ABCB1 polymorphisms in pancreatic cancer patients receiving mFOLFIRINOX or gemcitabine plus nab-paclitaxel. PG - 233-242 LID - 10.1038/s41397-020-00203-7 [doi] AB - 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. FAU - Vivaldi, Caterina AU - Vivaldi C AUID- ORCID: 0000-0001-9307-2326 AD - Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. FAU - Crucitta, Stefania AU - Crucitta S AD - Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Catanese, Silvia AU - Catanese S AD - Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. FAU - Cucchiara, Federico AU - Cucchiara F AD - Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Arrigoni, Elena AU - Arrigoni E AD - Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Pecora, Irene AU - Pecora I AD - Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. FAU - Rofi, Eleonora AU - Rofi E AD - Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. FAU - Fornaro, Lorenzo AU - Fornaro L AD - Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. FAU - Salani, Francesca AU - Salani F AD - Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. FAU - Massa, Valentina AU - Massa V AD - Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. FAU - Vasile, Enrico AU - Vasile E AD - Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. FAU - Morganti, Riccardo AU - Morganti R AD - Departmental Section of Statistical Support for Clinical Trials, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. FAU - Danesi, Romano AU - Danesi R AUID- ORCID: 0000-0002-4414-8934 AD - Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. romano.danesi@unipi.it. FAU - Del Re, Marzia AU - Del Re M AUID- ORCID: 0000-0001-7343-6161 AD - Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210118 PL - United States TA - Pharmacogenomics J JT - The pharmacogenomics journal JID - 101083949 RN - 0 (130-nm albumin-bound paclitaxel) RN - 0 (ABCB1 protein, human) RN - 0 (ATP Binding Cassette Transporter, Subfamily B) RN - 0 (Albumins) RN - 0 (Organoplatinum Compounds) RN - 0W860991D6 (Deoxycytidine) RN - EC 2.4.1.- (UGT1A1 enzyme) RN - EC 2.4.1.17 (Glucuronosyltransferase) RN - EC 3.5.4.5 (Cytidine Deaminase) RN - P88XT4IS4D (Paclitaxel) RN - Q573I9DVLP (Leucovorin) RN - U3P01618RT (Fluorouracil) RN - 0 (Gemcitabine) RN - Folfox protocol SB - IM MH - ATP Binding Cassette Transporter, Subfamily B/genetics MH - Adult MH - Aged MH - Albumins/administration & dosage MH - Alleles MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Cytidine Deaminase/*genetics MH - Deoxycytidine/administration & dosage/analogs & derivatives MH - Female MH - Fluorouracil/therapeutic use MH - Genotype MH - Glucuronosyltransferase/*genetics MH - Humans MH - Leucovorin/therapeutic use MH - Male MH - Middle Aged MH - Organoplatinum Compounds/therapeutic use MH - Paclitaxel/administration & dosage MH - Pancreatic Neoplasms/*drug therapy/*genetics MH - Pharmacogenomic Testing/methods MH - Polymorphism, Genetic/*genetics MH - Gemcitabine EDAT- 2021/01/20 06:00 MHDA- 2022/01/13 06:00 CRDT- 2021/01/19 05:53 PHST- 2020/04/20 00:00 [received] PHST- 2020/12/04 00:00 [accepted] PHST- 2020/11/09 00:00 [revised] PHST- 2021/01/20 06:00 [pubmed] PHST- 2022/01/13 06:00 [medline] PHST- 2021/01/19 05:53 [entrez] AID - 10.1038/s41397-020-00203-7 [pii] AID - 10.1038/s41397-020-00203-7 [doi] PST - ppublish SO - Pharmacogenomics J. 2021 Apr;21(2):233-242. doi: 10.1038/s41397-020-00203-7. Epub 2021 Jan 18.