REFERENCES
1. Pirmohamed M, James S, Meakin S, Green C, Scott AK, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 2004;329:15-9.
2. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279:1200-5.
3. Rottenkolber D, Schmiedl S, Rottenkolber M, Farker K, Saljé K, et al. Adverse drug reactions in Germany: direct costs of internal medicine hospitalizations. Pharmacoepidemiol Drug Saf 2011;20:626-34.
4. Gyllensten H, Hakkarainen KM, Hägg S, Carlsten A, Petzold M, et al. Economic impact of adverse drug events--a retrospective population-based cohort study of 4970 adults. PLoS One 2014;9:e92061.
5. Latremouille-Viau D, Chang J, Guerin A, Shi S, Wang E, et al. The economic burden of common adverse events associated with metastatic colorectal cancer treatment in the United States. J Med Econ 2017;20:54-62.
7. Twelves C, Wong A, Nowacki MP, Abt M, Burris H, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696-704.
8. André T, Quinaux E, Louvet C, Colin P, Gamelin E, et al. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol 2007;25:3732-8.
9. Sugihara K, Ohtsu A, Shimada Y, Mizunuma N, Gomi K, et al. Analysis of neurosensory adverse events induced by FOLFOX4 treatment in colorectal cancer patients: a comparison between two Asian studies and four Western studies. Cancer Med 2012;1:198-206.
10. Chiara DF, Jerry P, Rossana R, Elena DM, Fabrizio E, et al. DPYD gene activity score (GAS) predicts dose-limiting toxicity in fluoropyrimidine-treated colorectal cancer patients. JMCM 2018;1:143-50.
11. Van Cutsem E, Cervantes A, Nordlinger B, Arnold D; ESMO Guidelines Working Group. Metastatic colorectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25:iii1-9.
12. Danesi R, Del Re M, Ciccolini J, Schellens JHM, Schwab M, et al. Prevention of fluoropyrimidine toxicity: do we still have to try our patient’s luck? Ann Oncol 2017;28:183.
13. Deenen MJ, Meulendijks D. Recommendation on testing for dihydropyrimidine dehydrogenase deficiency in the ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2017;28:184.
14. Boige V, Vincent M, Alexandre P, Tejpar S, Landolfi S, et al. DPYD genotyping to predict adverse events following treatment with flourouracil-based adjuvant chemotherapy in patients with stage III colon cancer: a secondary analysis of the PETACC-8 randomized clinical trial. JAMA Oncol 2016; doi: 10.1001/jamaoncol.2015.5392.
15. Lee AM, Shi Q, Pavey E, Alberts SR, Sargent DJ, et al. DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147). J Natl Cancer Inst 2014;106:dju298.
16. Toffoli G, Giodini L, Buonadonna A, Berretta M, De Paoli A, et al. Clinical validity of a DPYD-based pharmacogenetic test to predict severe toxicity to fluoropyrimidines. Int J Cancer 2015;137:2971-80.
17. Deenen MJ, Meulendijks D, Cats A, Sechterberger MK, Severens JL, et al. Upfront Genotyping of DPYD*2A to individualize fluoropyrimidine therapy: a safety and cost analysis. J Clin Oncol 2016;34:227-34.
18. Henricks LM, Lunenburg CATC, Meulendijks D, Gelderblom H, Cats A, et al. Translating DPYD genotype into DPD phenotype: using the DPYD gene activity score. Pharmacogenomics 2015;16:1277-86.
19. Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clin Pharmacol Ther 2018;103:210-6.
20. Lunenburg CATC, Henricks LM, Dreussi E, Peters FP, Fiocco M, et al. Standard fluoropyrimidine dosages in chemoradiation therapy result in an increased risk of severe toxicity in DPYD variant allele carriers. Eur J Cancer 2018;104:210-8.
21. Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, et al. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015;16:1639-50.
22. Lunenburg CA, van Staveren MC, Gelderblom H, Guchelaar HJ, Swen JJ. Evaluation of clinical implementation of prospective DPYD genotyping in 5-fluorouracil- or capecitabine-treated patients. Pharmacogenomics 2016;17:721-9.
23. Innocenti F. DPYD variants to predict 5-FU toxicity: the ultimate proof. J Natl Cancer Inst 2014;106:dju351.
24. Roncato R, Cecchin E, Montico M, De Mattia E, Giodini L, et al. Cost evaluation of irinotecan-related toxicities associated with the UGT1A1*28 patient genotype. Clin Pharmacol Ther 2017;102:123-30.
25. Toffoli G, Innocenti F, Polesel J, De Mattia E, Sartor F, et al. The genotype for DPYD risk variants in colorectal cancer patients and the related toxicity management costs in clinical practice. Clin Pharmacol Ther 2018; doi: 10.1002/cpt.1257.
26. Henricks LM, Lunenburg CATC, de Man FM, Meulendijks D, Frederix GWJ, et al. A cost analysis of upfront DPYD genotype-guided dose individualisation in fluoropyrimidine-based anticancer therapy. Eur J Cancer 2019;107:60-7.
27. Keeling NJ, Rosenthal MM, West-Strum D, Patel AS, Haidar CE, et al. Preemptive pharmacogenetic testing: exploring the knowledge and perspectives of US payers. Genet Med 2017; doi: 10.1038/gim.2017.181.
28. Cecchin E, Roncato R, Guchelaar HJ, Toffoli G; Ubiquitous Pharmacogenomics Consortium. Ubiquitous pharmacogenomics (U-PGx): the time for implementation is now. An Horizon2020 Program to drive pharmacogenomics into clinical practice. Curr Pharm Biotechnol 2017;18:204-9.
29. van der Wouden CH, Cambon-Thomsen A, Cecchin E, Cheung KC, Dávila-Fajardo CL, et al. Implementing pharmacogenomics in Europe: design and implementation strategy of the ubiquitous pharmacogenomics consortium. Clin Pharmacol Ther 2017;101:341-58.
30. Duthie SJ. Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis 2011;34:101-9.
31. De Mattia E, Toffoli G. C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. Eur J Cancer 2009;45:1333-51.
32. Toffoli G, Rossi D, Gaidano G, Cecchin E, Boiocchi M, et al. Methylenetetrahydrofolate reductase genotype in diffuse large B-cell lymphomas with and without hypermethylation of the DNA repair gene O6-methylguanine DNA methyltransferase. Int J Biol Markers 2003;18:218-21.
33. Boisdron-Celle M, Capitain O, Faroux R, Borg C, Metges JP, et al. Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: assessment of a multiparametric approach. Semin Oncol 2017;44:13-23.
34. Terrazzino S, Cargnin S, Del Re M, Danesi R, Canonico PL, et al. DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis. Pharmacogenomics 2013;14:1255-72.
35. Falvella FS, Cheli S, Martinetti A, Mazzali C, Iacovelli R, et al. DPD and UGT1A1 deficiency in colorectalcancerpatientsreceivingtriple tchemotherapy with fluoropyrimidines, oxaliplatin and irinotecan. Br J Clin Pharmacol 2015;80:581-8.
36. Madi A, Fisher D, Maughan TS, Colley JP, Meade AM, et al. Pharmacogenetic analyses of 2183 patients with advanced colorectal cancer; potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy. Eur J Cancer 2018;102:31-9.
37. Pellicer M, García-González X, García MI, Blanco C, García-Alfonso P, et al. Use of exome sequencing to determine the full profile of genetic variants in the fluoropyrimidine pathway in colorectal cancer patients affected by severe toxicity. Pharmacogenomics 2017;18:1215-23.
38. Ruzzo A, Graziano F, Galli F, Galli F, Rulli E, et al. Dihydropyrimidinedehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients. Br J Cancer 2017;117:1269-77.
39. Rosmarin D, Palles C, Church D, Domingo E, Jones A, et al. Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol 2014;32:1031-9.
40. Offer SM, Wegner NJ, Fossum C, Wang K, Diasio RB. Phenotypic profiling of DPYD variations relevant to 5-fluorouracil sensitivity using real-time cellular analysis and in vitro measurement of enzyme activity. Cancer Res 2013;73:1958-68.
41. He YF, Wei W, Zhang X, Li YH, Li S, et al. Analysis of the DPYD gene implicated in 5-fluorouracil catabolism in Chinese cancer patients. J Clin Pharm Ther 2008;33:307-14.
42. Offer SM, Fossum CC, Wegner NJ, Stuflesser AJ, Butterfield GL, et al. Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity. Cancer Res 2014;74:2545-54.
43. Nie Q, Shrestha S, Tapper EE, Trogstad-Isaacson CS, Bouchonville KJ, et al. Quantitative contribution of rs75017182 to dihydropyrimidine dehydrogenase mRNA splicing and enzyme activity. Clin Pharmacol Ther 2017;102:662-70.
44. Launay M, Dahan L, Duval M, Rodallec A, Milano G, et al. Beating the odds: efficacy and toxicity of dihydropyrimidine dehydrogenase-driven adaptive dosing of 5-FU in patients with digestive cancer. Br J Clin Pharmacol 2016;81:124-30.
45. Launay M, Ciccolini J, Fournel C, Blanquicett C, Dupuis C, et al. Upfront DPD deficiency detection to secure 5-FU administration: part 2-application to head-and-neck cancer patients. Clin Cancer Drugs 2017;4:122-8.
46. Meulendijks D, Henricks LM, Jacobs BAW, Aliev A, Deenen MJ, et al. Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity. Br J Cancer 2017;116:1415-24.
47. Etienne-Grimaldi MC, Boyer JC, Beroud C, Mbatchi L, van Kuilenburg A, et al. New advances in DPYD genotype and risk of severe toxicity under capecitabine. PLoS One 2017;12:e0175998.
48. Botticelli A, Onesti CE, Strigari L, Occhipinti M, Di Pietro FR, et al. A nomogram to predict 5-fluorouracil toxicity: whenpharmacogenomicsmeets the patient. Anticancer Drugs 2017;28:55-6.
49. Meulendijks D, Rozeman EA, Cats A, Sikorska K, Joerger M, et al. Pharmacogenetic variants associated with outcome in patients with advanced gastric cancer treated with fluoropyrimidine and platinum-based triplet combinations: a pooled analysis of three prospective studies. Pharmacogenomics J 2017;17:441-51.
50. Cecchin E, Russo A, Campagnutta E, Martella L, Toffoli G. Lack of association of CYP1 B1*3 polymorphism and ovarian cancer in a Caucasian population. Int J Biol Markers 2004;19:160-3.
51. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003;3:330-8.
52. De Mattia E, Cecchin E, Toffoli G. Pharmacogenomics of intrinsic and acquired pharmacoresistance in colorectal cancer: toward targeted personalized therapy. Drug Resist Updat 2015;20:39-70.
53. Lima A, Azevedo R, Sousa H, Seabra V, Medeiros R. Current approaches for TYMS polymorphisms and their importance in molecular epidemiology and pharmacogenetics. Pharmacogenomics 2013;14:1337-51.
54. Jennings BA, Kwok CS, Willis G, Matthews V, Wawruch P, et al. Functional polymorphisms of folate metabolism and response to chemotherapy for colorectal cancer, a systematic review and meta-analysis. Pharmacogenet Genomics 2012;22:290-304.
55. Campbell JM, Stephenson MD, Bateman E, Peters MDJ, Keefe DM, et al. Irinotecan-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Pharmacogenomics J 2017;17:21-8.
56. Smyth E, Zhang S, Cunningham D, Wotherspoon A, Soong R, et al. Pharmacogenetic analysis of the UK MRC (Medical Research Council) MAGIC trial: association of polymorphisms with toxicity and survival in patients treated with perioperative epirubicin, cisplatin, and 5-fluorouracil (ECF) chemotherapy. Clin Cancer Res 2017;23:7543-9.
57. Tan BR, Thomas F, Myerson RJ, Zehnbauer B, Trinkaus K, et al. Thymidylate synthase genotype-directed neoadjuvant chemoradiation for patients with rectal adenocarcinoma. J Clin Oncol 2011;29:875-83.
58. Rosmarin D, Palles C, Pagnamenta A, Kaur K, Pita G, et al. A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS. Gut 2015;64:111-20.
59. García-González X, Cortejoso L, García MI, García-Alfonso P, Robles L, et al. Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer. Oncotarget 2015;6:6422-30.
60. Cecchin E, Agostini M, Pucciarelli S, De Paoli A, Canzonieri V, et al. Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy. Pharmacogenomics J 2011;11:214-26.
61. Libra M, Navolanic PM, Talamini R, Cecchin E, Sartor F, et al. Thymidylate synthetase mRNA levels are increased in liver metastases of colorectal cancer patients resistant to fluoropyrimidine-based chemotherapy. BMC Cancer 2004;4:11.
62. Cecchin E, Perrone G, Nobili S, Polesel J, De Mattia E, et al. MTHFR-1298 A>C (rs1801131) is a predictor of survival in two cohorts of stage II/III colorectal cancer patients treated with adjuvant fluoropyrimidine chemotherapy with or without oxaliplatin. Pharmacogenomics J 2015;15:219-25.
63. Pellicer M, García-González X, García MI, Robles L, Grávalos C, et al. Identification of new SNPs associated with severe toxicity to capecitabine. Pharmacol Res 2017;120:133-7.
64. Ose J, Botma A, Balavarca Y, Buck K, Scherer D, et al. Pathway analysis of genetic variants in folate-mediated one-carbon metabolism-related genes and survival in a prospectively followed cohort of colorectal cancer patients. Cancer Med 2018; doi: 10.1002/cam4.1407.
65. Ichikawa W, Takahashi T, Suto K, Sasaki Y, Hirayama R. Orotate phosphoribosyltransferase gene polymorphism predicts toxicity in patients treated with bolus 5-fluorouracil regimen. Clin Cancer Res 2006;12:3928-34.
66. Tsunoda A, Nakao K, Watanabe M, Matsui N, Ooyama A, et al. Associations of various gene polymorphisms with toxicity in colorectal cancer patients receiving oral uracil and tegafur plus leucovorin: a prospective study. Ann Oncol 2011;22:355-61.
67. Gusella M, Bertolaso L, Bolzonella C, Pasini F, Padrini R. Frequency of uridine monophosphate synthase Gly(213)Ala polymorphism in Caucasian gastrointestinal cancer patients and healthy subjects, investigated by means of new, rapid genotyping assays. Genet Test Mol Biomarkers 2011;15:691-5.
68. Jennings BA, Loke YK, Skinner J, Keane M, Chu GS, et al. Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines. PLoS One 2013;8:e78053.
69. Loganayagam A, Arenas Hernandez M, Corrigan A, Fairbanks L, Lewis CM, et al. Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer 2013;108:2505-15.
70. Caronia D, Martin M, Sastre J, de la Torre J, García-Sáenz JA, et al. A polymorphism in the cytidine deaminase promoter predicts severe capecitabine-induced hand-foot syndrome. Clin Cancer Res 2011;17:2006-13.
71. Dahan L, Ciccolini J, Evrard A, Mbatchi L, Tibbitts J, et al. Sudden death related to toxicity in a patient on capecitabine and irinotecan plus bevacizumab intake: pharmacogenetic implications. J Clin Oncol 2012;30:e41-44.
72. Lévi F, Karaboué A, Saffroy R, Desterke C, Boige V, et al. Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228). Br J Cancer 2017;117:965-73.
73. Yap YS, Kwok LL, Syn N, Chay WY, Chia JWK, et al. Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial. JAMA Oncol 2017;3:1538-45.
74. De Mattia E, Cecchin E, Montico M, Labriet A, Guillemette C, et al. Association of STAT-3 rs1053004 and VDR rs11574077 With FOLFIRI-related gastrointestinal toxicity in metastatic colorectal cancer patients. Front Pharmacol 2018;9:367.
75. Garziera M, Virdone S, De Mattia E, Scarabel L, Cecchin E, et al. HLA-G 3’UTR polymorphisms predict drug-induced G3-4 toxicity related to folinic acid/5-fluorouracil/oxaliplatin (FOLFOX4) chemotherapy in non-metastatic colorectal cancer. Int J Mol Sci 2017;18:E1366.
76. Garziera M, Bidoli E, Cecchin E, Mini E, Nobili S, et al. HLA-G 3’UTR polymorphisms impact the prognosis of stage II-III CRC patients in fluoropyrimidine-based treatment. PLoS One 2015;10:e0144000.
77. De Mattia E, Dreussi E, Montico M, Gagno S, Zanusso C, et al. A clinical-genetic score to identify surgically resected colorectal cancer patients benefiting from an adjuvant fluoropyrimidine-based therapy. Front Pharmacol 2018;9:1101.
78. Re VD, Caggiari L, Zorzi MD, Talamini R, Racanelli V, et al. Genetic diversity of the KIR/HLA system and outcome of patients with metastatic colorectal cancer treated with chemotherapy. PLoS One 2014;9:e84940.
79. Abad A, Martínez-Balibrea E, Viéitez JM, Alonso-Orduña V, García Alfonso P, et al. Genotype-based selection of treatment of patients with advanced colorectal cancer (SETICC): a pharmacogenetic-based randomized phase II trial. Ann Oncol 2018;29:439-44.
80. McLeod HL, Sargent DJ, Marsh S, Green EM, King CR, et al. Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741. J Clin Oncol 2010;28:3227-33.
81. Toffoli G, Cecchin E, Gasparini G, D’Andrea M, Azzarello G, et al. Genotype-driven phase I study of irinotecan administered in combination with fluorouracil/leucovorin in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:866-71.
82. Di Francia R, Frigeri F, Berretta M, Cecchin E, Orlando C, et al. Decision criteria for rational selection of homogeneous genotyping platforms for pharmacogenomics testing in clinical diagnostics. Clin Chem Lab Med 2010;48:447-59.
83. Afzal S, Gusella M, Vainer B, Vogel UB, Andersen JT, et al. Combinations of polymorphisms in genes involved in the 5-Fluorouracil metabolism pathway are associated with gastrointestinal toxicity in chemotherapy-treated colorectal cancer patients. Clin Cancer Res 2011;17:3822-9.