Didier Meulendijks1, Linda M Henricks1, Gabe S Sonke2, Maarten J Deenen1, Tanja K Froehlich3, Ursula Amstutz3, Carlo R Largiadèr3, Barbara A Jennings4, Anthony M Marinaki5, Jeremy D Sanderson6, Zdenek Kleibl7, Petra Kleiblova7, Matthias Schwab8, Ulrich M Zanger9, Claire Palles10, Ian Tomlinson10, Eva Gross11, André B P van Kuilenburg12, Cornelis J A Punt13, Miriam Koopman14, Jos H Beijnen15, Annemieke Cats16, Jan H M Schellens17. 1. Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands. 2. Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands. 3. University Institute of Clinical Chemistry, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. 4. Norwich Medical School, University of East Anglia, Norwich, UK. 5. Purine Research Laboratory, St Thomas' Hospital, London, UK. 6. Department of Gastroenterology, St Thomas' Hospital, London, UK. 7. Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. 8. Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany. 9. Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany. 10. Molecular and Population Genetics Laboratory and Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. 11. Department of Gynecology and Obstetrics, Technische Universität München, Munich, Germany. 12. Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. 13. Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. 14. Department of Medical Oncology, University Medical Center Utrecht, Utrecht, Netherlands. 15. Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands. 16. Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, Netherlands. 17. Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands. Electronic address: j.schellens@nki.nl.
Abstract
BACKGROUND: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. METHODS: We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). FINDINGS: 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively). INTERPRETATION: DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. FUNDING: None.
BACKGROUND: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. METHODS: We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). FINDINGS: 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively). INTERPRETATION:DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. FUNDING: None.
Authors: Bart A W Jacobs; Nikol Snoeren; Morsal Samim; Hilde Rosing; Niels de Vries; Maarten J Deenen; Jos H Beijnen; Jan H M Schellens; Miriam Koopman; Richard van Hillegersberg Journal: Eur J Clin Pharmacol Date: 2018-02-11 Impact factor: 2.953
Authors: Shikshya Shrestha; Erin E Tapper; Colbren Scout Trogstad-Isaacson; Timothy J Hobday; Steven M Offer; Robert B Diasio Journal: JCO Precis Oncol Date: 2018-10-03
Authors: Shikshya Shrestha; Cheng Zhang; Calvin R Jerde; Qian Nie; Hu Li; Steven M Offer; Robert B Diasio Journal: Clin Pharmacol Ther Date: 2018-02-02 Impact factor: 6.875
Authors: Q Nie; S Shrestha; E E Tapper; C S Trogstad-Isaacson; K J Bouchonville; A M Lee; R Wu; C R Jerde; Z Wang; P A Kubica; S M Offer; R B Diasio Journal: Clin Pharmacol Ther Date: 2017-05-26 Impact factor: 6.875
Authors: Adam M Lee; Qian Shi; Steven R Alberts; Daniel J Sargent; Frank A Sinicrope; Jeffrey L Berenberg; Axel Grothey; Blase Polite; Emily Chan; Sharlene Gill; Morton S Kahlenberg; Suresh G Nair; Anthony F Shields; Richard M Goldberg; Robert B Diasio Journal: Pharmacogenet Genomics Date: 2016-03 Impact factor: 2.089
Authors: Ursula Amstutz; Linda M Henricks; Steven M Offer; Julia Barbarino; Jan H M Schellens; Jesse J Swen; Teri E Klein; Howard L McLeod; Kelly E Caudle; Robert B Diasio; Matthias Schwab Journal: Clin Pharmacol Ther Date: 2017-11-20 Impact factor: 6.875
Authors: Elizabeth Smyth; Shenli Zhang; David Cunningham; Andrew Wotherspoon; Richie Soong; Clare Peckitt; Nicola Valeri; Matteo Fassan; Massimo Rugge; Alicia Okines; William Allum; Sally Stenning; Matthew Nankivell; Ruth Langley; Patrick Tan Journal: Clin Cancer Res Date: 2017-10-02 Impact factor: 12.531
Authors: S Hamzic; N Wenger; T K Froehlich; M Joerger; S Aebi; C R Largiadèr; U Amstutz Journal: Pharmacogenomics J Date: 2016-03-22 Impact factor: 3.550