Linda M Henricks1, Carin A T C Lunenburg2, Femke M de Man3, Didier Meulendijks4, Geert W J Frederix5, Emma Kienhuis3, Geert-Jan Creemers6, Arnold Baars7, Vincent O Dezentjé8, Alexander L T Imholz9, Frank J F Jeurissen10, Johanna E A Portielje11, Rob L H Jansen12, Paul Hamberg13, Albert J Ten Tije14, Helga J Droogendijk15, Miriam Koopman16, Peter Nieboer17, Marlène H W van de Poel18, Caroline M P W Mandigers19, Hilde Rosing20, Jos H Beijnen21, Erik van Werkhoven22, André B P van Kuilenburg23, Ron H N van Schaik24, Ron H J Mathijssen3, Jesse J Swen25, Hans Gelderblom2, Annemieke Cats26, Henk-Jan Guchelaar25, Jan H M Schellens27. 1. Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands. 2. Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands. 3. Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands. 4. Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands; Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, Netherlands. 5. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands. 6. Department of Medical Oncology, Catharina Hospital, Eindhoven, Netherlands. 7. Department of Internal Medicine, Hospital Gelderse Vallei, Ede, Netherlands. 8. Department of Internal Medicine, Reinier de Graaf Hospital, Delft, Netherlands; Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands. 9. Department of Internal Medicine, Deventer Hospital, Deventer, Netherlands. 10. Department of Internal Medicine, Haaglanden Medical Center, The Hague, Netherlands. 11. Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands; Department of Internal Medicine, Haga Hospital, The Hague, Netherlands. 12. Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands. 13. Department of Internal Medicine, Franciscus Gasthuis and Vlietland, Rotterdam, Netherlands. 14. Department of Internal Medicine, Amphia Hospital, Breda, Netherlands. 15. Department of Internal Medicine, Bravis Hospital, Roosendaal, Netherlands. 16. Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands. 17. Department of Internal Medicine, Wilhelmina Hospital Assen, Assen, Netherlands. 18. Department of Internal Medicine, Laurentius Hospital, Roermond, Netherlands. 19. Department of Internal Medicine, Canisius-Wilhelmina Hospital, Nijmegen, Netherlands. 20. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands. 21. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands. 22. Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, Netherlands. 23. Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology and Metabolism, Amsterdam, Netherlands. 24. Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, Netherlands. 25. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, Netherlands. 26. Department of Gastrointestinal Oncology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands. 27. Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Clinical Pharmacology, Division of Medical Oncology, The 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@gmail.com.
Abstract
BACKGROUND: Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care. METHODS: In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete. FINDINGS: Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63-2·73) for genotype-guided dosing compared with 2·87 (2·14-3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10-8·80) in c.1679T>G carriers, 2·00 (1·19-3·34) compared with 3·11 (2·25-4·28) for c.2846A>T carriers, and 1·69 (1·18-2·42) compared with 1·72 (1·22-2·42) for c.1236G>A carriers. INTERPRETATION: Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care. FUNDING: Dutch Cancer Society.
BACKGROUND:Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care. METHODS: In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete. FINDINGS: Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63-2·73) for genotype-guided dosing compared with 2·87 (2·14-3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10-8·80) in c.1679T>G carriers, 2·00 (1·19-3·34) compared with 3·11 (2·25-4·28) for c.2846A>T carriers, and 1·69 (1·18-2·42) compared with 1·72 (1·22-2·42) for c.1236G>A carriers. INTERPRETATION: Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care. FUNDING: Dutch Cancer Society.
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