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Lancet Oncol. 2015 Dec;16(16):1639-50. doi: 10.1016/S1470-2045(15)00286-7. Epub 2015 Oct 23.

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.

Author information

  • 1Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 2Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 3University Institute of Clinical Chemistry, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
  • 4Norwich Medical School, University of East Anglia, Norwich, UK.
  • 5Purine Research Laboratory, St Thomas' Hospital, London, UK.
  • 6Department of Gastroenterology, St Thomas' Hospital, London, UK.
  • 7Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
  • 8Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany.
  • 9Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany.
  • 10Molecular and Population Genetics Laboratory and Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
  • 11Department of Gynecology and Obstetrics, Technische Universität München, Munich, Germany.
  • 12Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
  • 13Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
  • 14Department of Medical Oncology, University Medical Center Utrecht, Utrecht, Netherlands.
  • 15Department 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.
  • 16Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 17Department 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.

PMID:
26603945
DOI:
10.1016/S1470-2045(15)00286-7
[PubMed - indexed for MEDLINE]
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