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Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis

Dan Rosmarin 1 Claire Palles 1 David Church 1 Enric Domingo 1 Angela Jones 1 Elaine Johnstone 1 Haitao Wang 1 Sharon Love 1 Patrick Julier 1 Claire Scudder 1 George Nicholson 1 Anna Gonzalez-Neira 2 Miguel Martin 3 Daniel Sargent 4 Erin Green 4 Howard Mcleod 5 Ulrich Zanger 6, 7 Matthias Schwab 6, 7 Michael Braun 8 Matthew Seymour 9 Lindsay Thompson 10 Benjamin Lacas 11, 12 Valérie Boige 11, 13 Nuria Ribelles 14 Shoaib Afzal 15 Henrik Enghusen 15 Søren Jensen 16 Marie-Christine Etienne-Grimaldi 17 Gérard Milano 17 Mia Wadelius 18 Bengt Glimelius 18 Hans Garmo 18 Milena Gusella Thierry Lecomte 19 Pierre Laurent-Puig 19 Eva Martinez-Balibrea 20 Rohini Sharma 21 Jesus Garcia-Foncillas 22 Zdenek Kleibl 23 Alain Morel 24, 25 Jean-Pierre Pignon 11, 12 Rachel Midgley 1 David Kerr 1 Ian Tomlinson 1
Abstract :

Purpose Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain.Patients and Methods We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. Results Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5′VNTR2R/3R and 3′UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10−6). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. Conclusion A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value—better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.

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Contributeur : Okina Univ Angers Connectez-vous pour contacter le contributeur
Soumis le : jeudi 21 octobre 2021 - 10:24:21
Dernière modification le : jeudi 3 mars 2022 - 16:44:02

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Dan Rosmarin, Claire Palles, David Church, Enric Domingo, Angela Jones, et al.. Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2014, 32 (10), pp.1031 - 1039. ⟨10.1200/JCO.2013.51.1857⟩. ⟨hal-03389747⟩



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