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

Autor: Rosmarin, D, Palles, C, Church, D, Domingo, E, Jones, A, Johnstone, E, Wang, H, Love, S, Julier, P, Scudder, C, Nicholson, G, Gonzalez-Neira, A, Martin, M, Sargent, D, Green, E, McLeod, H, Zanger, UM, Schwab, M, Braun, M, Seymour, M, Thompson, L, Lacas, B, Boige, V, Ribelles, N, Afzal, S, Enghusen, H, Jensen, SA, Etienne-Grimaldi, MC, Milano, G, Wadelius, M, Glimelius, B, Garmo, H, Gusella, M, Lecomte, T, Laurent-Puig, P, Martinez-Balibrea, E, Sharma, R, Garcia-Foncillas, J, Kleibl, Z, Morel, A, Pignon, JP, Midgley, R, Kerr, D, Tomlinson, I
Přispěvatelé: University of Oxford [Oxford], Spanish National Cancer Research Center (CNIO), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Mayo Clinic [Rochester], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Molecular Mechanisms of Origin and Treatment of Breast Cancer, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University Hospital Tuebingen, The Christie NHS Foundation Trust [Manchester, Royaume-Uni], St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Medical Research Council Clinical Trials Unit (MRC CTU), University College of London [London] (UCL), Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Hospital Universitario Virgen de la Victoria [Malaga, Espagne], Rigshospitalet [Copenhagen], Copenhagen University Hospital, Herlev and Gentofte Hospital, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Uppsala University, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Català d'Oncologia, Imperial College Healthcare NHS Trust [Londres, Royaume-Uni], Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Charles University [Prague] (CU), Cytokines : structure, signalisation et prolifération tumorale, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Paul Papin, CRLCC Paul Papin
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Zdroj: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
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⟩
ISSN: 1527-7755
Popis: International audience; 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.
Databáze: OpenAIRE
Externí odkaz: