Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis

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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. / Rosmarin, Dan; Palles, Claire; Church, David; Domingo, Enric; Jones, Angela; Johnstone, Elaine; Wang, Haitao; Love, Sharon; Julier, Patrick; Scudder, Claire; Nicholson, George; Gonzalez-Neira, Anna; Martin, Miguel; Sargent, Daniel; Green, Erin; McLeod, Howard; Zanger, Ulrich M; Schwab, Matthias; Braun, Michael; Seymour, Matthew; Thompson, Lindsay ; Lacas, Benjamin; Boige, Valerie; Ribelles, Nuria ; Afzal, Shoaib ; Enghusen, Henrik ; Jensen, Søren Astrup ; Etienne-Grimaldi , Marie-Christine ; Milano, Gérard ; Wadelius, Mia; Glimelius, Bengt; Garmo, Hans; Gusella , Milena; Lecomte, Thierry; Laurent-Puig, Pierre; Martinez-Balibrea, Eva; Sharma, Rohini; Garcia-Foncillas, Jesus; Kleibl, Zdenek; Morel , Alain; Pignon, Jean-Pierre ; Midgley, Rachel; Kerr, David; Tomlinson, Ian.

In: Journal of Clinical Oncology , Vol. 32, No. 10, 01.04.2014, p. 1031-1039.

Research output: Contribution to journalArticlepeer-review

Harvard

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 , M-C, 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, J-P, Midgley, R, Kerr, D & Tomlinson, I 2014, '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 , vol. 32, no. 10, pp. 1031-1039. https://doi.org/10.1200/JCO.2013.51.1857

APA

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, U. M., Schwab, M., Braun, M., ... Tomlinson, I. (2014). 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 , 32(10), 1031-1039. https://doi.org/10.1200/JCO.2013.51.1857

Vancouver

Author

Rosmarin, Dan ; Palles, Claire ; Church, David ; Domingo, Enric ; Jones, Angela ; Johnstone, Elaine ; Wang, Haitao ; Love, Sharon ; Julier, Patrick ; Scudder, Claire ; Nicholson, George ; Gonzalez-Neira, Anna ; Martin, Miguel ; Sargent, Daniel ; Green, Erin ; McLeod, Howard ; Zanger, Ulrich M ; Schwab, Matthias ; Braun, Michael ; Seymour, Matthew ; Thompson, Lindsay ; Lacas, Benjamin ; Boige, Valerie ; Ribelles, Nuria ; Afzal, Shoaib ; Enghusen, Henrik ; Jensen, Søren Astrup ; Etienne-Grimaldi , Marie-Christine ; Milano, Gérard ; Wadelius, Mia ; Glimelius, Bengt ; Garmo, Hans ; Gusella , Milena ; Lecomte, Thierry ; Laurent-Puig, Pierre ; Martinez-Balibrea, Eva ; Sharma, Rohini ; Garcia-Foncillas, Jesus ; Kleibl, Zdenek ; Morel , Alain ; Pignon, Jean-Pierre ; Midgley, Rachel ; Kerr, David ; Tomlinson, Ian. / Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens : investigation in the QUASAR2 study, systematic review, and meta-analysis. In: Journal of Clinical Oncology . 2014 ; Vol. 32, No. 10. pp. 1031-1039.

Bibtex

@article{2118aaa97d444c2189639ec5e6bdbd84,
title = "Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis",
abstract = "PurposeFluourouracil (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 MethodsWe 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.ResultsGlobal 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.ConclusionA 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.",
author = "Dan Rosmarin and Claire Palles and David Church and Enric Domingo and Angela Jones and Elaine Johnstone and Haitao Wang and Sharon Love and Patrick Julier and Claire Scudder and George Nicholson and Anna Gonzalez-Neira and Miguel Martin and Daniel Sargent and Erin Green and Howard McLeod and Zanger, {Ulrich M} and Matthias Schwab and Michael Braun and Matthew Seymour and Lindsay Thompson and Benjamin Lacas and Valerie Boige and Nuria Ribelles and Shoaib Afzal and Henrik Enghusen and Jensen, {S{\o}ren Astrup} and Marie-Christine Etienne-Grimaldi and G{\'e}rard Milano and Mia Wadelius and Bengt Glimelius and Hans Garmo and Milena Gusella and Thierry Lecomte and Pierre Laurent-Puig and Eva Martinez-Balibrea and Rohini Sharma and Jesus Garcia-Foncillas and Zdenek Kleibl and Alain Morel and Jean-Pierre Pignon and Rachel Midgley and David Kerr and Ian Tomlinson",
year = "2014",
month = apr,
day = "1",
doi = "10.1200/JCO.2013.51.1857",
language = "English",
volume = "32",
pages = "1031--1039",
journal = "Journal of Clinical Oncology ",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "10",

}

RIS

TY - JOUR

T1 - Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens

T2 - investigation in the QUASAR2 study, systematic review, and meta-analysis

AU - Rosmarin, Dan

AU - Palles, Claire

AU - Church, David

AU - Domingo, Enric

AU - Jones, Angela

AU - Johnstone, Elaine

AU - Wang, Haitao

AU - Love, Sharon

AU - Julier, Patrick

AU - Scudder, Claire

AU - Nicholson, George

AU - Gonzalez-Neira, Anna

AU - Martin, Miguel

AU - Sargent, Daniel

AU - Green, Erin

AU - McLeod, Howard

AU - Zanger, Ulrich M

AU - Schwab, Matthias

AU - Braun, Michael

AU - Seymour, Matthew

AU - Thompson, Lindsay

AU - Lacas, Benjamin

AU - Boige, Valerie

AU - Ribelles, Nuria

AU - Afzal, Shoaib

AU - Enghusen, Henrik

AU - Jensen, Søren Astrup

AU - Etienne-Grimaldi , Marie-Christine

AU - Milano, Gérard

AU - Wadelius, Mia

AU - Glimelius, Bengt

AU - Garmo, Hans

AU - Gusella , Milena

AU - Lecomte, Thierry

AU - Laurent-Puig, Pierre

AU - Martinez-Balibrea, Eva

AU - Sharma, Rohini

AU - Garcia-Foncillas, Jesus

AU - Kleibl, Zdenek

AU - Morel , Alain

AU - Pignon, Jean-Pierre

AU - Midgley, Rachel

AU - Kerr, David

AU - Tomlinson, Ian

PY - 2014/4/1

Y1 - 2014/4/1

N2 - PurposeFluourouracil (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 MethodsWe 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.ResultsGlobal 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.ConclusionA 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.

AB - PurposeFluourouracil (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 MethodsWe 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.ResultsGlobal 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.ConclusionA 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.

U2 - 10.1200/JCO.2013.51.1857

DO - 10.1200/JCO.2013.51.1857

M3 - Article

VL - 32

SP - 1031

EP - 1039

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 10

ER -